Synaptically evoked Ca2+ release from intracellular stores is not influenced by vesicular zinc in CA3 hippocampal pyramidal neurones

PubMed Central

Evstratova, Alesya; Tóth, Katalin

2011-01-01

Abstract The co-release of neuromodulatory substances in combination with classic neurotransmitters such as glutamate and GABA from individual presynaptic nerve terminals has the capacity to dramatically influence synaptic efficacy and plasticity. At hippocampal mossy fibre synapses vesicular zinc is suggested to serve as a cotransmitter capable of regulating calcium release from internal stores in postsynaptic CA3 pyramidal cells. Here we investigated this possibility using combined intracellular ratiometric calcium imaging and patch-clamp recording techniques. In acute hippocampal slices a brief train of mossy fibre stimulation produced a large, delayed postsynaptic Ca2+ wave that was spatially restricted to the proximal apical dendrites of CA3 pyramidal cells within stratum lucidum. This calcium increase was sensitive to intracellularly applied heparin indicating reliance upon release from internal stores and was triggered by activation of both group I metabotropic glutamate and NMDA receptors. Importantly, treatment of slices with the membrane-impermeant zinc chelator CaEDTA did not influence the synaptically evoked postsynaptic Ca2+ waves. Moreover, mossy fibre stimulus evoked postsynaptic Ca2+ signals were not significantly different between wild-type and zinc transporter 3 (ZnT3) knock-out animals. Considered together our data do not support a role for vesicular zinc in regulating mossy fibre evoked Ca2+ release from CA3 pyramidal cell internal stores. PMID:21986206

Synaptic calcium regulation in hair cells of the chicken basilar papilla.

PubMed

Im, Gi Jung; Moskowitz, Howard S; Lehar, Mohammed; Hiel, Hakim; Fuchs, Paul Albert

2014-12-10

Cholinergic inhibition of hair cells occurs by activation of calcium-dependent potassium channels. A near-membrane postsynaptic cistern has been proposed to serve as a store from which calcium is released to supplement influx through the ionotropic ACh receptor. However, the time and voltage dependence of acetylcholine (ACh)-evoked potassium currents reveal a more complex relationship between calcium entry and release from stores. The present work uses voltage steps to regulate calcium influx during the application of ACh to hair cells in the chicken basilar papilla. When calcium influx was terminated at positive membrane potential, the ACh-evoked potassium current decayed exponentially over ∼100 ms. However, at negative membrane potentials, this current exhibited a secondary rise in amplitude that could be eliminated by dihydropyridine block of the voltage-gated calcium channels of the hair cell. Calcium entering through voltage-gated channels may transit through the postsynaptic cistern, since ryanodine and sarcoendoplasmic reticulum calcium-ATPase blockers altered the time course and magnitude of this secondary, voltage-dependent contribution to ACh-evoked potassium current. Serial section electron microscopy showed that efferent and afferent synaptic structures are juxtaposed, supporting the possibility that voltage-gated influx at afferent ribbon synapses influences calcium homeostasis during long-lasting cholinergic inhibition. In contrast, spontaneous postsynaptic currents ("minis") resulting from stochastic efferent release of ACh were made briefer by ryanodine, supporting the hypothesis that the synaptic cistern serves primarily as a calcium barrier and sink during low-level synaptic activity. Hypolemmal cisterns such as that at the efferent synapse of the hair cell can play a dynamic role in segregating near-membrane calcium for short-term and long-term signaling. Copyright © 2014 the authors 0270-6474/14/3416688-10$15.00/0.

Synaptic Calcium Regulation in Hair Cells of the Chicken Basilar Papilla

PubMed Central

Im, Gi Jung; Moskowitz, Howard S.; Lehar, Mohammed; Hiel, Hakim

2014-01-01

Cholinergic inhibition of hair cells occurs by activation of calcium-dependent potassium channels. A near-membrane postsynaptic cistern has been proposed to serve as a store from which calcium is released to supplement influx through the ionotropic ACh receptor. However, the time and voltage dependence of acetylcholine (ACh)-evoked potassium currents reveal a more complex relationship between calcium entry and release from stores. The present work uses voltage steps to regulate calcium influx during the application of ACh to hair cells in the chicken basilar papilla. When calcium influx was terminated at positive membrane potential, the ACh-evoked potassium current decayed exponentially over ∼100 ms. However, at negative membrane potentials, this current exhibited a secondary rise in amplitude that could be eliminated by dihydropyridine block of the voltage-gated calcium channels of the hair cell. Calcium entering through voltage-gated channels may transit through the postsynaptic cistern, since ryanodine and sarcoendoplasmic reticulum calcium-ATPase blockers altered the time course and magnitude of this secondary, voltage-dependent contribution to ACh-evoked potassium current. Serial section electron microscopy showed that efferent and afferent synaptic structures are juxtaposed, supporting the possibility that voltage-gated influx at afferent ribbon synapses influences calcium homeostasis during long-lasting cholinergic inhibition. In contrast, spontaneous postsynaptic currents (“minis”) resulting from stochastic efferent release of ACh were made briefer by ryanodine, supporting the hypothesis that the synaptic cistern serves primarily as a calcium barrier and sink during low-level synaptic activity. Hypolemmal cisterns such as that at the efferent synapse of the hair cell can play a dynamic role in segregating near-membrane calcium for short-term and long-term signaling. PMID:25505321

The potential role of postsynaptic phospholipase C activity in synaptic facilitation and behavioral sensitization in Aplysia.

PubMed

Fulton, Daniel; Condro, Michael C; Pearce, Kaycey; Glanzman, David L

2008-07-01

Previous findings indicate that synaptic facilitation, a cellular mechanism underlying sensitization of the siphon withdrawal response (SWR) in Aplysia, depends on a cascade of postsynaptic events, including activation of inositol triphosphate (IP3) receptors and release of Ca2+ from postsynaptic intracellular stores. These findings suggest that phospholipase C (PLC), the enzyme that catalyzes IP3 formation, may play an important role in postsynaptic signaling during facilitation and learning in Aplysia. Using the PLC inhibitor U73122, we found that PLC activity is required for synaptic facilitation following a 10-min treatment with 5-HT, as measured at 20 min after 5-HT washout. Prior work has indicated that facilitation at this time is supported primarily by postsynaptic processes. To determine whether postsynaptic PLC activity is involved in 5-HT-mediated facilitatory actions, we examined the effect of U73122 on enhancement of the response of motor neurons isolated in cell culture to glutamate, the sensory neuron transmitter. A 10-min application of 5-HT induced persistent (>40 min) enhancement of glutamate-evoked potentials (Glu-EPs) recorded from isolated motor neurons, and this enhancement was blocked by U73122. Finally, we showed that injecting U73122 into intact animals before behavioral training impaired intermediate-term sensitization, indicating that PLC activity contributes to this form of nonassociative learning.

Dynamical model of long-term synaptic plasticity

PubMed Central

Abarbanel, Henry D. I.; Huerta, R.; Rabinovich, M. I.

2002-01-01

Long-term synaptic plasticity leading to enhancement in synaptic efficacy (long-term potentiation, LTP) or decrease in synaptic efficacy (long-term depression, LTD) is widely regarded as underlying learning and memory in nervous systems. LTP and LTD at excitatory neuronal synapses are observed to be induced by precise timing of pre- and postsynaptic events. Modification of synaptic transmission in long-term plasticity is a complex process involving many pathways; for example, it is also known that both forms of synaptic plasticity can be induced by various time courses of Ca2+ introduction into the postsynaptic cell. We present a phenomenological description of a two-component process for synaptic plasticity. Our dynamical model reproduces the spike time-dependent plasticity of excitatory synapses as a function of relative timing between pre- and postsynaptic events, as observed in recent experiments. The model accounts for LTP and LTD when the postsynaptic cell is voltage clamped and depolarized (LTP) or hyperpolarized (LTD) and no postsynaptic action potentials are evoked. We are also able to connect our model with the Bienenstock, Cooper, and Munro rule. We give model predictions for changes in synaptic strength when periodic spike trains of varying frequency and Poisson distributed spike trains with varying average frequency are presented pre- and postsynaptically. When the frequency of spike presentation exceeds ≈30–40 Hz, only LTP is induced. PMID:12114531

Nociceptin/orphanin FQ decreases glutamate transmission and blocks ethanol-induced effects in the central amygdala of naive and ethanol-dependent rats.

PubMed

Kallupi, Marsida; Varodayan, Florence P; Oleata, Christopher S; Correia, Diego; Luu, George; Roberto, Marisa

2014-04-01

The central nucleus of the amygdala (CeA) mediates several addiction-related processes and nociceptin/orphanin FQ (nociceptin) regulates ethanol intake and anxiety-like behaviors. Glutamatergic synapses, in the CeA and throughout the brain, are very sensitive to ethanol and contribute to alcohol reinforcement, tolerance, and dependence. Previously, we reported that in the rat CeA, acute and chronic ethanol exposures significantly decrease glutamate transmission by both pre- and postsynaptic actions. In this study, using electrophysiological techniques in an in vitro CeA slice preparation, we investigated the effects of nociceptin on glutamatergic transmission and its interaction with acute ethanol in naive and ethanol-dependent rats. We found that nociceptin (100-1000 nM) diminished basal-evoked compound glutamatergic receptor-mediated excitatory postsynaptic potentials (EPSPs) and spontaneous and miniature EPSCs (s/mEPSCs) by mainly decreasing glutamate release in the CeA of naive rats. Notably, nociceptin blocked the inhibition induced by acute ethanol (44 mM) and ethanol blocked the nociceptin-induced inhibition of evoked EPSPs in CeA neurons of naive rats. In neurons from chronic ethanol-treated (ethanol-dependent) rats, the nociceptin-induced inhibition of evoked EPSP amplitude was not significantly different from that in naive rats. Application of [Nphe1]Nociceptin(1-13)NH2, a nociceptin receptor (NOP) antagonist, revealed tonic inhibitory activity of NOP on evoked CeA glutamatergic transmission only in ethanol-dependent rats. The antagonist also blocked nociceptin-induced decreases in glutamatergic responses, but did not affect ethanol-induced decreases in evoked EPSP amplitude. Taken together, these studies implicate a potential role for the nociceptin system in regulating glutamatergic transmission and a complex interaction with ethanol at CeA glutamatergic synapses.

Extracellular pH modulates GABAergic neurotransmission in rat hypothalamus.

PubMed

Chen, Z L; Huang, R Q

2014-06-20

Changes in extracellular pH have a modulatory effect on GABAA receptor function. It has been reported that pH sensitivity of the GABA receptor is dependent on subunit composition and GABA concentration. Most of previous investigations focused on GABA-evoked currents, which only reflect the postsynaptic receptors. The physiological relevance of pH modulation of GABAergic neurotransmission is not fully elucidated. In the present studies, we examined the influence of extracellular pH on the GABAA receptor-mediated inhibitory neurotransmission in rat hypothalamic neurons. The inhibitory postsynaptic currents (IPSCs), tonic currents, and the GABA-evoked currents were recorded with whole-cell patch techniques on the hypothalamic slices from Sprague-Dawley rats at 15-26 postnatal days. The amplitude and frequency of spontaneous GABA IPSCs were significantly increased while the external pH was changed from 7.3 to 8.4. In the acidic pH (6.4), the spontaneous GABA IPSCs were reduced in amplitude and frequency. The pH induced changes in miniature GABA IPSCs (mIPSCs) similar to that in spontaneous IPSCs. The pH effect on the postsynaptic GABA receptors was assessed with exogenously applied varying concentrations of GABA. The tonic currents and the currents evoked by sub-saturating concentration of GABA ([GABA]) (10 μM) were inhibited by acidic pH and potentiated by alkaline pH. In contrast, the currents evoked by saturating [GABA] (1mM) were not affected by pH changes. We also investigated the influence of pH buffers and buffering capacity on pH sensitivity of GABAA receptors on human recombinant α1β2γ2 GABAA receptors stably expressed in HEK 293 cells. The pH influence on GABAA receptors was similar in HEPES- and MES-buffered media, and not dependent on protonated buffers, suggesting that the observed pH effect on GABA response is a specific consequence of changes in extracellular protons. Our data suggest that the hydrogen ions suppress the GABAergic neurotransmission, which is mediated by both presynaptic and postsynaptic mechanisms. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons

PubMed Central

Roberto, Marisa; Madamba, Samuel G.; Moore, Scott D.; Tallent, Melanie K.; Siggins, George R.

2003-01-01

We examined the interaction of ethanol with the γ-aminobutyric acid (GABA)ergic system in neurons of slices of the rat central amygdala nucleus (CeA), a brain region thought to be critical for the reinforcing effects of ethanol. Brief superfusion of 11–66 mM ethanol significantly increased GABA type A (GABAA) receptor-mediated inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in most CeA neurons, with a low apparent EC50 of 20 mM. Acute superfusion of 44 mM ethanol increased the amplitude of evoked GABAA IPSPs and IPSCs in 70% of CeA neurons. The ethanol enhancement of IPSPs and IPSCs occurred to a similar extent in the presence of the GABA type B (GABAB) receptor antagonist CGP 55845A, suggesting that this receptor is not involved in the ethanol effect on CeA neurons. Ethanol superfusion also decreased paired-pulse facilitation of evoked GABAA IPSPs and IPSCs and always increased the frequency and sometimes the amplitude of spontaneous miniature GABAA IPSCs as well as responses to local GABA application, indicating both presynaptic and postsynaptic sites of action for ethanol. Thus, the CeA is the first brain region to reveal, without conditional treatments such as GABAB antagonists, consistent, low-dose ethanol enhancement of GABAergic transmission at both pre- and postsynaptic sites. These findings add further support to the contention that the ethanol–GABA interaction in CeA plays an important role in the reinforcing effects of ethanol. PMID:12566570

Presynaptic muscarinic control of glutamatergic synaptic transmission.

PubMed

Buño, W; Cabezas, C; Fernández de Sevilla, D

2006-01-01

The hippocampus receives cholinergic projections from the medial septal nucleus and Broca's diagonal band that terminate in the CA1, CA3, and dentate gyrus regions (Frotscher and Leranth, 1985). Glutamatergic synapses between CA3 and CA1 pyramidal neurons are presynaptically inhibited by acetylcholine (ACh), via activation of muscarinic ACh receptors (mAChRs) at the terminals of Schaffer collaterals (SCs) (Hounsgaard, 1978; Fernández de Sevilla et al., 2002, 2003). There are two types of SC-CA1 pyramidal neuron synapses. One type, called functional synapse, shows postsynaptic alpha- amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-receptor mediated currents at resting potential (Vm) and both AMPA and N-methyl-D-aspartate receptor (NMDAR)-mediated currents when depolarized. The other type, termed silent synapse, only displays postsynaptic NMDAR-mediated currents at depolarized Vms, but does not respond at the resting Vm (Isaac et al., 1995). Using hippocampal slices obtained from young Wistar rats, we examined the effects of activation of cholinergic afferents at the stratum oriens/alveus on excitatory postsynaptic currents (EPSCs) evoked in CA1 pyramidal neurons by stimulation of SCs. We also tested the action of the nonhydrolyzable cholinergic agonist carbamylcholine chloride (CCh) on EPSCs evoked by minimal stimulation of SCs (which activates a single or very few synapses) in functional and silent synapses.

Activity-dependent dendritic spine neck changes are correlated with synaptic strength

PubMed Central

Araya, Roberto; Vogels, Tim P.; Yuste, Rafael

2014-01-01

Most excitatory inputs in the mammalian brain are made on dendritic spines, rather than on dendritic shafts. Spines compartmentalize calcium, and this biochemical isolation can underlie input-specific synaptic plasticity, providing a raison d’etre for spines. However, recent results indicate that the spine can experience a membrane potential different from that in the parent dendrite, as though the spine neck electrically isolated the spine. Here we use two-photon calcium imaging of mouse neocortical pyramidal neurons to analyze the correlation between the morphologies of spines activated under minimal synaptic stimulation and the excitatory postsynaptic potentials they generate. We find that excitatory postsynaptic potential amplitudes are inversely correlated with spine neck lengths. Furthermore, a spike timing-dependent plasticity protocol, in which two-photon glutamate uncaging over a spine is paired with postsynaptic spikes, produces rapid shrinkage of the spine neck and concomitant increases in the amplitude of the evoked spine potentials. Using numerical simulations, we explore the parameter regimes for the spine neck resistance and synaptic conductance changes necessary to explain our observations. Our data, directly correlating synaptic and morphological plasticity, imply that long-necked spines have small or negligible somatic voltage contributions, but that, upon synaptic stimulation paired with postsynaptic activity, they can shorten their necks and increase synaptic efficacy, thus changing the input/output gain of pyramidal neurons. PMID:24982196

Presynaptic control of transmission along the pathway mediating disynaptic reciprocal inhibition in the cat

PubMed Central

Enríquez-Denton, M; Nielsen, J; Perreault, M-C; Morita, H; Petersen, N; Hultborn, H

2000-01-01

In cat lumbar motoneurones, disynaptic inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of antagonist motor nerves were depressed for at least 150 ms following conditioning stimulation of flexor (1.7-2 times threshold (T)) and ankle extensor (5T) nerves. The aim of the present study was to investigate the possibility that this depression is caused by presynaptic inhibitory mechanisms acting at the terminals of group I afferent fibres projecting to the Ia inhibitory interneurones and/or the terminals of these interneurones to the target motoneurones. Conditioning stimulation of flexor, but not ankle extensor, nerves evoked a depression of the monosynaptic Ia excitatory postsynaptic potentials (EPSPs) recorded intracellularly in Ia inhibitory interneurones. This depression lasted between 200 and 700 ms and was not accompanied by a depression of the monosynaptic EPSPs evoked by stimulation of descending pathways. These results suggest that flexor, but not ankle extensor, group I afferent fibres can modulate sensory transmission at the synapse between Ia afferent fibres and Ia inhibitory interneurones. Conditioning stimulation of flexor muscle nerves, extensor muscle nerves and cutaneous nerves produced a long-lasting increase in excitability of the terminals of the Ia inhibitory interneurones. The increase in the excitability of the terminals was not secondary to an electrotonic spread of synaptic excitation at the soma. Indeed, concomitant with the excitability increase of the terminals there were signs of synaptic inhibition in the soma. The unitary IPSPs induced in target motoneurones following the spike activity of single Ia inhibitory interneurones were depressed by conditioning stimulation of muscle and cutaneous nerves. Since the conditioning stimulation also evoked compound IPSPs in those motoneurones, a firm conclusion as to whether unitary IPSP depression involved presynaptic inhibitory mechanism of the terminals of the interneurones could not be reached. The possibility that the changes in excitability of the Ia interneuronal terminals reflect the presence of a presynaptic inhibitory mechanism similar to that operating at the terminals of the afferent fibres (presynaptic inhibition) is discussed.1. In cat lumbar motoneurones, disynaptic inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of antagonist motor nerves were depressed for at least 150 ms following conditioning stimulation of flexor (1.7-2 times threshold (T)) and ankle extensor (5T) nerves. The aim of the present study was to investigate the possibility that this depression is caused by presynaptic inhibitory mechanisms acting at the terminals of group I afferent fibres projecting to the Ia inhibitory interneurones and/or the terminals of these interneurones to the target motoneurones. PMID:10922013

μ-Opioid Receptors Selectively Regulate Basal Inhibitory Transmission in the Central Amygdala: Lack of Ethanol Interactions

PubMed Central

Kang-Park, Maeng-Hee; Kieffer, Brigitte L.; Roberts, Amanda J.; Roberto, Marisa; Madamba, Samuel G.; Siggins, George Robert; Moore, Scott D.

2009-01-01

Endogenous opioid systems are implicated in the actions of ethanol. For example, μ-opioid receptor (MOR) knockout (KO) mice self-administer less alcohol than the genetically intact counterpart wild-type (WT) mice (Roberts et al., 2000). MOR KO mice also exhibit less anxiety-like behavior than WT mice (Filliol et al., 2000). To investigate the neurobiological mechanisms underlying these behaviors, we examined the effect of ethanol in brain slices from MOR KO and WT mice using sharp-electrode and whole-cell patch recording techniques. We focused our study in the central nucleus of the amygdala (CeA) because it is implicated in alcohol drinking behavior and stress behavior. We found that the amplitudes of evoked inhibitory postsynaptic currents (IPSCs) or inhibitory postsynaptic potentials (IPSPs) were significantly greater in MOR KO mice than WT mice. In addition, the baseline frequencies of spontaneous and miniature GABAA receptor-mediated inhibitory postsynaptic currents were significantly greater in CeA neurons from MOR KO than WT mice. However, ethanol enhancements of evoked IPSP and IPSC amplitudes and the frequency of miniature IPSCs were comparable between WT and MOR KO mice. Baseline spontaneous and miniature excitatory postsynaptic currents (EPSCs) and ethanol effects on EPSCs were not significantly different between MOR KO and WT mice. Based on knowledge of CeA circuitry and projections, we hypothesize that the role of MOR- and GABA receptor-mediated mechanisms in CeA underlying reinforcing effects of ethanol operate independently, possibly through pathway-specific responses within CeA. PMID:18854491

Anterograde Activin signaling regulates postsynaptic membrane potential and GluRIIA/B abundance at the Drosophila neuromuscular junction.

PubMed

Kim, Myung-Jun; O'Connor, Michael B

2014-01-01

Members of the TGF-β superfamily play numerous roles in nervous system development and function. In Drosophila, retrograde BMP signaling at the neuromuscular junction (NMJ) is required presynaptically for proper synapse growth and neurotransmitter release. In this study, we analyzed whether the Activin branch of the TGF-β superfamily also contributes to NMJ development and function. We find that elimination of the Activin/TGF-β type I receptor babo, or its downstream signal transducer smox, does not affect presynaptic NMJ growth or evoked excitatory junctional potentials (EJPs), but instead results in a number of postsynaptic defects including depolarized membrane potential, small size and frequency of miniature excitatory junction potentials (mEJPs), and decreased synaptic densities of the glutamate receptors GluRIIA and B. The majority of the defective smox synaptic phenotypes were rescued by muscle-specific expression of a smox transgene. Furthermore, a mutation in actβ, an Activin-like ligand that is strongly expressed in motor neurons, phenocopies babo and smox loss-of-function alleles. Our results demonstrate that anterograde Activin/TGF-β signaling at the Drosophila NMJ is crucial for achieving normal abundance and localization of several important postsynaptic signaling molecules and for regulating postsynaptic membrane physiology. Together with the well-established presynaptic role of the retrograde BMP signaling, our findings indicate that the two branches of the TGF-β superfamily are differentially deployed on each side of the Drosophila NMJ synapse to regulate distinct aspects of its development and function.

Anterograde Activin Signaling Regulates Postsynaptic Membrane Potential and GluRIIA/B Abundance at the Drosophila Neuromuscular Junction

PubMed Central

Kim, Myung-Jun; O’Connor, Michael B.

2014-01-01

Members of the TGF-β superfamily play numerous roles in nervous system development and function. In Drosophila, retrograde BMP signaling at the neuromuscular junction (NMJ) is required presynaptically for proper synapse growth and neurotransmitter release. In this study, we analyzed whether the Activin branch of the TGF-β superfamily also contributes to NMJ development and function. We find that elimination of the Activin/TGF-β type I receptor babo, or its downstream signal transducer smox, does not affect presynaptic NMJ growth or evoked excitatory junctional potentials (EJPs), but instead results in a number of postsynaptic defects including depolarized membrane potential, small size and frequency of miniature excitatory junction potentials (mEJPs), and decreased synaptic densities of the glutamate receptors GluRIIA and B. The majority of the defective smox synaptic phenotypes were rescued by muscle-specific expression of a smox transgene. Furthermore, a mutation in actβ, an Activin-like ligand that is strongly expressed in motor neurons, phenocopies babo and smox loss-of-function alleles. Our results demonstrate that anterograde Activin/TGF-β signaling at the Drosophila NMJ is crucial for achieving normal abundance and localization of several important postsynaptic signaling molecules and for regulating postsynaptic membrane physiology. Together with the well-established presynaptic role of the retrograde BMP signaling, our findings indicate that the two branches of the TGF-β superfamily are differentially deployed on each side of the Drosophila NMJ synapse to regulate distinct aspects of its development and function. PMID:25255438

Low-frequency rTMS inhibitory effects in the primary motor cortex: Insights from TMS-evoked potentials.

PubMed

Casula, Elias P; Tarantino, Vincenza; Basso, Demis; Arcara, Giorgio; Marino, Giuliana; Toffolo, Gianna Maria; Rothwell, John C; Bisiacchi, Patrizia S

2014-09-01

The neuromodulatory effects of repetitive transcranial magnetic stimulation (rTMS) have been mostly investigated by peripheral motor-evoked potentials (MEPs). New TMS-compatible EEG systems allow a direct investigation of the stimulation effects through the analysis of TMS-evoked potentials (TEPs). We investigated the effects of 1-Hz rTMS over the primary motor cortex (M1) of 15 healthy volunteers on TEP evoked by single pulse TMS over the same area. A second experiment in which rTMS was delivered over the primary visual cortex (V1) of 15 healthy volunteers was conducted to examine the spatial specificity of the effects. Single-pulse TMS evoked four main components: P30, N45, P60 and N100. M1-rTMS resulted in a significant decrease of MEP amplitude and in a significant increase of P60 and N100 amplitude. There was no effect after V1-rTMS. 1-Hz rTMS appears to increase the amount of inhibition following a TMS pulse, as demonstrated by the higher N100 and P60, which are thought to originate from GABAb-mediated inhibitory post-synaptic potentials. Our results confirm the reliability of the TMS-evoked N100 as a marker of cortical inhibition and provide insight into the neuromodulatory effects of 1-Hz rTMS. The present finding could be of relevance for therapeutic and diagnostic purposes. Copyright © 2014 Elsevier Inc. All rights reserved.

Long-term depression of inhibitory synaptic transmission induced by spike-timing dependent plasticity requires coactivation of endocannabinoid and muscarinic receptors.

PubMed

Ahumada, Juan; Fernández de Sevilla, David; Couve, Alejandro; Buño, Washington; Fuenzalida, Marco

2013-12-01

The precise timing of pre-postsynaptic activity is vital for the induction of long-term potentiation (LTP) or depression (LTD) at many central synapses. We show in synapses of rat CA1 pyramidal neurons in vitro that spike timing dependent plasticity (STDP) protocols that induce LTP at glutamatergic synapses can evoke LTD of inhibitory postsynaptic currents or STDP-iLTD. The STDP-iLTD requires a postsynaptic Ca(2+) increase, a release of endocannabinoids (eCBs), the activation of type-1 endocananabinoid receptors and presynaptic muscarinic receptors that mediate a decreased probability of GABA release. In contrast, the STDP-iLTD is independent of the activation of nicotinic receptors, GABAB Rs and G protein-coupled postsynaptic receptors at pyramidal neurons. We determine that the downregulation of presynaptic Cyclic adenosine monophosphate/protein Kinase A pathways is essential for the induction of STDP-iLTD. These results suggest a novel mechanism by which the activation of cholinergic neurons and retrograde signaling by eCBs can modulate the efficacy of GABAergic synaptic transmission in ways that may contribute to information processing and storage in the hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

Dopaminergic Modulation of Excitatory Transmission in the Anterior Cingulate Cortex of Adult Mice

PubMed Central

Darvish-Ghane, Soroush; Yamanaka, Manabu

2016-01-01

Dopamine (DA) possesses potent neuromodulatory properties in the central nervous system. In the anterior cingulate cortex, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) are key ion channels in mediating nerve injury induced long-term potentiation (LTP) and chronic pain phenotype. In the present study, we reported the effects of DA on glutamate mediated excitatory post-synaptic currents (EPSCs) in pyramidal neurons of layer II/III of the ACC in adult mice. Bath application of DA (50 μM) caused a significant, rapid and reversible inhibition of evoked EPSCs (eEPSC). This inhibitory effect is dose-related and was absent in lower concentration of DA (5 μM). Furthermore, selective postsynaptic application of GDP-β-S (1.6 mM) in the internal solution completely abolished the inhibitory effects of DA (50 μM). We also investigated modulation of spontaneous EPSCs (sEPSCs) and TTX sensitive, miniature EPSCs (mEPSCs) by DA. Our results indicated mixed effects of potentiation and inhibition of frequency and amplitude for sEPSCs and mEPSCs. Furthermore, high doses of SCH23390 (100 μM) and sulpiride (100 μM) revealed that, inhibition of eEPSCs is mediated by postsynaptic D2-receptors (D2R). Our finding posits a pre- and postsynaptic mode of pyramidal neuron EPSC modulation in mice ACC by DA. PMID:27317578

Calcium–calmodulin signalling pathway up-regulates glutamatergic synaptic function in non-pyramidal, fast spiking rat hippocampal CA1 neurons

PubMed Central

Wang, Jin-Hui; Kelly, Paul

2001-01-01

The role of Ca2+-calmodulin (CaM) signalling cascades in modulating glutamatergic synaptic transmission on CA1 non-pyramidal fast-spiking neurons was investigated using whole-cell recording and perfusion in rat hippocampal slices. Paired stimuli (PS), consisting of postsynaptic depolarization to 0 mV and presynaptic stimulation at 1 Hz for 30 s, enhanced excitatory postsynaptic currents (EPSCs) on non-pyramidal neurons in the stratum pyramidale (SP). The potentiation was reduced by the extracellular application of d-amino-5-phosphonovaleric acid (DAP-5, 40 μm), and blocked by the postsynaptic perfusion of 1,2-bis(2-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid (BAPTA, 10 mm), a CaM-binding peptide (100 μm) or CaMKII (281–301) (an autoinhibitory peptide of CaM-dependent protein kinases, 100 μm). The application of adenophostin, an agonist of inositol trisphosphate receptors (IP3Rs) that evokes Ca2+ release, into SP non-pyramidal neurons via the patch pipette (1 μm) enhanced EPSCs and occluded PS-induced synaptic potentiation. The co-application of BAPTA (10 mm) with adenophostin blocked synaptic potentiation. In addition, Ca2+-CaM (40:10 μm) induced synaptic potentiation, which occluded PS-induced potentiation and was attenuated by introducing CaMKII (281–301) (100 μm). EPSCs were sensitive to an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR). Application of Ca2+-CaM into SP non-pyramidal neurons induced the emergence of AMPAR-mediated EPSCs that were not evoked by low stimulus intensity before perfusion. Ca2+-CaM also increased the amplitude and frequency of spontaneous EPSCs. A scavenger of nitric oxide, carboxy-PTIO (30 μm in slice-perfusion solution), did not affect these increases in sEPSCs. The magnitude of PS-, adenophostin- or Ca2+-CaM-induced synaptic potentiation in SP non-pyramidal neurons increased during postnatal development. These results indicate that Ca2+-CaM signalling pathways in CA1 SP non-pyramidal neurons up-regulate glutamatergic synaptic transmission probably through the conversion of inactive-to-active synapses. PMID:11389201

Synaptic hyperpolarization and inhibition of turtle cochlear hair cells.

PubMed

Art, J J; Fettiplace, R; Fuchs, P A

1984-11-01

Intracellular recordings were made from turtle cochlear hair cells in order to examine the properties of the post-synaptic potentials evoked by electrical stimulation of the efferent axons. Single shocks to the efferents generated a hair cell membrane hyperpolarization with an average amplitude generally less than 1 mV and lasting for about 100 ms. With short trains of shocks, the size of the post-synaptic potential grew markedly to a maximum of 20-30 mV. The interaction between pairs of shocks separated by a varying interval was studied. For an interval of 4 ms, the response to the second shock was increased on average by a factor of 3 and the conditioning effect of the first shock decayed with a time constant of about 100 ms. We suggest the augmentation in response to trains of shocks may be partly due to facilitation of efferent transmitter release. The efferent post-synaptic potentials could be reversibly abolished by perfusion with perilymphs containing 3 microM-curare or atropine, and infusion of acetylcholine gave a transient membrane hyperpolarization. These observations are consistent with efferent action being mediated via a cholinergic synapse onto the hair cells. The post-synaptic potentials could be reversed in polarity by injection of hyperpolarizing currents through the recording electrode. The reversal potential was estimated as about -80 mV, 30 mV negative to the resting potential. Near reversal, a small brief depolarization was evident and may constitute a minor component of the synaptic response. The value of the reversal potential was unaffected by substitution of the perilymphatic chloride, but was altered in a predictable manner by changes in extracellular potassium concentration indicating that the post-synaptic potentials arise mainly by an increase in the permeability of the hair cell membrane to potassium ions. Throughout the post-synaptic hyperpolarization there was a reduction in the sensitivity of the hair cell to tones at its characteristic frequency. The desensitization, maximal for low sound pressures, varied in different cells from a factor of 1.6 to 28. At the peak of the largest synaptic potentials, the receptor potential remained negative to the resting potential with all but the loudest characteristic frequency tone s. We suggest that there are two factors in efferent inhibition; one a r duction in the receptor potential at the hair cell's characteristic frequency and the other a hyperpolarization of its membrane potential which should reduce the release of excitatory transmitter onto the afferent terminals.

Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease.

PubMed

Holley, Sandra M; Joshi, Prasad R; Parievsky, Anna; Galvan, Laurie; Chen, Jane Y; Fisher, Yvette E; Huynh, My N; Cepeda, Carlos; Levine, Michael S

2015-01-01

In Huntington's disease (HD), a hereditary neurodegenerative disorder, striatal medium-sized spiny neurons undergo degenerative changes. In contrast, large cholinergic interneurons (LCIs) are relatively spared. However, their ability to release acetylcholine (ACh) is impaired. The present experiments examined morphological and electrophysiological properties of LCIs in the R6/2 mouse model of HD. R6/2 mice show a severe, rapidly progressing phenotype. Immunocytochemical analysis of choline acetyltransferase-positive striatal neurons showed that, although the total number of cells was not changed, somatic areas were significantly smaller in symptomatic R6/2 mice compared to wildtype (WT) littermates, For electrophysiology, brain slices were obtained from presymptomatic (3-4 weeks) and symptomatic (>8 weeks) R6/2 mice and their WT littermates. Striatal LCIs were identified by somatic size and spontaneous action potential firing in the cell-attached mode. Passive and active membrane properties of LCIs were similar in presymptomatic R6/2 and WT mice. In contrast, LCIs from symptomatic R6/2 animals displayed smaller membrane capacitance and higher input resistance, consistent with reduced somatic size. In addition, more LCIs from symptomatic mice displayed irregular firing patterns and bursts of action potentials. They also displayed a higher frequency of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) and larger amplitude of electrically evoked IPSCs. Selective optogenetic stimulation of somatostatin- but not parvalbumin-containing interneurons also evoked larger amplitude IPSCs in LCIs from R6/2 mice. In contrast, glutamatergic spontaneous or evoked postsynaptic currents were not affected. Morphological and electrophysiological alterations, in conjunction with the presence of mutant huntingtin in LCIs, could explain impaired ACh release in HD mouse models.

Use of NK1 receptor antagonists in the exploration of physiological functions of substance P and neurokinin A.

PubMed

Otsuka, M; Yoshioka, K; Yanagisawa, M; Suzuki, H; Zhao, F Y; Guo, J Z; Hosoki, R; Kurihara, T

1995-07-01

Tachykinin NK1 receptor antagonists were used to explore the physiological functions of substance P (SP) and neurokinin A (NKA). Pharmacological profiles of three NK1 receptor antagonists, GR71251, GR82334, and RP 67580, were examined in the isolated spinal cord preparation of the neonatal rat. These tachykinin receptor antagonists exhibited considerable specificities and antagonized the actions of both SP and NKA to induce the depolarization of ventral roots. Electrical stimulation of the saphenous nerve with C-fiber strength evoked a depolarization lasting about 30 s of the ipsilateral L3 ventral root. This response, which is referred to as saphenous-nerve-evoked slow ventral root potential (VRP), was depressed by these NK1 receptor antagonists. In contrast, the saphenous-nerve-evoked slow VRP was potentiated by application of a mixture of peptidase inhibitors, including thiorphan, actinonin, and captopril in the presence of naloxone, but not after further addition of GR71251. Likewise, in the isolated coeliac ganglion of the guinea pig, electrical stimulation of the mesenteric nerves evoked in some ganglionic cells slow excitatory postsynaptic potentials (EPSPs), which were depressed by GR71251 and potentiated by peptidase inhibitors. These results further support the notion that SP and NKA serve as neurotransmitters producing slow EPSPs in the neonatal rat spinal cord and guinea pig prevertebral ganglia.

Phenytoin attenuates the hyper-exciting neurotransmission in cultured embryonic cortical neurons.

PubMed

Chou, Ming-Yi; Lee, Chun-Yao; Liou, Horng-Huei; Pan, Chien-Yuan

2014-08-01

Phenytoin is an effective anti-epileptic drug that inhibits Na(+) channel activities; however, how phenytoin modulates synaptic transmission to soothe epileptic symptoms is not clear. To characterize the effects of phenytoin regulation on neurotransmission, we studied the electrophysical properties of cultured embryonic cortical neurons. Phenytoin inhibited the inward Na(+) current in a dose-dependent manner with an IC50 of 16.8 μM, and at 100 μM, the inhibitory effect of phenytoin on the Na(+) current was proportional to the frequency applied. In cultured neurons, phenytoin significantly decreased the action potential firing rate and the peak potential. To study the effect of phenytoin in neurotransmission, we measured the Ca(2+) responses from stimulated target neurons and their neighboring neurons. Phenytoin significantly suppressed the Ca(2+) responses evoked by strong stimulations in the target and neighboring neurons, and exerted a decreased inhibitory effect under moderate stimulation. Picrotoxin, a GABAA receptor antagonist, enhanced the recorded spontaneous excitatory postsynaptic current activities. After picrotoxin-induced enhancement, phenytoin had a more pronounced effect on the suppression of the spontaneous hyper-exciting excitatory postsynaptic current (>100 pA), but it only mildly inhibited the general excitatory postsynaptic current. Our results demonstrate that phenytoin suppresses the efficacy of neurotransmission especially for the high-frequency stimulation by reducing the Na(+) channel activity and can potentially alleviate epileptiform activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Unitary IPSPs evoked by interneurons at the stratum radiatum-stratum lacunosum-moleculare border in the CA1 area of the rat hippocampus in vitro

PubMed Central

Vida, Imre; Halasy, Katalin; Szinyei, Csaba; Somogyi, Peter; Buhl, Eberhard H

1998-01-01

Hippocampal non-principal neurons at the stratum radiatum-stratum lacunosum-moleculare border (R-LM interneurons) of the CA1 area may constitute several cell classes and have been implicated in the generation of GABAergic unitary IPSPs. Using biocytin-filled electrodes we recorded R-LM interneurons intracellularly in vitro and determined their postsynaptic effects in concomitantly recorded pyramidal cells. Light microscopic analysis revealed four populations of R-LM interneurons with distinct axons: (1) basket cells (n= 4) with axons predominantly ramifying in the pyramidal cell layer; (2) Schaffer collateral/commissural pathway-associated interneurons (n= 10) stratifying in stratum radiatum and, to a lesser extent, stratum oriens; (3) perforant pathway-associated interneurons (n= 6) innervating the perforant path termination zone in stratum lacunosum-moleculare of the CA1 area as well as equivalent portions of the dentate gyrus and subiculum; and (4) neurogliaform interneurons (n= 2) characterized by their dense, compact axonal and dendritic arbour. Random electron microscopic sampling of synaptic targets revealed a preponderance of pyramidal neurons as postsynaptic elements. Basket cells had a synaptic target preference for somata and proximal dendrites, whereas the remainder of R-LM interneurons innervated dendritic shafts and spines. The axon of dendrite-targeting cells formed up to six putative contacts with individual postsynaptic pyramidal cells. Anatomically recovered R-LM interneurons (n= 22) had a mean resting membrane potential of -56.7 ± 3.6 mV, a membrane time constant of 12.9 ± 7.7 ms and an input resistance of 86.4 ± 29.2 MΩ. Depolarizing current pulses generally elicited overshooting action potentials (70.8 ± 6.9 mV) which had a mean duration, when measured at half-amplitude, of 0.7 ± 0.1 ms. In response to prolonged (> 200 ms) depolarizing current pulses all R-LM interneurons displayed (a varying degree of) spike frequency adaptation. Basket cells, Schaffer-associated and neurogliaform interneurons elicited small-amplitude (< 2 mV), short-latency IPSPs in postsynaptic pyramids (n= 5, 13 and 1, respectively). Those interactions in which an effect was elicited with the repetitive activation of the presynaptic neuron (n= 13) showed a substantial degree of postsynaptic response summation. Unitary IPSPs had fast kinetics and, whenever tested (n= 5; 1 basket cell and 4 Schaffer-associated interneurons), were abolished by the GABAA receptor antagonist bicuculline. Thus, R-LM interneurons comprise several distinct populations which evoke fast GABAA receptor-mediated IPSPs. The domain-specific innervation of postsynaptic pyramidal cells suggests functionally diverse effects on the integration of afferent information in functionally non-equivalent compartments of pyramidal cells. PMID:9503336

Xenon inhibits excitatory but not inhibitory transmission in rat spinal cord dorsal horn neurons

PubMed Central

2010-01-01

Background The molecular targets for the promising gaseous anaesthetic xenon are still under investigation. Most studies identify N-methyl-D-aspartate (NMDA) receptors as the primary molecular target for xenon, but the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid (AMPA) receptors is less clear. In this study we evaluated the effect of xenon on excitatory and inhibitory synaptic transmission in the superficial dorsal horn of the spinal cord using in vitro patch-clamp recordings from rat spinal cord slices. We further evaluated the effects of xenon on innocuous and noxious stimuli using in vivo patch-clamp method. Results In vitro, xenon decreased the amplitude and area under the curve of currents induced by exogenous NMDA and AMPA and inhibited dorsal root stimulation-evoked excitatory postsynaptic currents. Xenon decreased the amplitude, but not the frequency, of miniature excitatory postsynaptic currents. There was no discernible effect on miniature or evoked inhibitory postsynaptic currents or on the current induced by inhibitory neurotransmitters. In vivo, xenon inhibited responses to tactile and painful stimuli even in the presence of NMDA receptor antagonist. Conclusions Xenon inhibits glutamatergic excitatory transmission in the superficial dorsal horn via a postsynaptic mechanism. There is no substantial effect on inhibitory synaptic transmission at the concentration we used. The blunting of excitation in the dorsal horn lamina II neurons could underlie the analgesic effect of xenon. PMID:20444263

Y2-receptor-mediated selective inhibition of slow, inhibitory postsynaptic potential in submucous neurones of guinea-pig caecum.

PubMed Central

Cunningham, S M; Mihara, S; Lees, G M

1994-01-01

1. The subtype of neuropeptide Y receptor mediating the selective inhibition of the slow inhibitory postsynaptic potential (i.p.s.p.) of submucous neurones in guinea-pig caecum was investigated by use of conventional intracellular electrophysiological recording techniques. 2. Neuropeptide Y (NPY) (1-300 nM) was found to depress or abolish reversibly the slow i.p.s.p. evoked by focal stimulation of internodal fibre tracts. At low concentrations (1-30 nM), a reduction in the duration of the slow i.p.s.p. was often apparent before any inhibition of the amplitude of this synaptic potential. 3. These inhibitory effects of NPY were mimicked by peptide YY (PYY; 0.3-100 nM), NPY13-36 (1-300 nM) and NPY22-36 (10-100 nM); [Leu31,Pro34]NPY ([Pro34]NPY) and bovine pancreatic polypeptide (bPP) were without pre- or postsynaptic effects at concentrations of up to 300 nM. The IC50 +/- s.e. mean values for PYY, NPY, and NPY13-36 were 2.7 +/- 0.3, 7.8 +/- 2.1 and 30 +/- 4.8 nM, respectively, and were significantly different from each other. Thus, the apparent rank order of potency was PYY > NPY > NPY13-36 >> [Pro34]NPY and bPP. 4. In concentrations of up to 300 nM, NPY and its analogues had no depressant effects on the active and passive properties of the impaled neurone and did not affect the amplitude or duration of either cholinergic fast synaptic potentials or non-cholinergic, slow excitatory postsynaptic potentials (e.p.s.ps). Furthermore, none of these peptides altered the amplitude or time-course of changes in membrane potential induced by focal application of acetylcholine or noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7858881

Synaptic transmission and short-term plasticity at the calyx of Held synapse revealed by multielectrode array recordings.

PubMed

Haustein, Martin D; Reinert, Thomas; Warnatsch, Annika; Englitz, Bernhard; Dietz, Beatrice; Robitzki, Andrea; Rübsamen, Rudolf; Milenkovic, Ivan

2008-09-30

We assessed the potential of using multielectrode arrays (MEAs) to investigate several physiological properties of the calyx of Held synapse in the medial nucleus of the trapezoid body of gerbil. Due to the large size of the synapse, it became widely employed in studies on synaptic mechanisms. Electrical stimulation at the midline evoked a characteristic compound signal consisting of a presynaptic volley (C(1)) and a postsynaptic response (C(2)). The C(1) was blocked by tetrodotoxin, whilst the C(2) was blocked by perfusion of low Ca(2+) external solution, or the AMPA-R antagonists CNQX, and GYKI52466. NMDA-R blocker D-AP5, partially inhibited the postsynaptic response at P12, but showed no effect in P30 animals. The inhibitory effects of GABA or glycine on postsynaptic responses were reciprocal with regard to animal's maturity: GABA caused a pronounced reduction of C(2) amplitude in P20-22 animals, while glycine showed a stronger inhibition in P27-28 animals. Low-frequency super-threshold stimulation of the afferents induced facilitation of the postsynaptic C(2) amplitudes and only minor changes in temporal characteristics of the signals. At stimulation frequencies >200 Hz, however, significant depression occurs accompanied by increases in transmission delay and in the width of the postsynaptic response. This study suggests MEAs as a useful tool to study calyx of Held synapse by simultaneous recordings of pre- and postsynaptic elements of synaptically interconnected neurons in the auditory brainstem. Moreover, MEAs enable convenient analysis of activity-dependent depression and modulation of neuronal activity by glycine and GABA at later developmental stages not accessible to patch recordings.

Astrocytes Modulate a Postsynaptic NMDA–GABAA-Receptor Crosstalk in Hypothalamic Neurosecretory Neurons

PubMed Central

Potapenko, Evgeniy S.; Biancardi, Vinicia C.; Zhou, Yiqiang

2013-01-01

A dynamic balance between the excitatory and inhibitory neurotransmitters glutamate and GABA is critical for maintaining proper neuronal activity in the brain. This balance is partly achieved via presynaptic interactions between glutamatergic and GABAAergic synapses converging into the same targets. Here, we show that in hypothalamic magnocellular neurosecretory neurons (MNCs), a direct crosstalk between postsynaptic NMDA receptors (NMDARs) and GABAA receptors (GABAARs) contributes to the excitatory/inhibitory balance in this system. We found that activation of NMDARs by endogenous glutamate levels controlled by astrocyte glutamate transporters, evokes a transient and reversible potentiation of postsynaptic GABAARs. This inter-receptor crosstalk is calcium-dependent and involves a kinase-dependent phosphorylation mechanism, but does not require nitric oxide as an intermediary signal. Finally, we found the NMDAR–GABAAR crosstalk to be blunted in rats with heart failure, a pathological condition in which the hypothalamic glutamate–GABA balance is tipped toward an excitatory predominance. Together, our findings support a novel form of glutamate–GABA interactions in MNCs, which involves crosstalk between NMDA and GABAA postsynaptic receptors, whose strength is controlled by the activity of local astrocytes. We propose this inter-receptor crosstalk to act as a compensatory, counterbalancing mechanism to dampen glutamate-mediated overexcitation. Finally, we propose that an uncoupling between NMDARs and GABAARs may contribute to exacerbated neuronal activity and, consequently, sympathohumoral activation in such disease conditions as heart failure. PMID:23303942

Glutamate receptor activation in the kindled dentate gyrus.

PubMed

Behr, J; Heinemann, U; Mody, I

2000-01-01

The contribution of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate receptor activation to the enhanced seizure susceptibility of the dentate gyrus was investigated in an experimental model of temporal lobe epilepsy. Using the specific NMDA and AMPA receptor antagonists D-APV and SYM 2206, we examined alterations in glutamate receptor-dependent synaptic currents 48 hours and 28 days after kindling in field-potential and voltage-clamp recordings. Forty-eight hours after kindling, the fractions of AMPA and NMDA receptor-mediated excitatory postsynaptic current components shifted dramatically in favor of the NMDA receptor-mediated response. Four weeks after kindling, however, AMPA and NMDA receptor-mediated excitatory postsynaptic currents reverted to control-like values. Neither single nor repetitive perforant path stimuli evoked kainate receptor-mediated excitatory postsynaptic currents in dentate gyrus granule cells of control or kindled rats. The enhanced excitability of the kindled dentate gyrus 48 hours after the last seizure most likely results from transiently enhanced NMDA receptor activation. The NMDA receptor seems to play a critical role in the induction of the kindled state rather than in the persistence of the enhanced seizure susceptibility.

Postsynaptic elevation of calcium induces persistent depression of developing neuromuscular synapses.

PubMed

Cash, S; Dan, Y; Poo, M M; Zucker, R

1996-04-01

Synaptic activity is known to modulate neuronal connectivity in the nervous system. At developing Xenopus neuromuscular synapses in culture, repetitive postsynaptic application of ACh near the synapse leads to immediate and persistent synaptic depression, which was shown to be caused by reduction of presynaptic evoked transmitter release. However, little depression was found when ACh was applied to the muscle 20 microns or further from the synapse. Fluorescence imaging of cytosolic Ca2+ ([Ca2+]i) showed that each ACh pulse induced a transient elevation of myocyte [Ca2+]i that spread approximately 20 microns. Local photoactivated release of Ca2+ from the caged Ca2+ chelators nitr-5 or nitrophen in the postsynaptic cell was sufficient to induce persistent synaptic depression. These results support a model in which localized Ca2+ influx into the postsynaptic myocyte initiates transsynaptic retrograde modulation of presynaptic secretion mechanisms.

Evidence that protons act as neurotransmitters at vestibular hair cell-calyx afferent synapses.

PubMed

Highstein, Stephen M; Holstein, Gay R; Mann, Mary Anne; Rabbitt, Richard D

2014-04-08

Present data support the conclusion that protons serve as an important neurotransmitter to convey excitatory stimuli from inner ear type I vestibular hair cells to postsynaptic calyx nerve terminals. Time-resolved pH imaging revealed stimulus-evoked extrusion of protons from hair cells and a subsequent buildup of [H(+)] within the confined chalice-shaped synaptic cleft (ΔpH ∼ -0.2). Whole-cell voltage-clamp recordings revealed a concomitant nonquantal excitatory postsynaptic current in the calyx terminal that was causally modulated by cleft acidification. The time course of [H(+)] buildup limits the speed of this intercellular signaling mechanism, but for tonic signals such as gravity, protonergic transmission offers a significant metabolic advantage over quantal excitatory postsynaptic currents--an advantage that may have driven the proliferation of postsynaptic calyx terminals in the inner ear vestibular organs of contemporary amniotes.

Saccular and utricular inputs to sternocleidomastoid motoneurons of decerebrate cats.

PubMed

Kushiro, K; Zakir, M; Ogawa, Y; Sato, H; Uchino, Y

1999-06-01

Connections from the otolithic organs to sternocleidomastoid (SCM) motoneurons were studied in 20 decerebrate cats. The electrical stimulation was selective for the saccular or the utricular nerves. Postsynaptic potentials were recorded from antidromically identified SCM motoneurons; these muscles participate mainly in neck rotation and flexion. Partial transections of the brainstem at the level of the obex were performed to identify the possible pathway from the otolithic organs to the SCM motoneurons. Saccular or utricular nerve stimulation mainly evoked inhibitory postsynaptic potentials (IPSPs) in the ipsilateral SCM motoneurons. Some of the sacculus-induced IPSPs were preceded by small-amplitude excitatory PSPs (EPSPs). The latencies of the PSPs ranged from 1.8 to 3.1 ms after saccular nerve stimulation and from 1.7 to 2.8 ms after utricular nerve stimulation, indicating that most of the ipsilateral connections were disynaptic. In the contralateral SCM motoneurons, saccular nerve stimulation had no or faint effects, whereas utricular nerve stimulation evoked EPSPs in about two-thirds of neurons, and no visible PSPs in about one-third of neurons. The latencies of the EPSPs ranged from 1.5 to 2.0 ms, indicating the disynaptic connection. Thus, the results suggest a difference between the two otolithic innervating patterns of SCM motoneurons. After transection of the medial vestibulospinal tract (MVST), saccular nerve stimulation did not evoke IPSPs at all in ipsilateral SCM motoneurons, but some (11/40) neurons showed small-amplitude EPSPs. Most (24/33) of the utricular-activated IPSPs disappeared after transection, whereas the other 9 neurons still indicated IPSPs. In the contralateral SCM motoneurons, no utricular-activated EPSPs were recorded after transection. These MVST transection results suggest that most of the otolith-SCM pathways are located in the MVST at the obex level. However, the results also suggest the possibility that other otolith-SCM pathways exist at the obex level.

Parvalbumin-producing cortical interneurons receive inhibitory inputs on proximal portions and cortical excitatory inputs on distal dendrites.

PubMed

Kameda, Hiroshi; Hioki, Hiroyuki; Tanaka, Yasuyo H; Tanaka, Takuma; Sohn, Jaerin; Sonomura, Takahiro; Furuta, Takahiro; Fujiyama, Fumino; Kaneko, Takeshi

2012-03-01

To examine inputs to parvalbumin (PV)-producing interneurons, we generated transgenic mice expressing somatodendritic membrane-targeted green fluorescent protein specifically in the interneurons, and completely visualized their dendrites and somata. Using immunolabeling for vesicular glutamate transporter (VGluT)1, VGluT2, and vesicular GABA transporter, we found that VGluT1-positive terminals made contacts 4- and 3.1-fold more frequently with PV-producing interneurons than VGluT2-positive and GABAergic terminals, respectively, in the primary somatosensory cortex. Even in layer 4, where VGluT2-positive terminals were most densely distributed, VGluT1-positive inputs to PV-producing interneurons were 2.4-fold more frequent than VGluT2-positive inputs. Furthermore, although GABAergic inputs to PV-producing interneurons were as numerous as VGluT2-positive inputs in most cortical layers, GABAergic inputs clearly preferred the proximal dendrites and somata of the interneurons, indicating that the sites of GABAergic inputs were more optimized than those of VGluT2-positive inputs. Simulation analysis with a PV-producing interneuron model compatible with the present morphological data revealed a plausible reason for this observation, by showing that GABAergic and glutamatergic postsynaptic potentials evoked by inputs to distal dendrites were attenuated to 60 and 87%, respectively, of those evoked by somatic inputs. As VGluT1-positive and VGluT2-positive axon terminals were presumed to be cortical and thalamic glutamatergic inputs, respectively, cortical excitatory inputs to PV-producing interneurons outnumbered the thalamic excitatory and intrinsic inhibitory inputs more than two-fold in any cortical layer. Although thalamic inputs are known to evoke about two-fold larger unitary excitatory postsynaptic potentials than cortical ones, the present results suggest that cortical inputs control PV-producing interneurons at least as strongly as thalamic inputs. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Synaptic excitation mediated by AMPA receptors in rat cerebellar slices is selectively enhanced by aniracetam and cyclothiazide.

PubMed

Boxall, A R; Garthwaite, J

1995-05-01

AMPA receptors mediate fast, glutamatergic synaptic transmission in the central nervous system. The time-course of the associated postsynaptic current has been suggested to be determined principally by the kinetics of glutamate binding and receptor desensitization. Aniracetam and cyclothiazide are drugs capable of selectively preventing desensitization of the AMPA receptor. To investigate the relevance of desensitization to fast synaptic transmission in the cerebellum we have tested these compounds against AMPA-induced depolarizations and postsynaptic potentials using the grease-gap recording technique. Aniracetam (1 microM-5 mM) and cyclothiazide (1 microM-500 microM) both enhanced the depolarising action of AMPA (1 microM) on Purkinje cells in a concentration-dependent manner. At the highest concentrations tested, the increases over controls were approximately 600% and 800% respectively. Aniracetam also increased, in a concentration-dependent manner, the amplitude of the evoked synaptic potentials of both parallel fibre-Purkinje cell and mossy fibre-granule cell pathways, with the highest concentrations tested enhancing the potentials by approximately 60% and 75% respectively. These data suggest that, at two different synapses in the cerebellum, AMPA receptor desensitization occurs physiologically and is likely to contribute to the shape of fast synaptic currents.

Presynaptic and postsynaptic effects of local cathodal DC polarization within the spinal cord in anaesthetized animal preparations

PubMed Central

Bolzoni, F; Jankowska, E

2015-01-01

The present study aimed to compare presynaptic and postsynaptic actions of direct current polarization in the spinal cord, focusing on DC effects on primary afferents and motoneurons. To reduce the directly affected spinal cord region, a weak polarizing direct current (0.1–0.3 μA) was applied locally in deeply anaesthetized cats and rats; within the hindlimb motor nuclei in the caudal lumbar segments, or in the dorsal horn within the terminal projection area of low threshold skin afferents. Changes in the excitability of primary afferents activated by intraspinal stimuli (20–50 μA) were estimated using increases or decreases in compound action potentials recorded from the dorsal roots or peripheral nerves as their measure. Changes in the postsynaptic actions of the afferents were assessed from intracellularly recorded monosynaptic EPSPs in hindlimb motoneurons and monosynaptic extracellular field potentials (evoked by group Ia afferents in motor nuclei, or by low threshold cutaneous afferents in the dorsal horn). The excitability of motoneurons activated by intraspinal stimuli was assessed using intracellular records or motoneuronal discharges recorded from a ventral root or a muscle nerve. Cathodal polarization was found to affect motoneurons and afferents providing input to them to a different extent. The excitability of both was markedly increased during DC application, although post-polarization facilitation was found to involve presynaptic afferents and some of their postsynaptic actions, but only negligibly motoneurons themselves. Taken together, these results indicate that long-lasting post-polarization facilitation of spinal activity induced by locally applied cathodal current primarily reflects the facilitation of synaptic transmission. PMID:25416625

Postsynaptic N-type or P/Q-type calcium channels mediate long-term potentiation by group I metabotropic glutamate receptors in the trigeminal oralis.

PubMed

Weon, Haein; Kim, Tae Wan; Youn, Dong-Ho

2017-11-01

Both N-type and P/Q-type voltage-gated Ca 2+ channels (VGCCs) are involved in the induction of long-term potentiation (LTP), the long-lasting increase of synaptic strength, in the central nervous system. To provide further information on the roles of N-type and P/Q-type VGCCs in the induction of LTP at excitatory synapses of trigeminal primary afferents in the spinal trigeminal subnucleus oralis (Vo), we investigated whether they contribute to the induction of LTP by activation of group I metabotropic glutamate receptors (mGluRs). (S)-3,5-Dihydroxyphenylglycine (DHPG; 10μM for 5min), the group I mGluR agonist, was used to induce LTP of excitatory postsynaptic currents that were evoked in the Vo neurons by stimulating the trigeminal track. Weak blockade of the N-type or P/Q-type VGCCs by ω-conotoxin GVIA or ω-agatoxin IVA, respectively, which inhibited only 20-40% of Ca 2+ currents recorded in isolated trigeminal ganglion neurons but had no effect on the basal excitatory synaptic transmission, completely blocked the induction of LTP. In contrast, stronger blockade of the channels, which inhibited >50% of Ca 2+ currents and about 30% of basal synaptic transmission, resulted in the development of long-term depression (LTD), the long-lasting decrease of synaptic strength. Interestingly, the postsynaptic mechanism of DHPG-induced LTP, which was determined by paired-pulse ratio, disappeared when LTP was blocked, or LTD occurred, while a presynaptic mechanism still remained. Our data suggest that postsynaptic N-type and P/Q-type VGCCs mediate the DHPG-induced LTP at the trigeminal afferent synapses in the Vo. Copyright © 2017 Elsevier Inc. All rights reserved.

Mechanisms and consequences of action potential burst firing in rat neocortical pyramidal neurons

PubMed Central

Williams, Stephen R; Stuart, Greg J

1999-01-01

Electrophysiological recordings and pharmacological manipulations were used to investigate the mechanisms underlying the generation of action potential burst firing and its postsynaptic consequences in visually identified rat layer 5 pyramidal neurons in vitro.Based upon repetitive firing properties and subthreshold membrane characteristics, layer 5 pyramidal neurons were separated into three classes: regular firing and weak and strong intrinsically burst firing.High frequency (330 ± 10 Hz) action potential burst firing was abolished or greatly weakened by the removal of Ca2+ (n = 5) from, or by the addition of the Ca2+ channel antagonist Ni2+ (250–500 μm; n = 8) to, the perfusion medium.The blockade of apical dendritic sodium channels by the local dendritic application of TTX (100 nm; n = 5) abolished or greatly weakened action potential burst firing, as did the local apical dendritic application of Ni2+ (1 mm; n = 5).Apical dendritic depolarisation resulted in low frequency (157 ± 26 Hz; n = 6) action potential burst firing in regular firing neurons, as classified by somatic current injection. The intensity of action potential burst discharges in intrinsically burst firing neurons was facilitated by dendritic depolarisation (n = 11).Action potential amplitude decreased throughout a burst when recorded somatically, suggesting that later action potentials may fail to propagate axonally. Axonal recordings demonstrated that each action potential in a burst is axonally initiated and that no decrement in action potential amplitude is apparent in the axon > 30 μm from the soma.Paired recordings (n = 16) from synaptically coupled neurons indicated that each action potential in a burst could cause transmitter release. EPSPs or EPSCs evoked by a presynaptic burst of action potentials showed use-dependent synaptic depression.A postsynaptic, TTX-sensitive voltage-dependent amplification process ensured that later EPSPs in a burst were amplified when generated from membrane potentials positive to -60 mV, providing a postsynaptic mechanism that counteracts use-dependent depression at synapses between layer 5 pyramidal neurons. PMID:10581316

Interactions between Dorsal and Ventral Root Stimulation on the Generation of Locomotor-Like Activity in the Neonatal Mouse Spinal Cord

PubMed Central

2016-01-01

Abstract We investigated whether dorsal (DR) and ventral root (VR) stimulus trains engage common postsynaptic components to activate the central pattern generator (CPG) for locomotion in the neonatal mouse spinal cord. VR stimulation did not activate the first order interneurons mediating the activation of the locomotor CPG by sacrocaudal afferent stimulation. Simultaneous stimulation of adjacent dorsal or ventral root pairs, subthreshold for evoking locomotor-like activity, did not summate to activate the CPG. This suggests that locomotor-like activity is triggered when a critical class of efferent or afferent axons is stimulated and does not depend on the number of stimulated axons or activated postsynaptic neurons. DR- and VR-evoked episodes exhibited differences in the coupling between VR pairs. In DR-evoked episodes, the coupling between the ipsilateral and contralateral flexor/extensor roots was similar and stronger than the bilateral extensor roots. In VR-evoked episodes, ipsilateral flexor/extensor coupling was stronger than both the contralateral flexor/extensor and the bilateral extensor coupling. For both types of stimulation, the coupling was greatest between the bilateral L1/L2 flexor-dominated roots. This indicates that the recruitment and/or the firing pattern of motoneurons differed in DR and VR-evoked episodes. However, the DR and VR trains do not appear to activate distinct CPGs because trains of DR and VR stimuli at frequencies too low to evoke locomotor-like activity did so when they were interleaved. These results indicate that the excitatory actions of VR stimulation converge onto the CPG through an unknown pathway that is not captured by current models of the locomotor CPG. PMID:27419215

Neuromuscular paralysis by the basic phospholipase A2 subunit of crotoxin from Crotalus durissus terrificus snake venom needs its acid chaperone to concurrently inhibit acetylcholine release and produce muscle blockage.

PubMed

Cavalcante, Walter L G; Noronha-Matos, José B; Timóteo, Maria A; Fontes, Marcos R M; Gallacci, Márcia; Correia-de-Sá, Paulo

2017-11-01

Crotoxin (CTX), a heterodimeric phospholipase A 2 (PLA 2 ) neurotoxin from Crotalus durissus terrificus snake venom, promotes irreversible blockade of neuromuscular transmission. Indirect electrophysiological evidence suggests that CTX exerts a primary inhibitory action on transmitter exocytosis, yet contribution of a postsynaptic action of the toxin resulting from nicotinic receptor desensitization cannot be excluded. Here, we examined the blocking effect of CTX on nerve-evoked transmitter release measured directly using radioisotope neurochemistry and video microscopy with the FM4-64 fluorescent dye. Experiments were conducted using mice phrenic-diaphragm preparations. Real-time fluorescence video microscopy and liquid scintillation spectrometry techniques were used to detect transmitter exocytosis and nerve-evoked [ 3 H]-acetylcholine ([ 3 H]ACh) release, respectively. Nerve-evoked myographic recordings were also carried out for comparison purposes. Both CTX (5μg/mL) and its basic PLA 2 subunit (CB, 20μg/mL) had biphasic effects on nerve-evoked transmitter exocytosis characterized by a transient initial facilitation followed by a sustained decay. CTX and CB reduced nerve-evoked [ 3 H]ACh release by 60% and 69%, respectively, but only the heterodimer, CTX, decreased the amplitude of nerve-evoked muscle twitches. Data show that CTX exerts a presynaptic inhibitory action on ACh release that is highly dependent on its intrinsic PLA 2 activity. Given the high safety margin of the neuromuscular transmission, one may argue that the presynaptic block caused by the toxin is not enough to produce muscle paralysis unless a concurrent postsynaptic inhibitory action is also exerted by the CTX heterodimer. Copyright © 2017. Published by Elsevier Inc.

Frequency-dependent glycinergic inhibition modulates plasticity in hippocampus.

PubMed

Keck, Tara; Lillis, Kyle P; Zhou, Yu-Dong; White, John A

2008-07-16

Previous studies have demonstrated the presence of functional glycine receptors (GlyRs) in hippocampus. In this work, we examine the baseline activity and activity-dependent modulation of GlyRs in region CA1. We find that strychnine-sensitive GlyRs are open in the resting CA1 pyramidal cell, creating a state of tonic inhibition that "shunts" the magnitude of EPSPs evoked by electrical stimulation of the Schaffer collateral inputs. This GlyR-mediated shunting conductance is independent of the presynaptic stimulation rate; however, pairs of presynaptic and postsynaptic action potentials, repeated at frequencies above 5 Hz, reduce the GlyR-mediated conductance and increase peak EPSP magnitudes to levels at least 20% larger than those seen with presynaptic stimulation alone. We refer to this phenomenon as rate-dependent efficacy (RDE). Exogenous GlyR agonists (glycine, taurine) block RDE by preventing the closure of postsynaptic GlyRs. The GlyR antagonist strychnine blocks postsynaptic GlyRs under all conditions, occluding RDE. During RDE, GlyRs are less responsive to local glycine application, suggesting that a reduction in the number or sensitivity of membrane-inserted GlyRs underlies RDE. By extending the RDE induction protocol to include 500 paired presynaptic and postsynaptic spikes, we can induce long-term synaptic depression (LTD). Manipulations that lead to reduced functionality of GlyRs, either pharmacologically or through RDE, also lead to increased LTD. This result suggests that RDE contributes to long-term synaptic plasticity in the hippocampus.

Parvalbumin-expressing interneurons can act solo while somatostatin-expressing interneurons act in chorus in most cases on cortical pyramidal cells.

PubMed

Safari, Mir-Shahram; Mirnajafi-Zadeh, Javad; Hioki, Hiroyuki; Tsumoto, Tadaharu

2017-10-06

Neural circuits in the cerebral cortex consist primarily of excitatory pyramidal (Pyr) cells and inhibitory interneurons. Interneurons are divided into several subtypes, in which the two major groups are those expressing parvalbumin (PV) or somatostatin (SOM). These subtypes of interneurons are reported to play distinct roles in tuning and/or gain of visual response of pyramidal cells in the visual cortex. It remains unclear whether there is any quantitative and functional difference between the PV → Pyr and SOM → Pyr connections. We compared unitary inhibitory postsynaptic currents (uIPSCs) evoked by electrophysiological activation of single presynaptic interneurons with population IPSCs evoked by photo-activation of a mass of interneurons in vivo and in vitro in transgenic mice in which PV or SOM neurons expressed channelrhodopsin-2, and found that at least about 14 PV neurons made strong connections with a postsynaptic Pyr cell while a much larger number of SOM neurons made weak connections. Activation or suppression of single PV neurons modified visual responses of postsynaptic Pyr cells in 6 of 7 pairs whereas that of single SOM neurons showed no significant modification in 8 of 11 pairs, suggesting that PV neurons can act solo whereas most of SOM neurons may act in chorus on Pyr cells.

Nucleus reticularis neurons mediate diverse inhibitory effects in thalamus.

PubMed

Cox, C L; Huguenard, J R; Prince, D A

1997-08-05

Detailed information regarding the contribution of individual gamma-aminobutyric acid (GABA)-containing inhibitory neurons to the overall synaptic activity of single postsynaptic cells is essential to our understanding of fundamental elements of synaptic integration and operation of neuronal circuits. For example, GABA-containing cells in the thalamic reticular nucleus (nRt) provide major inhibitory innervation of thalamic relay nuclei that is critical to thalamocortical rhythm generation. To investigate the contribution of individual nRt neurons to the strength of this internuclear inhibition, we obtained whole-cell recordings of unitary inhibitory postsynaptic currents (IPSCs) evoked in ventrobasal thalamocortical (VB) neurons by stimulation of single nRt cells in rat thalamic slices, in conjunction with intracellular biocytin labeling. Two types of monosynaptic IPSCs could be distinguished. "Weak" inhibitory connections were characterized by a significant number of postsynaptic failures in response to presynaptic nRt action potentials and relatively small IPSCs. In contrast, "strong" inhibition was characterized by the absence of postsynaptic failures and significantly larger unitary IPSCs. By using miniature IPSC amplitudes to infer quantal size, we estimated that unitary IPSCs associated with weak inhibition resulted from activation of 1-3 release sites, whereas stronger inhibition would require simultaneous activation of 5-70 release sites. The inhibitory strengths were positively correlated with the density of axonal swellings of the presynaptic nRt neurons, an indicator that characterizes different nRt axonal arborization patterns. These results demonstrate that there is a heterogeneity of inhibitory interactions between nRt and VB neurons, and that variations in gross morphological features of axonal arbors in the central nervous system can be associated with significant differences in postsynaptic response characteristics.

Presynaptic DLG regulates synaptic function through the localization of voltage-activated Ca2+ Channels

PubMed Central

Astorga, César; Jorquera, Ramón A.; Ramírez, Mauricio; Kohler, Andrés; López, Estefanía; Delgado, Ricardo; Córdova, Alex; Olguín, Patricio; Sierralta, Jimena

2016-01-01

The DLG-MAGUK subfamily of proteins plays a role on the recycling and clustering of glutamate receptors (GLUR) at the postsynaptic density. discs-large1 (dlg) is the only DLG-MAGUK gene in Drosophila and originates two main products, DLGA and DLGS97 which differ by the presence of an L27 domain. Combining electrophysiology, immunostaining and genetic manipulation at the pre and postsynaptic compartments we study the DLG contribution to the basal synaptic-function at the Drosophila larval neuromuscular junction. Our results reveal a specific function of DLGS97 in the regulation of the size of GLUR fields and their subunit composition. Strikingly the absence of any of DLG proteins at the presynaptic terminal disrupts the clustering and localization of the calcium channel DmCa1A subunit (Cacophony), decreases the action potential-evoked release probability and alters short-term plasticity. Our results show for the first time a crucial role of DLG proteins in the presynaptic function in vivo. PMID:27573697

Presynaptic DLG regulates synaptic function through the localization of voltage-activated Ca(2+) Channels.

PubMed

Astorga, César; Jorquera, Ramón A; Ramírez, Mauricio; Kohler, Andrés; López, Estefanía; Delgado, Ricardo; Córdova, Alex; Olguín, Patricio; Sierralta, Jimena

2016-08-30

The DLG-MAGUK subfamily of proteins plays a role on the recycling and clustering of glutamate receptors (GLUR) at the postsynaptic density. discs-large1 (dlg) is the only DLG-MAGUK gene in Drosophila and originates two main products, DLGA and DLGS97 which differ by the presence of an L27 domain. Combining electrophysiology, immunostaining and genetic manipulation at the pre and postsynaptic compartments we study the DLG contribution to the basal synaptic-function at the Drosophila larval neuromuscular junction. Our results reveal a specific function of DLGS97 in the regulation of the size of GLUR fields and their subunit composition. Strikingly the absence of any of DLG proteins at the presynaptic terminal disrupts the clustering and localization of the calcium channel DmCa1A subunit (Cacophony), decreases the action potential-evoked release probability and alters short-term plasticity. Our results show for the first time a crucial role of DLG proteins in the presynaptic function in vivo.

Kinetics of fast short-term depression are matched to spike train statistics to reduce noise.

PubMed

Khanbabaie, Reza; Nesse, William H; Longtin, Andre; Maler, Leonard

2010-06-01

Short-term depression (STD) is observed at many synapses of the CNS and is important for diverse computations. We have discovered a form of fast STD (FSTD) in the synaptic responses of pyramidal cells evoked by stimulation of their electrosensory afferent fibers (P-units). The dynamics of the FSTD are matched to the mean and variance of natural P-unit discharge. FSTD exhibits switch-like behavior in that it is immediately activated with stimulus intervals near the mean interspike interval (ISI) of P-units (approximately 5 ms) and recovers immediately after stimulation with the slightly longer intervals (>7.5 ms) that also occur during P-unit natural and evoked discharge patterns. Remarkably, the magnitude of evoked excitatory postsynaptic potentials appear to depend only on the duration of the previous ISI. Our theoretical analysis suggests that FSTD can serve as a mechanism for noise reduction. Because the kinetics of depression are as fast as the natural spike statistics, this role is distinct from previously ascribed functional roles of STD in gain modulation, synchrony detection or as a temporal filter.

A novel component of cannabis extract potentiates excitatory synaptic transmission in rat olfactory cortex in vitro.

PubMed

Whalley, Benjamin J; Wilkinson, Jonathan D; Williamson, Elizabeth M; Constanti, Andrew

2004-07-15

Cannabis is a potential treatment for epilepsy, although the few human studies supporting this use have proved inconclusive. Previously, we showed that a standardized cannabis extract (SCE), isolated Delta9-tetrahydrocannabinol (Delta9-THC), and even Delta9-THC-free SCE inhibited muscarinic agonist-induced epileptiform bursting in rat olfactory cortical brain slices, acting via CB1 receptors. The present work demonstrates that although Delta9-THC (1 microM) significantly depressed evoked depolarizing postsynaptic potentials (PSPs) in rat olfactory cortex neurones, both SCE and Delta9-THC-free SCE significantly potentiated evoked PSPs (all results were fully reversed by the CB1 receptor antagonist SR141716A, 1 microM); interestingly, the potentiation by Delta9-THC-free SCE was greater than that produced by SCE. On comparing the effects of Delta9-THC-free SCE upon evoked PSPs and artificial PSPs (aPSPs; evoked electrotonically following brief intracellular current injection), PSPs were enhanced, whereas aPSPs were unaffected, suggesting that the effect was not due to changes in background input resistance. Similar recordings made using CB1 receptor-deficient knockout mice (CB1-/-) and wild-type littermate controls revealed cannabinoid or extract-induced changes in membrane resistance, cell excitability and synaptic transmission in wild-type mice that were similar to those seen in rat neurones, but no effect on these properties were seen in CB1-/- cells. It appears that the unknown extract constituent(s) effects over-rode the suppressive effects of Delta9-THC on excitatory neurotransmitter release, which may explain some patients' preference for herbal cannabis rather than isolated Delta9-THC (due to attenuation of some of the central Delta9-THC side effects) and possibly account for the rare incidence of seizures in some individuals taking cannabis recreationally.

Mechanisms of Kappa Opioid Receptor Potentiation of Dopamine D2 Receptor Function in Quinpirole-Induced Locomotor Sensitization in Rats.

PubMed

Escobar, Angélica P; González, Marcela P; Meza, Rodrigo C; Noches, Verónica; Henny, Pablo; Gysling, Katia; España, Rodrigo A; Fuentealba, José A; Andrés, María E

2017-08-01

Increased locomotor activity in response to the same stimulus is an index of behavioral sensitization observed in preclinical models of drug addiction and compulsive behaviors. Repeated administration of quinpirole, a D2/D3 dopamine agonist, induces locomotor sensitization. This effect is potentiated and accelerated by co-administration of U69593, a kappa opioid receptor agonist. The mechanism underlying kappa opioid receptor potentiation of quinpirole-induced locomotor sensitization remains to be elucidated. Immunofluorescence anatomical studies were undertaken in mice brain slices and rat presynaptic synaptosomes to reveal kappa opioid receptor and D2R pre- and postsynaptic colocalization in the nucleus accumbens. Tonic and phasic dopamine release in the nucleus accumbens of rats repeatedly treated with U69593 and quinpirole was assessed by microdialysis and fast scan cyclic voltammetry. Anatomical data show that kappa opioid receptor and D2R colocalize postsynaptically in medium spiny neurons of the nucleus accumbens and the highest presynaptic colocalization occurs on the same dopamine terminals. Significantly reduced dopamine levels were observed in quinpirole, and U69593-quinpirole treated rats, explaining sensitization of D2R. Presynaptic inhibition induced by kappa opioid receptor and D2R of electrically evoked dopamine release was faster in U69593-quinpirole compared with quinpirole-repeatedly treated rats. Pre- and postsynaptic colocalization of kappa opioid receptor and D2R supports a role for kappa opioid receptor potentiating both the D2R inhibitory autoreceptor function and the inhibitory action of D2R on efferent medium spiny neurons. Kappa opioid receptor co-activation accelerates D2R sensitization by contributing to decrease dopamine release in the nucleus accumbens. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Activation of cannabinoid CB1 receptors modulates evoked action potentials in rat retinal ganglion cells.

PubMed

Jiang, Shu-Xia; Li, Qian; Wang, Xiao-Han; Li, Fang; Wang, Zhong-Feng

2013-08-25

Activation of cannabinoid CB1 receptors (CB1Rs) regulates a variety of physiological functions in the vertebrate retina through modulating various types of ion channels. The aim of the present study was to investigate the effects of this receptor on cell excitability of rat retinal ganglion cells (RGCs) in retinal slices using whole-cell patch-clamp techniques. The results showed that under current-clamped condition perfusing WIN55212-2 (WIN, 5 μmol/L), a CB1R agonist, did not significantly change the spontaneous firing frequency and resting membrane potential of RGCs. In the presence of cocktail synaptic blockers, including excitatory postsynaptic receptor blockers CNQX and D-APV, and inhibitory receptor blockers bicuculline and strychnine, perfusion of WIN (5 μmol/L) hardly changed the frequencies of evoked action potentials by a series of positive current injection (from +10 to +100 pA). Phase-plane plot analysis showed that both average threshold voltage for triggering action potential and delay time to reach threshold voltage were not affected by WIN. However, WIN significantly decreased +dV/dtmax and -dV/dtmax of action potentials, suggestive of reduced rising and descending velocities of action potentials. The effects of WIN were reversed by co-application of SR141716, a CB1R selective antagonist. Moreover, WIN did not influence resting membrane potential of RGCs with synaptic inputs being blocked. These results suggest that activation of CB1Rs may regulate intrinsic excitability of rat RGCs through modulating evoked action potentials.

Heterogeneous chloride homeostasis and GABA responses in the median preoptic nucleus of the rat

PubMed Central

Grob, Magali; Mouginot, Didier

2005-01-01

The median preoptic nucleus (MnPO) is an integrative structure of the hypothalamus receiving periphery-derived information pertinent to hydromineral and cardiovascular homeostasis. In this context, excitability of MnPO neurones is controlled by fast GABAergic, glutamatergic and angiotensinergic projection from the subfornical organ (SFO). Taking advantage of a brain slice preparation preserving synaptic connection between the SFO and the MnPO, and appropriate bicarbonate-free artificial cerebrospinal fluid (CSF), we investigated a possible implication of an active outward Cl− transport in regulating efficacy of the GABAA receptor-mediated inhibitory response at the SFO–MnPO synapse. When somata of the MnPO neurones was loaded with 18 mm chloride, stimulation of the SFO evoked outward inhibitory postsynaptic currents (IPSCs) in 81% of the MnPO neurones held at −60 mV. Accordingly, EIPSC was found 25 mV hyperpolarized from the theoretical value calculated from the Nernst equation, indicating that IPSC polarity and amplitude were driven by an active Cl− extrusion system in these neurones. EIPSC estimated with gramicidin-based perforated-patch recordings amounted −89.2 ± 4.3 mV. Furosemide (100 μm), a pharmacological compound known to block the activity of the neurone-specific K+–Cl− cotransporter, KCC2, reversed IPSC polarity and shifted EIPSC towards its theoretical value. Presence of the KCC2 protein in the MnPO was further detected with immunohistochemistry, revealing a dense network of KCC2-positive intermingled fibres. In the presence of a GABAB receptor antagonist, high-frequency stimulation (5 Hz) of the SFO evoked a train of IPSCs or inhibitory postsynaptic potentials (IPSPs), whose amplitude was maintained throughout the sustained stimulation. Contrastingly, similar 5 Hz stimulation carried out in the presence of furosemide (50 μm) evoked IPSCs/IPSPs, whose amplitude collapsed during the high-frequency stimulation. Similar reduction in inhibitory neurotransmission was also observed in MnPO neurones lacking the functional Cl− extrusion mechanism. We conclude that a majority of MnPO neurones were characterized by a functional Cl− transporter that ensured an efficient activity-dependent Cl− transport rate, allowing sustained synaptic inhibition of these neurones. Pharmacological and anatomical data strongly suggested the involvement of KCC2, as an essential postsynaptic determinant of the inhibitory neurotransmission afferent to the MnPO, a key-structure in the physiology of the hydromineral and cardiovascular homeostasis. PMID:16239278

[Electrophysiological characteristics of hippocampal postnatal early development mediated by AMPA receptors in rats].

PubMed

Chen, Xue-Yi; Zhang, Ai-Feng; Zhao, Wen; Gao, Yu-Dan; Duan, Hong-Mei; Hao, Peng; Yang, Zhao-Yang; Li, Xiao-Guang

2018-04-25

The present study was aimed to investigate the electrophysiological characteristics of hippocampal postnatal early development mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in rats. Forty-eight Wistar rats were divided into postnatal 0.5-, 1-, 2- and 3-month groups (n = 12). Spontaneous excitatory postsynaptic currents (sEPSCs) and field excitatory postsynaptic potentials (fEPSPs) mediated by AMPA receptors were recorded to evaluate the changes in the intrinsic membrane properties of hippocampal CA1 pyramidal neurons by using patch-clamp and MED64 planar microelectrode array technique respectively. The results showed that, during the period of postnatal 0.5-3 months, some of the intrinsic membrane properties of hippocampal CA1 pyramidal neurons, such as the membrane capacitance (Cm) and the resting membrane potential (RMP), showed no significant changes, while the membrane input resistance (Rin) and the time constant (τ) of the cells were decreased significantly. The amplitude, frequency and kinetics (both rise and decay times) of sEPSCs were significantly increased during the period of postnatal 0.5-1 month, but they were all decreased during the period of postnatal 1-3 months. In addition, the range of evoked fEPSPs in hippocamal CA1 region was significantly expanded, but the fEPSP amplitudes were decreased significantly during the period of postnatal 0.5-3 months. Furthermore, the evoked fEPSPs could be significantly inhibited by extracellular application of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These results suggest that AMPA receptor may act as a major type of excitatory receptor to regulate synaptic transmission and connections during the early stage of hippocampal postnatal development, which promotes the development and functional maturation of hippocampus in rats.

Different forms of decision-making involve changes in the synaptic strength of the thalamic, hippocampal, and amygdalar afferents to the medial prefrontal cortex.

PubMed

López-Ramos, Juan Carlos; Guerra-Narbona, Rafael; Delgado-García, José M

2015-01-01

Decision-making and other cognitive processes are assumed to take place in the prefrontal cortex. In particular, the medial prefrontal cortex (mPFC) is identified in rodents by its dense connectivity with the mediodorsal (MD) thalamus, and because of its inputs from other sites, such as hippocampus and amygdala (Amyg). The aim of this study was to find a putative relationship between the behavior of mice during the performance of decision-making tasks that involve penalties as a consequence of induced actions, and the strength of field postsynaptic potentials (fPSPs) evoked in the prefrontal cortex from its thalamic, hippocampal, and amygdalar afferents. Mice were chronically implanted with stimulating electrodes in the MD thalamus, the hippocampal CA1 area, or the basolateral amygdala (BLA), and with recording electrodes in the prelimbic/infralimbic area of the prefrontal cortex. Additional stimulating electrodes aimed at evoking negative reinforcements were implanted on the trigeminal nerve. FPSPs evoked at the mPFC from the three selected projecting areas during the food/shock decision-making task decreased in amplitude with shock intensity and animals' avoidance of the reward. FPSPs collected during the operant task also decreased in amplitude (but that evoked by amygdalar stimulation) when lever presses were associated with a trigeminal shock. Results showed a general decrease in the strength of these potentials when animals inhibited their natural or learned appetitive behaviors, suggesting an inhibition of the prefrontal cortex in these conflicting situations.

Different forms of decision-making involve changes in the synaptic strength of the thalamic, hippocampal, and amygdalar afferents to the medial prefrontal cortex

PubMed Central

López-Ramos, Juan Carlos; Guerra-Narbona, Rafael; Delgado-García, José M.

2015-01-01

Decision-making and other cognitive processes are assumed to take place in the prefrontal cortex. In particular, the medial prefrontal cortex (mPFC) is identified in rodents by its dense connectivity with the mediodorsal (MD) thalamus, and because of its inputs from other sites, such as hippocampus and amygdala (Amyg). The aim of this study was to find a putative relationship between the behavior of mice during the performance of decision-making tasks that involve penalties as a consequence of induced actions, and the strength of field postsynaptic potentials (fPSPs) evoked in the prefrontal cortex from its thalamic, hippocampal, and amygdalar afferents. Mice were chronically implanted with stimulating electrodes in the MD thalamus, the hippocampal CA1 area, or the basolateral amygdala (BLA), and with recording electrodes in the prelimbic/infralimbic area of the prefrontal cortex. Additional stimulating electrodes aimed at evoking negative reinforcements were implanted on the trigeminal nerve. FPSPs evoked at the mPFC from the three selected projecting areas during the food/shock decision-making task decreased in amplitude with shock intensity and animals’ avoidance of the reward. FPSPs collected during the operant task also decreased in amplitude (but that evoked by amygdalar stimulation) when lever presses were associated with a trigeminal shock. Results showed a general decrease in the strength of these potentials when animals inhibited their natural or learned appetitive behaviors, suggesting an inhibition of the prefrontal cortex in these conflicting situations. PMID:25688195

Bidirectional Hebbian Plasticity Induced by Low-Frequency Stimulation in Basal Dendrites of Rat Barrel Cortex Layer 5 Pyramidal Neurons.

PubMed

Díez-García, Andrea; Barros-Zulaica, Natali; Núñez, Ángel; Buño, Washington; Fernández de Sevilla, David

2017-01-01

According to Hebb's original hypothesis (Hebb, 1949), synapses are reinforced when presynaptic activity triggers postsynaptic firing, resulting in long-term potentiation (LTP) of synaptic efficacy. Long-term depression (LTD) is a use-dependent decrease in synaptic strength that is thought to be due to synaptic input causing a weak postsynaptic effect. Although the mechanisms that mediate long-term synaptic plasticity have been investigated for at least three decades not all question have as yet been answered. Therefore, we aimed at determining the mechanisms that generate LTP or LTD with the simplest possible protocol. Low-frequency stimulation of basal dendrite inputs in Layer 5 pyramidal neurons of the rat barrel cortex induces LTP. This stimulation triggered an EPSP, an action potential (AP) burst, and a Ca 2+ spike. The same stimulation induced LTD following manipulations that reduced the Ca 2+ spike and Ca 2+ signal or the AP burst. Low-frequency whisker deflections induced similar bidirectional plasticity of action potential evoked responses in anesthetized rats. These results suggest that both in vitro and in vivo similar mechanisms regulate the balance between LTP and LTD. This simple induction form of bidirectional hebbian plasticity could be present in the natural conditions to regulate the detection, flow, and storage of sensorimotor information.

Bidirectional Hebbian Plasticity Induced by Low-Frequency Stimulation in Basal Dendrites of Rat Barrel Cortex Layer 5 Pyramidal Neurons

PubMed Central

Díez-García, Andrea; Barros-Zulaica, Natali; Núñez, Ángel; Buño, Washington; Fernández de Sevilla, David

2017-01-01

According to Hebb's original hypothesis (Hebb, 1949), synapses are reinforced when presynaptic activity triggers postsynaptic firing, resulting in long-term potentiation (LTP) of synaptic efficacy. Long-term depression (LTD) is a use-dependent decrease in synaptic strength that is thought to be due to synaptic input causing a weak postsynaptic effect. Although the mechanisms that mediate long-term synaptic plasticity have been investigated for at least three decades not all question have as yet been answered. Therefore, we aimed at determining the mechanisms that generate LTP or LTD with the simplest possible protocol. Low-frequency stimulation of basal dendrite inputs in Layer 5 pyramidal neurons of the rat barrel cortex induces LTP. This stimulation triggered an EPSP, an action potential (AP) burst, and a Ca2+ spike. The same stimulation induced LTD following manipulations that reduced the Ca2+ spike and Ca2+ signal or the AP burst. Low-frequency whisker deflections induced similar bidirectional plasticity of action potential evoked responses in anesthetized rats. These results suggest that both in vitro and in vivo similar mechanisms regulate the balance between LTP and LTD. This simple induction form of bidirectional hebbian plasticity could be present in the natural conditions to regulate the detection, flow, and storage of sensorimotor information. PMID:28203145

Fast calcium and voltage-sensitive dye imaging in enteric neurones reveal calcium peaks associated with single action potential discharge.

PubMed

Michel, K; Michaelis, M; Mazzuoli, G; Mueller, K; Vanden Berghe, P; Schemann, M

2011-12-15

Slow changes in [Ca(2+)](i) reflect increased neuronal activity. Our study demonstrates that single-trial fast [Ca(2+)](i) imaging (≥200 Hz sampling rate) revealed peaks each of which are associated with single spike discharge recorded by consecutive voltage-sensitive dye (VSD) imaging in enteric neurones and nerve fibres. Fast [Ca(2+)](i) imaging also revealed subthreshold fast excitatory postsynaptic potentials. Nicotine-evoked [Ca(2+)](i) peaks were reduced by -conotoxin and blocked by ruthenium red or tetrodotoxin. Fast [Ca(2+)](i) imaging can be used to directly record single action potentials in enteric neurones. [Ca(2+)](i) peaks required opening of voltage-gated sodium and calcium channels as well as Ca(2+) release from intracellular stores.

Attention Enhances Synaptic Efficacy and Signal-to-Noise in Neural Circuits

PubMed Central

Briggs, Farran; Mangun, George R.; Usrey, W. Martin

2013-01-01

Summary Attention is a critical component of perception. However, the mechanisms by which attention modulates neuronal communication to guide behavior are poorly understood. To elucidate the synaptic mechanisms of attention, we developed a sensitive assay of attentional modulation of neuronal communication. In alert monkeys performing a visual spatial attention task, we probed thalamocortical communication by electrically stimulating neurons in the lateral geniculate nucleus of the thalamus while simultaneously recording shock-evoked responses from monosynaptically connected neurons in primary visual cortex. We found that attention enhances neuronal communication by (1) increasing the efficacy of presynaptic input in driving postsynaptic responses, (2) increasing synchronous responses among ensembles of postsynaptic neurons receiving independent input, and (3) decreasing redundant signals between postsynaptic neurons receiving common input. These results demonstrate that attention finely tunes neuronal communication at the synaptic level by selectively altering synaptic weights, enabling enhanced detection of salient events in the noisy sensory milieu. PMID:23803766

The quantal release at a neuro-neuronal synapse is regulated by the content of acetylcholine in the presynaptic cell.

PubMed

Poulain, B; Baux, G; Tauc, L

1986-01-01

Transmitter release was studied with respect to the presynaptic acetylcholine (ACh) content at a central identified inhibitory synapse (Cl- conductance) of Aplysia californica. Statistical analysis of the synaptic noise evoked by sustained depolarization of the presynaptic neuron allowed us to calculate the quantal parameters of the postsynaptic responses. Loading of the presynaptic neurone with injected ACh led to an increase in the postsynaptic responses whereas the calculated miniature postsynaptic current (MPSC) was unmodified. Destruction of choline by choline oxidase either applied extracellularly and coupled to intense stimulations of the presynaptic cell or injected into the presynaptic neuron induced a depression of the postsynaptic response although the amplitude of the calculated MPSC remained constant. As the size of the MPSC, i.e. the size of the quantum, did not change in these experiments, it was concluded that the presynaptic ACh content controls the number of quanta released by a given presynaptic depolarization. As additional evidence, effects of abrupt increase in tonicity of the external medium were studied. The observed transient enhancement of the quantal content of the postsynaptic response could be attributed to an increase in the presynaptic concentration of ACh, resulting from the reduction in cellular volume.

Reversal of Cocaine-Associated Synaptic Plasticity in Medial Prefrontal Cortex Parallels Elimination of Memory Retrieval.

PubMed

Otis, James M; Mueller, Devin

2017-09-01

Addiction is characterized by abnormalities in prefrontal cortex that are thought to allow drug-associated cues to drive compulsive drug seeking and taking. Identification and reversal of these pathologic neuroadaptations are therefore critical for treatment of addiction. Previous studies using rodents reveal that drugs of abuse cause dendritic spine plasticity in prelimbic medial prefrontal cortex (PL-mPFC) pyramidal neurons, a phenomenon that correlates with the strength of drug-associated memories in vivo. Thus, we hypothesized that cocaine-evoked plasticity in PL-mPFC may underlie cocaine-associated memory retrieval, and therefore disruption of this plasticity would prevent retrieval. Indeed, using patch clamp electrophysiology we find that cocaine place conditioning increases excitatory presynaptic and postsynaptic transmission in rat PL-mPFC pyramidal neurons. This was accounted for by increases in excitatory presynaptic release, paired-pulse facilitation, and increased AMPA receptor transmission. Noradrenergic signaling is known to maintain glutamatergic plasticity upon reactivation of modified circuits, and we therefore next determined whether inhibition of noradrenergic signaling during memory reactivation would reverse the cocaine-evoked plasticity and/or disrupt the cocaine-associated memory. We find that administration of the β-adrenergic receptor antagonist propranolol before memory retrieval, but not after (during memory reconsolidation), reverses the cocaine-evoked presynaptic and postsynaptic modifications in PL-mPFC and causes long-lasting memory impairments. Taken together, these data reveal that cocaine-evoked synaptic plasticity in PL-mPFC is reversible in vivo, and suggest a novel strategy that would allow normalization of prefrontal circuitry in addiction.

Calcium permeable AMPA receptors and autoreceptors in external tufted cells of rat olfactory bulb

PubMed Central

Ma, Jie; Lowe, Graeme

2007-01-01

Glomeruli are functional units of the olfactory bulb responsible for early processing of odor information encoded by single olfactory receptor genes. Glomerular neural circuitry includes numerous external tufted (ET) cells whose rhythmic burst firing may mediate synchronization of bulbar activity with the inhalation cycle. Bursting is entrained by glutamatergic input from olfactory nerve terminals, so specific properties of ionotropic glutamate receptors on ET cells are likely to be important determinants of olfactory processing. Particularly intriguing is recent evidence that α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors of juxta-glomerular neurons may permeate calcium. This could provide a novel pathway for regulating ET cell signaling. We tested the hypothesis that ET cells express functional calcium-permeable AMPA receptors. In rat olfactory bulb slices, excitatory postsynaptic currents (EPSCs) in ET cells were evoked by olfactory nerve shock, and by uncaging glutamate. We found attenuation of AMPA/kainate EPSCs by 1-naphthyl acetyl-spermine (NAS), an open-channel blocker specific for calcium permeable AMPA receptors. Cyclothiazide strongly potentiated EPSCs, indicating a major contribution from AMPA receptors. The current-voltage (I-V) relation of uncaging EPSCs showed weak inward rectification which was lost after > ~ 10 min of whole-cell dialysis, and was absent in NAS. In kainate-stimulated slices, Co2+ ions permeated cells of the glomerular layer. Large AMPA EPSCs were accompanied by fluorescence signals in fluo-4 loaded cells, suggesting calcium permeation. Depolarizing pulses evoked slow tail currents with pharmacology consistent with involvement of calcium permeable AMPA autoreceptors. Tail currents were abolished by Cd2+ and NBQX, and were sensitive to NAS block. Glutamate autoreceptors were confirmed by uncaging intracellular calcium to evoke a large inward current. Our results provide evidence that calcium permeable AMPA receptors reside on ET cells, and are divided into at least two functionally distinct pools – postsynaptic receptors at olfactory nerve synaptic terminals, and autoreceptors sensitive to glutamate released from dendrodendritic synapses. PMID:17156930

MT-7716, a novel selective nonpeptidergic NOP receptor agonist, effectively blocks ethanol-induced increase in GABAergic transmission in the rat central amygdala

PubMed Central

Kallupi, Marsida; Oleata, Christopher S.; Luu, George; Teshima, Koji; Ciccocioppo, Roberto; Roberto, Marisa

2014-01-01

The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. A large body of evidence shows that Nociceptin/Orphanin FQ (N/OFQ) regulates ethanol intake and anxiety-like behavior. In the rat, ethanol significantly augments CeA GABA release, whereas N/OFQ diminishes it. Using electrophysiological techniques in an in vitro slice preparation, in this study we investigated the effects of a nonpeptidergic NOP receptor agonist, MT-7716 [(R)-2-3-[1-(Acenaphthen-1-yl)piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl-N-methylacetamide hydrochloride hydrate], and its interaction with ethanol on GABAergic transmission in CeA slices of naïve rats. We found that MT-7716 dose-dependently (100–1000 nM) diminished evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) and increased paired-pulse facilitation (PPF) ratio of these evoked IPSPs, suggesting a presynaptic site of action of the MT-7716 by decreasing GABA release at CeA synapses. The presynaptic action of MT-7716 was also supported by the significant decrease in the frequency of miniature inhibitory postsynaptic currents (mIPSCs) induced by the nociceptin receptor (NOP) agonist. Interestingly, MT-7716 prevented the ethanol-induced augmentation of evoked IPSPs. A putative selective NOP antagonist, [Nphe1]Nociceptin(1–13)NH2, totally prevented the MT-7716-induced inhibition of IPSP amplitudes indicating that MT-7716 exerts its effect through NOPs. These data provide support for an interaction between the nociceptin and GABAergic systems in the CeA and for the anti-alcohol properties of the NOP activation. The development of a synthetic nonpeptidergic NOP receptor agonist such as MT-7716 may represent a useful therapeutic target for alcoholism. PMID:24600360

Transfer characteristics of the hair cell's afferent synapse

NASA Astrophysics Data System (ADS)

Keen, Erica C.; Hudspeth, A. J.

2006-04-01

The sense of hearing depends on fast, finely graded neurotransmission at the ribbon synapses connecting hair cells to afferent nerve fibers. The processing that occurs at this first chemical synapse in the auditory pathway determines the quality and extent of the information conveyed to the central nervous system. Knowledge of the synapse's input-output function is therefore essential for understanding how auditory stimuli are encoded. To investigate the transfer function at the hair cell's synapse, we developed a preparation of the bullfrog's amphibian papilla. In the portion of this receptor organ representing stimuli of 400-800 Hz, each afferent nerve fiber forms several synaptic terminals onto one to three hair cells. By performing simultaneous voltage-clamp recordings from presynaptic hair cells and postsynaptic afferent fibers, we established that the rate of evoked vesicle release, as determined from the average postsynaptic current, depends linearly on the amplitude of the presynaptic Ca2+ current. This result implies that, for receptor potentials in the physiological range, the hair cell's synapse transmits information with high fidelity. auditory system | exocytosis | glutamate | ribbon synapse | synaptic vesicle

Optical responses evoked by white matter stimulation in rat visual cortical slices and their relation to neural activities.

PubMed

Tanifuji, M; Yamanaka, A; Sunaba, R; Terakawa, S; Toyama, K

1996-10-28

To characterize optical responses (ORs) evoked by white matter (WM) stimulation in slices of rat visual cortex (VC) stained with voltage sensitive dyes, time course of ORs in each layer was investigated by recording ORs with a linearly aligned photodiode array, and the spatial patterns of the ORs at specified time after stimulation were investigated by a CCD camera in combination with stroboscopic illumination. The ORs recorded by the photodiode array were an increase in absorption at 700 nm and a decrease in the wavelength below 650 nm, suggesting that the ORs were dye related. The ORs were compared with field potentials (FPs) to clarify that neural events were represented by the ORs, and in support of this view, we found that the first order spatial differentials of ORs and that of FPs were in good agreement. We further compared ORs with intracellular responses, and found that the ORs mainly represent postsynaptic potentials (PSPs) of VC neurons except for the deeper part of layer VI, where a component representing action potentials in fibers stimulated directly was observed. The time-lapse imaging of ORs showed that excitation first propagated vertically up to layer I and subsequently in the horizontal direction along layers II-III and V-VI as in previous investigations. Spatio-temporal patterns of ORs under blockade of synaptic transmission were also investigated to reveal activity of fibers evoked by WM stimulation which produced such patterns of propagation.

Nitric oxide-related species inhibit evoked neurotransmission but enhance spontaneous miniature synaptic currents in central neuronal cultures.

PubMed

Pan, Z H; Segal, M M; Lipton, S A

1996-12-24

Nitric oxide (NO.) does not react significantly with thiol groups under physiological conditions, whereas a variety of endogenous NO donor molecules facilitate rapid transfer to thiol of nitrosonium ion (NO+, with one less electron than NO.). Here, nitrosonium donors are shown to decrease the efficacy of evoked neurotransmission while increasing the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs). In contrast, pure NO donors have little effect (displaying at most only a slight increase) on the amplitude of evoked EPSCs and frequency of spontaneous mEPSCs in our preparations. These findings may help explain heretofore paradoxical observations that the NO moiety can either increase, decrease, or have no net effect on synaptic activity in various preparations.

An experimental model for the study of cognitive disorders: the hippocampus and associative learning in mice.

PubMed

Delgado-García, José M; Gruart, Agnès

2008-12-01

The availability of transgenic mice mimicking selective human neurodegenerative and psychiatric disorders calls for new electrophysiological and microstimulation techniques capable of being applied in vivo in this species. In this article, we will concentrate on experiments and techniques developed in our laboratory during the past few years. Thus we have developed different techniques for the study of learning and memory capabilities of wild-type and transgenic mice with deficits in cognitive functions, using classical conditioning procedures. These techniques include different trace (tone/SHOCK and shock/SHOCK) conditioning procedures ? that is, a classical conditioning task involving the cerebral cortex, including the hippocampus. We have also developed implantation and recording techniques for evoking long-term potentiation (LTP) in behaving mice and for recording the evolution of field excitatory postsynaptic potentials (fEPSP) evoked in the hippocampal CA1 area by the electrical stimulation of the commissural/Schaffer collateral pathway across conditioning sessions. Computer programs have also been developed to quantify the appearance and evolution of eyelid conditioned responses and the slope of evoked fEPSPs. According to the present results, the in vivo recording of the electrical activity of selected hippocampal sites during classical conditioning of eyelid responses appears to be a suitable experimental procedure for studying learning capabilities in genetically modified mice, and an excellent model for the study of selected neuropsychiatric disorders compromising cerebral cortex functioning.

Characterization of auditory synaptic inputs to gerbil perirhinal cortex

PubMed Central

Kotak, Vibhakar C.; Mowery, Todd M.; Sanes, Dan H.

2015-01-01

The representation of acoustic cues involves regions downstream from the auditory cortex (ACx). One such area, the perirhinal cortex (PRh), processes sensory signals containing mnemonic information. Therefore, our goal was to assess whether PRh receives auditory inputs from the auditory thalamus (MG) and ACx in an auditory thalamocortical brain slice preparation and characterize these afferent-driven synaptic properties. When the MG or ACx was electrically stimulated, synaptic responses were recorded from the PRh neurons. Blockade of type A gamma-aminobutyric acid (GABA-A) receptors dramatically increased the amplitude of evoked excitatory potentials. Stimulation of the MG or ACx also evoked calcium transients in most PRh neurons. Separately, when fluoro ruby was injected in ACx in vivo, anterogradely labeled axons and terminals were observed in the PRh. Collectively, these data show that the PRh integrates auditory information from the MG and ACx and that auditory driven inhibition dominates the postsynaptic responses in a non-sensory cortical region downstream from the ACx. PMID:26321918

Brain-derived neurotrophic factor blocks long-term depression in solitary neurones cultured from rat visual cortex

PubMed Central

Kumura, Eiji; Kimura, Fumitaka; Taniguchi, Nobuaki; Tsumoto, Tadaharu

2000-01-01

To address questions of whether long-term depression (LTD) in the visual cortex is expressed in pre- or postsynaptic sites, whether brain-derived neurotrophic factor (BDNF) exerts its LTD-blocking action without involvement of GABAergic inhibition, and whether the action of BDNF is pre- or postsynaptic, we observed excitatory postsynaptic currents (EPSCs) from solitary neurones cultured on glial microislands. In this preparation GABAergic inhibition is not involved and a group of synapses (autapses) which generate evoked EPSCs is thought to be the same as those generating spontaneous EPSCs. A short depolarising voltage step to the soma generated Na+ spikes which were followed by autaptic EPSCs. When this somatic activation was paired with prolonged depolarisation for 100 ms to −30 mV and repeated at 1 Hz for 5 min, LTD was induced in all of the nine cells tested. Then, the frequency of spontaneous EPSCs decreased, but the amplitude did not change, suggesting that the site of LTD expression is presynaptic. Application of BDNF at 50 ng ml−1 blocked the depression of evoked EPSCs and the decrease in the frequency of spontaneous EPSCs. An inhibitor for receptor tyrosine kinases, K252a, antagonised the action of BDNF, suggesting an involvement of BDNF receptors, TrkB. These results suggest that BDNF prevents low-frequency inputs from inducing LTD of excitatory synaptic transmission through presynaptic mechanisms in the developing visual cortex. PMID:10747192

Optogenetic identification of hypothalamic orexin neuron projections to paraventricular spinally projecting neurons.

PubMed

Dergacheva, Olga; Yamanaka, Akihiro; Schwartz, Alan R; Polotsky, Vsevolod Y; Mendelowitz, David

2017-04-01

Orexin neurons, and activation of orexin receptors, are generally thought to be sympathoexcitatory; however, the functional connectivity between orexin neurons and a likely sympathetic target, the hypothalamic spinally projecting neurons (SPNs) in the paraventricular nucleus of the hypothalamus (PVN) has not been established. To test the hypothesis that orexin neurons project directly to SPNs in the PVN, channelrhodopsin-2 (ChR2) was selectively expressed in orexin neurons to enable photoactivation of ChR2-expressing fibers while examining evoked postsynaptic currents in SPNs in rat hypothalamic slices. Selective photoactivation of orexin fibers elicited short-latency postsynaptic currents in all SPNs tested ( n = 34). These light-triggered responses were heterogeneous, with a majority being excitatory glutamatergic responses (59%) and a minority of inhibitory GABAergic (35%) and mixed glutamatergic and GABAergic currents (6%). Both glutamatergic and GABAergic responses were present in the presence of tetrodotoxin and 4-aminopyridine, suggesting a monosynaptic connection between orexin neurons and SPNs. In addition to generating postsynaptic responses, photostimulation facilitated action potential firing in SPNs (current clamp configuration). Glutamatergic, but not GABAergic, postsynaptic currents were diminished by application of the orexin receptor antagonist almorexant, indicating orexin release facilitates glutamatergic neurotransmission in this pathway. This work identifies a neuronal circuit by which orexin neurons likely exert sympathoexcitatory control of cardiovascular function. NEW & NOTEWORTHY This is the first study to establish, using innovative optogenetic approaches in a transgenic rat model, that there are robust heterogeneous projections from orexin neurons to paraventricular spinally projecting neurons, including excitatory glutamatergic and inhibitory GABAergic neurotransmission. Endogenous orexin release modulates glutamatergic, but not GABAergic, neurotransmission in these pathways. Copyright © 2017 the American Physiological Society.

CHRONIC HYPERTENSION ENHANCES PRE-SYNAPTIC INHIBITION BY BACLOFEN IN THE NUCLEUS OF THE SOLITARY TRACT

PubMed Central

Zhang, Weirong; Mifflin, Steve

2010-01-01

The selective γ-aminobutyric acid B-subtype receptor agonist baclofen activates both pre- and post-synaptic receptors in the brain. Microinjection of baclofen into the nucleus of the solitary tract increases arterial pressure, heart rate and sympathetic nerve discharge consistent with inhibition of the arterial baroreflex. The magnitude of these responses is enhanced in hypertension and is associated with increased post-synaptic GABAB receptor function. We tested whether a pre-synaptic mechanism contributes to the enhanced baclofen inhibition in hypertension. Whole-cell recordings of second-order baroreceptor neurons, identified by 4-(4-(dihexadecylamino)styryl)-N-methylpyridinium iodide labeling of aortic nerve, were obtained in brainstem slices from normotensive control and renal-wrap hypertensive rats. After 4 weeks, arterial blood pressure was 162±9 mmHg in hypertensive (n=6) and 107±3 mmHg in control rats (n=6/11, p<0.001). Baclofen reduced the amplitude of excitatory post-synaptic currents evoked by solitary tract stimulation and the EC50 of this inhibition was greater in control (1.5±0.5 µmol/L, n=6) than hypertensive cells (0.6±0.1 µmol/L, n=9, p<0.05). Baclofen (1 µmol/L) elicited greater inhibition on evoked response in hypertensive (58±6%, n=9) than control cells (40±6%, n=8, p<0.05). Another index of pre-synaptic inhibition, the paired-pulse ratio (ratio of second to first evoked response amplitudes at stimulus intervals of 40 ms), was greater in hypertensive (0.60±0.08, n=8) than control cells (0.48±0.06. n=5, p<0.05). The results suggest that in renal-wrap hypertensive rats, baclofen causes an enhanced pre-synaptic inhibition of glutamate release from baroreceptor afferent terminals to second-order neurons in the nucleus of the solitary tract. This enhanced pre-synaptic inhibition could contribute to altered baroreflex function in hypertension. PMID:20038748

D-amphetamine (A)-induced dopamine (DA) release is not strictly dependent on newly-synthesized transmitter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parker, E.; Cubeddu, L.

1986-03-05

A is thought to exert its stimulant effects by releasing DA from a newly synthesized transmitter pool. This hypothesis was evaluated directly by measuring the basal efflux and electrically-evoked release of endogenous DA and dihydroxyphenylacetic acid (DOPAC). In striatal slices from reserpine-treated rabbits A increased DA efflux, reduced DOPAC efflux, and inhibited electrically-evoked /sup 3/H-ACh release in a concentration-dependent manner. These effects could not be mimicked by inhibition of neuronal uptake or MAO, but were blocked by inhibition of DA synthesis or neuronal uptake, and were potentiated by inhibition of MAO. In slices with intact vesicular transmitter stores A inducedmore » DA efflux was 2-fold greater than that seen in slices having no vesicular stores. Inhibition of DA synthesis reduced A-induced DA efflux by 60%, but had little effect on the ability of A to inhibit /sup 3/H-ACh release. A also increased the electrical stimulation-evoked overflow of DA (an effect which was attenuated slightly by synthesis inhibition), and potently inhibited DOPAC overflow. These results suggest that: 1) A facilitates efflux of axoplasmic DA by an accelerated exchange diffusion mechanism. The releasable axoplasmic pool is derived from newly synthesized and vesicular transmitter pools; 2) postsynaptic indices of transmitter release may be misleading; and 3) A increases electrically-evoked DA release possibly by inhibiting neuronal uptake.« less

Equilibrium potential for the postsynaptic response in the squid giant synapse.

PubMed

Llinás, R; Joyner, R W; Nicholson, C

1974-11-01

The reversal potential for the EPSP in the squid giant synapse has been studied by means of an intracellular, double oil gap technique. This method allows the electrical isolation of a portion of the axon from the rest of the fiber and generates a quasi-isopotential segment. In order to make the input resistance of this nerve segment as constant as possible, the electroresponsive properties of the nerve membrane were blocked by intracellular injection of tetraethylammonium (TEA) and local extracellular application of tetrodotoxin (TTX). Thus, EPSP's could be evoked in the isolated segment with a minimal amount of electroresponsive properties. The reversal potential for the EPSP (EEPSP) was measured by recording the synaptic potential or the synaptic current during voltage clamping. The results indicate that EEPSP may vary from +15 to +25 mV, which is more positive than would be expected for a 1:1 conductance change for Na(+) and K(+) (approximately -15 mV) and too negative for a pure Na(+) conductance ((+)40 mV). This latter value (E(Na)) was directly determined in the voltage clamp experiments. The results suggest that the synaptic potential is probably produced by a permeability change to Na(+) to K(+) in a 4:1 ratio. No change in time-course was observed in the synaptic current at clamp levels of -100 and +90 mV. The implications of a variable ratio for Na(+)-K(+) permeability in subsynaptic-postsynaptic membranes are discussed.

Acute suppression of spontaneous neurotransmission drives synaptic potentiation.

PubMed

Nosyreva, Elena; Szabla, Kristen; Autry, Anita E; Ryazanov, Alexey G; Monteggia, Lisa M; Kavalali, Ege T

2013-04-17

The impact of spontaneous neurotransmission on neuronal plasticity remains poorly understood. Here, we show that acute suppression of spontaneous NMDA receptor-mediated (NMDAR-mediated) neurotransmission potentiates synaptic responses in the CA1 regions of rat and mouse hippocampus. This potentiation requires protein synthesis, brain-derived neurotrophic factor expression, eukaryotic elongation factor-2 kinase function, and increased surface expression of AMPA receptors. Our behavioral studies link this same synaptic signaling pathway to the fast-acting antidepressant responses elicited by ketamine. We also show that selective neurotransmitter depletion from spontaneously recycling vesicles triggers synaptic potentiation via the same pathway as NMDAR blockade, demonstrating that presynaptic impairment of spontaneous release, without manipulation of evoked neurotransmission, is sufficient to elicit postsynaptic plasticity. These findings uncover an unexpectedly dynamic impact of spontaneous glutamate release on synaptic efficacy and provide new insight into a key synaptic substrate for rapid antidepressant action.

Accumulation of K+ in the synaptic cleft modulates activity by influencing both vestibular hair cell and calyx afferent in the turtle

PubMed Central

Contini, Donatella; Price, Steven D.

2016-01-01

Key points In the synaptic cleft between type I hair cells and calyceal afferents, K+ ions accumulate as a function of activity, dynamically altering the driving force and permeation through ion channels facing the synaptic cleft.High‐fidelity synaptic transmission is possible due to large conductances that minimize hair cell and afferent time constants in the presence of significant membrane capacitance.Elevated potassium maintains hair cells near a potential where transduction currents are sufficient to depolarize them to voltages necessary for calcium influx and synaptic vesicle fusion.Elevated potassium depolarizes the postsynaptic afferent by altering ion permeation through hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels, and contributes to depolarizing the afferent to potentials where a single EPSP (quantum) can generate an action potential.With increased stimulation, hair cell depolarization increases the frequency of quanta released, elevates [K+]cleft and depolarizes the afferent to potentials at which smaller and smaller EPSPs would be sufficient to trigger APs. Abstract Fast neurotransmitters act in conjunction with slower modulatory effectors that accumulate in restricted synaptic spaces found at giant synapses such as the calyceal endings in the auditory and vestibular systems. Here, we used dual patch‐clamp recordings from turtle vestibular hair cells and their afferent neurons to show that potassium ions accumulating in the synaptic cleft modulated membrane potentials and extended the range of information transfer. High‐fidelity synaptic transmission was possible due to large conductances that minimized hair cell and afferent time constants in the presence of significant membrane capacitance. Increased potassium concentration in the cleft maintained the hair cell near potentials that promoted the influx of calcium necessary for synaptic vesicle fusion. The elevated potassium concentration also depolarized the postsynaptic neuron by altering ion permeation through hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels. This depolarization enabled the afferent to reliably generate action potentials evoked by single AMPA‐dependent EPSPs. Depolarization of the postsynaptic afferent could also elevate potassium in the synaptic cleft, and would depolarize other hair cells enveloped by the same neuritic process increasing the fidelity of neurotransmission at those synapses as well. Collectively, these data demonstrate that neuronal activity gives rise to potassium accumulation, and suggest that potassium ion action on HCN channels can modulate neurotransmission, preserving the fidelity of high‐speed synaptic transmission by dynamically shifting the resting potentials of both presynaptic and postsynaptic cells. PMID:27633787

Squids in the Study of Cerebral Magnetic Field

NASA Astrophysics Data System (ADS)

Romani, G. L.; Narici, L.

The following sections are included: * INTRODUCTION * HISTORICAL OVERVIEW * NEUROMAGNETIC FIELDS AND AMBIENT NOISE * DETECTORS * Room temperature sensors * SQUIDs * DETECTION COILS * Magnetometers * Gradiometers * Balancing * Planar gradiometers * Choice of the gradiometer parameters * MODELING * Current pattern due to neural excitations * Action potentials and postsynaptic currents * The current dipole model * Neural population and detected fields * Spherically bounded medium * SPATIAL CONFIGURATION OF THE SENSORS * SOURCE LOCALIZATION * Localization procedure * Experimental accuracy and reproducibility * SIGNAL PROCESSING * Analog Filtering * Bandpass filters * Line rejection filters * DATA ANALYSIS * Analysis of evoked/event-related responses * Simple average * Selected average * Recursive techniques * Similarity analysis * Analysis of spontaneous activity * Mapping and localization * EXAMPLES OF NEUROMAGNETIC STUDIES * Neuromagnetic measurements * Studies on the normal brain * Clinical applications * Epilepsy * Tinnitus * CONCLUSIONS * ACKNOWLEDGEMENTS * REFERENCES

Synaptic depolarization is more effective than back-propagating action potentials during induction of associative long-term potentiation in hippocampal pyramidal neurons.

PubMed

Hardie, Jason; Spruston, Nelson

2009-03-11

Long-term potentiation (LTP) requires postsynaptic depolarization that can result from EPSPs paired with action potentials or larger EPSPs that trigger dendritic spikes. We explored the relative contribution of these sources of depolarization to LTP induction during synaptically driven action potential firing in hippocampal CA1 pyramidal neurons. Pairing of a weak test input with a strong input resulted in large LTP (approximately 75% increase) when the weak and strong inputs were both located in the apical dendrites. This form of LTP did not require somatic action potentials. When the strong input was located in the basal dendrites, the resulting LTP was smaller (< or =25% increase). Pairing the test input with somatically evoked action potentials mimicked this form of LTP. Thus, back-propagating action potentials may contribute to modest LTP, but local synaptic depolarization and/or dendritic spikes mediate a stronger form of LTP that requires spatial proximity of the associated synaptic inputs.

Subunit-dependent postsynaptic expression of kainate receptors on hippocampal interneurons in area CA1

PubMed Central

Wondolowski, Joyce; Frerking, Matthew

2009-01-01

Kainate receptors (KARs) contribute to postsynaptic excitation in only a select subset of neurons. To define the parameters that specify the postsynaptic expression of KARs, we examined the contribution of KARs to EPSCs on hippocampal interneurons in area CA1. Interneurons in stratum radiatum/lacunosum-moleculare (SR/SLM) express KARs both with and without the GluR5 subunit, but KAR-mediated EPSCs are generated mainly, if not entirely, by GluR5-containing KARs. Extrasynaptic glutamate spillover profoundly recruits AMPARs with little effect on KARs, indicating that KARs are targeted at the synapse more precisely than AMPARs. However, spontaneous EPSCs with a conventional AMPAR component did not have a resolvable contribution of KARs, suggesting that the KARs that contribute to the evoked EPSCs are at a distinct set of synapses. GluR5-containing KARs on interneurons in stratum oriens do not contribute substantially to the EPSC. We conclude that KARs are localized to synapses by cell type-, synapse-, and subunit-selective mechanisms. PMID:19144856

Coincident postsynaptic activity gates presynaptic dopamine release to induce plasticity in Drosophila mushroom bodies

PubMed Central

Ueno, Kohei; Suzuki, Ema; Naganos, Shintaro; Ofusa, Kyoko; Horiuchi, Junjiro; Saitoe, Minoru

2017-01-01

Simultaneous stimulation of the antennal lobes (ALs) and the ascending fibers of the ventral nerve cord (AFV), two sensory inputs to the mushroom bodies (MBs), induces long-term enhancement (LTE) of subsequent AL-evoked MB responses. LTE induction requires activation of at least three signaling pathways to the MBs, mediated by nicotinic acetylcholine receptors (nAChRs), NMDA receptors (NRs), and D1 dopamine receptors (D1Rs). Here, we demonstrate that inputs from the AL are transmitted to the MBs through nAChRs, and inputs from the AFV are transmitted by NRs. Dopamine signaling occurs downstream of both nAChR and NR activation, and requires simultaneous stimulation of both pathways. Dopamine release requires the activity of the rutabaga adenylyl cyclase in postsynaptic MB neurons, and release is restricted to MB neurons that receive coincident stimulation. Our results indicate that postsynaptic activity can gate presynaptic dopamine release to regulate plasticity. DOI: http://dx.doi.org/10.7554/eLife.21076.001 PMID:28117664

Dual actions of lysergic acid diethylamide tartrate (LSD), 2-bromo-D-lysergic acid diethylamide bitartrate (BOL) and methysergide on dorsal root potentials evoked by stimulation of raphe nuclei.

PubMed

Larson, A A; Chinn, C; Proudfit, H K; Anderson, E G

1981-04-01

A variety of drugs reported to antagonize serotonin were found to affect spinal cord potentials evoked by electrical stimulation of the caudal raphe nuclei of the cat. These brain stem-evoked dorsal root potentials (DRPs) consisted of a short latency depolarization (DRP-1), which was evoked by stimulation of a wide variety of sites in the medial brain stem and a long latency potential (DRP-2), which was elicited only when stimuli were applied near the raphe. The ability of serotonergic antagonists to increase or decrease these DRPs was dependent on the dose of the drug administered. High doses of lysergic acid diethylamide tartrate (LSD), 2-bromo-D-lysergic acid diethylamide bitartrate (BOL), methysergide and cinanserin each produced an immediate inhibition of DRP-2 and a simultaneous enhancement of DRP-1, both of which recovered by approximately 30 min. Each of the drugs produced a dose-related inhibition of DRP-2 at high doses, with LSD being the most potent and cinanserin the least potent. In contrast, low doses of LSD, BOL and methysergide elicited little or no immediate change in either DRP-2 or DRP-1, but produced an enhancement of DRP-2 which developed slowly over a period of 60 to 90 min. This increase in DRP-2 was most dramatic after administration of LSD and was not accompanied by changes in DRP-1. The inhibition of DRP-2 by high doses of LSD, BOL, methysergide and cinanserin may result primarily from inhibition of postsynaptic serotonergic receptors located on the primary afferent terminals. The increase in DRP-2 produced by low doses of LSD, BOL and methysergide is postulated to result from an interaction with receptors distinct from those which produced the inhibition of DRP-2 at higher doses.

Presynaptic membrane potential affects transmitter release in an identified neuron in Aplysia by modulating the Ca2+ and K+ currents.

PubMed

Shapiro, E; Castellucci, V F; Kandel, E R

1980-01-01

We have examined the relationships between the modulation of transmitter release and of specific ionic currents by membrane potential in the cholinergic interneuron L10 of the abdominal ganglion of Aplysia californica. The presynaptic cell body was voltage-clamped under various pharmacological conditions and transmitter release from the terminals was assayed simultaneously by recording the synaptic potentials in the postsynaptic cell. When cell L10 was voltage-clamped from a holding potential of -60 mV in the presence of tetrodotoxin, graded transmitter release was evoked by depolarizing command pulses in the membrane voltage range (-35 mV to + 10 mV) in which the Ca(2+) current was also increasing. Depolarizing the holding potential of L10 results in increased transmitter output. Two ionic mechanisms contribute to this form of plasticity. First, depolarization inactivates some K(+) channels so that depolarizing command pulses recruit a smaller K(+) current. In unclamped cells the decreased K(+) conductance causes spike-broadening and increased influx of Ca(2+) during each spike. Second, small depolarizations around resting potential (-55 mV to -35 mV) activate a steady-state Ca(2+) current that also contributes to the modulation of transmitter release, because, even with most presynaptic K(+) currents blocked pharmacologically, depolarizing the holding potential still increases transmitter release. In contrast to the steady-state Ca(2+) current, the transient inward Ca(2+) current evoked by depolarizing clamp steps is relatively unchanged from various holding potentials.

New Treatments for Drug-Resistant Epilepsy that Target Presynaptic Transmitter Release

DTIC Science & Technology

2013-05-01

induced status epilepticus persistently increases size, vesicular release rate and endocytosis of mossy fiber boutons in SpH-expressing mice Size... status epilepticus rats We also examined the effects of LEV on miniature excitatory postsynaptic currents (mEPSCs) evoked by spontaneous release...Pilocarpine vs. lithium-pilocarpine for induction of status epilepticus in mice: development of spontaneous seizures, behavioral alterations and

Sensory-evoked LTP driven by dendritic plateau potentials in vivo.

PubMed

Gambino, Frédéric; Pagès, Stéphane; Kehayas, Vassilis; Baptista, Daniela; Tatti, Roberta; Carleton, Alan; Holtmaat, Anthony

2014-11-06

Long-term synaptic potentiation (LTP) is thought to be a key process in cortical synaptic network plasticity and memory formation. Hebbian forms of LTP depend on strong postsynaptic depolarization, which in many models is generated by action potentials that propagate back from the soma into dendrites. However, local dendritic depolarization has been shown to mediate these forms of LTP as well. As pyramidal cells in supragranular layers of the somatosensory cortex spike infrequently, it is unclear which of the two mechanisms prevails for those cells in vivo. Using whole-cell recordings in the mouse somatosensory cortex in vivo, we demonstrate that rhythmic sensory whisker stimulation efficiently induces synaptic LTP in layer 2/3 (L2/3) pyramidal cells in the absence of somatic spikes. The induction of LTP depended on the occurrence of NMDAR (N-methyl-d-aspartate receptor)-mediated long-lasting depolarizations, which bear similarities to dendritic plateau potentials. In addition, we show that whisker stimuli recruit synaptic networks that originate from the posteromedial complex of the thalamus (POm). Photostimulation of channelrhodopsin-2 expressing POm neurons generated NMDAR-mediated plateau potentials, whereas the inhibition of POm activity during rhythmic whisker stimulation suppressed the generation of those potentials and prevented whisker-evoked LTP. Taken together, our data provide evidence for sensory-driven synaptic LTP in vivo, in the absence of somatic spiking. Instead, LTP is mediated by plateau potentials that are generated through the cooperative activity of lemniscal and paralemniscal synaptic circuitry.

Hypocretin-2 (orexin-B) modulation of superficial dorsal horn activity in rat

PubMed Central

Grudt, Timothy J; van den Pol, Anthony N; Perl, Edward R

2002-01-01

The hypothalamic peptides hypocretin-1 (orexin A) and hypocretin-2 (Hcrt-2; orexin B) are important in modulating behaviours demanding arousal, including sleep and appetite. Fibres containing hypocretin project from the hypothalamus to the superficial dorsal horn (SDH) of the spinal cord (laminae I and II); however, the effects produced by hypocretins on SDH neurones are unknown. To study the action of Hcrt-2 on individual SDH neurones, tight-seal, whole-cell recordings were made with biocytin-filled electrodes from rat lumbar spinal cord slices. In 19 of 63 neurones, Hcrt-2 (30 nm to 1 μm) evoked an inward (excitatory) current accompanied by an increase in baseline noise. The inward current and noise were unaffected by TTX but were blocked by the P2X purinergic receptor antagonist suramin (300–500 μm). Hcrt-2 (30 nm to 1 μm) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in the majority of neurones. The sIPSC increase was blocked by strychnine (1 μm) and by TTX (1 μm), suggesting that the increased sIPSC frequency was glycine and action potential dependent. Hcrt-2 increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in a few neurones but had no effect on dorsal root-evoked EPSCs in these or in other neurones. Neurones located in outer lamina II, particularly radial and vertical cells, were most likely to respond to Hcrt-2. We conclude that Hcrt-2 has excitatory effects on certain SDH neurones, some of which exert inhibitory influences on other cells of the region, consistent with the perspective that hypocretin has a role in orchestrating reactions related to arousal, including nociception, pain and temperature sense. PMID:11790816

The N-methyl-D-aspartate-evoked cytoplasmic calcium increase in adult rat dorsal root ganglion neuronal somata was potentiated by substance P pretreatment in a protein kinase C-dependent manner.

PubMed

Castillo, C; Norcini, M; Baquero-Buitrago, J; Levacic, D; Medina, R; Montoya-Gacharna, J V; Blanck, T J J; Dubois, M; Recio-Pinto, E

2011-03-17

The involvement of substance P (SP) in neuronal sensitization through the activation of the neurokinin-1-receptor (NK1r) in postsynaptic dorsal horn neurons has been well established. In contrast, the role of SP and NK1r in primary sensory dorsal root ganglion (DRG) neurons, in particular in the soma, is not well understood. In this study, we evaluated whether SP modulated the NMDA-evoked transient increase in cytoplasmic Ca2+ ([Ca2+]cyt) in the soma of dissociated adult DRG neurons. Cultures were treated with nerve growth factor (NGF), prostaglandin E2 (PGE2) or both NGF+PGE2. Treatment with NGF+PGE2 increased the percentage of N-methyl-D-aspartate (NMDA) responsive neurons. There was no correlation between the percentage of NMDA responsive neurons and the level of expression of the NR1 and NR2B subunits of the NMDA receptor or of the NK1r. Pretreatment with SP did not alter the percentage of NMDA responsive neurons; while it potentiated the NMDA-evoked [Ca2+]cyt transient by increasing its magnitude and by prolonging the period during which small- and some medium-sized neurons remained NMDA responsive. The SP-mediated potentiation was blocked by the SP-antagonist ([D-Pro4, D-Trp7,9]-SP (4-11)) and by the protein kinase C (PKC) blocker bisindolylmaleimide I (BIM); and correlated with the phosphorylation of PKCε. The Nk1r agonist [Sar9, Met(O2)11]-SP (SarMet-SP) also potentiated the NMDA-evoked [Ca2+]cyt transient. Exposure to SP or SarMet-SP produced a rapid increase in the labeling of phosphorylated-PKCε. In none of the conditions we detected phosphorylation of the NR2B subunit at Ser-1303. Phosphorylation of the NR2B subunit at Tyr1472 was enhanced to a similar extent in cells exposed to NMDA, SP or NMDA+SP, and that enhancement was blocked by BIM. Our findings suggest that NGF and PGE2 may contribute to the injury-evoked sensitization of DRG neurons in part by enhancing their NMDA-evoked [Ca2+]cyt transient in all sized DRG neurons; and that SP may further contribute to the DRG sensitization by enhancing and prolonging the NMDA-evoked increase in [Ca2+]cyt in small- and medium-sized DRG neurons. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Fast retrieval and autonomous regulation of single spontaneously recycling synaptic vesicles

PubMed Central

Leitz, Jeremy; Kavalali, Ege T

2014-01-01

Presynaptic terminals release neurotransmitters spontaneously in a manner that can be regulated by Ca2+. However, the mechanisms underlying this regulation are poorly understood because the inherent stochasticity and low probability of spontaneous fusion events has curtailed their visualization at individual release sites. Here, using pH-sensitive optical probes targeted to synaptic vesicles, we visualized single spontaneous fusion events and found that they are retrieved extremely rapidly with faster re-acidification kinetics than their action potential-evoked counterparts. These fusion events were coupled to postsynaptic NMDA receptor-driven Ca2+ signals, and at elevated Ca2+ concentrations there was an increase in the number of vesicles that would undergo fusion. Furthermore, spontaneous vesicle fusion propensity in a synapse was Ca2+-dependent but regulated autonomously: independent of evoked fusion probability at the same synapse. Taken together, these results expand classical quantal analysis to incorporate endocytic and exocytic phases of single fusion events and uncover autonomous regulation of spontaneous fusion. DOI: http://dx.doi.org/10.7554/eLife.03658.001 PMID:25415052

The metabotropic glutamate receptor mGluR3 is critically required for hippocampal long-term depression and modulates long-term potentiation in the dentate gyrus of freely moving rats.

PubMed

Pöschel, Beatrice; Wroblewska, Barbara; Heinemann, Uwe; Manahan-Vaughan, Denise

2005-09-01

Group II metabotropic glutamate receptors (mGluRs) play an important role in the regulation of hippocampal synaptic plasticity in vivo: long-term potentiation (LTP) is inhibited and long-term depression (LTD) is enhanced by activation of these receptors. The contribution, in vivo, of the individual group II mGluR subtypes has not been characterized. We analysed the involvement of the subtype mGluR3 in LTD and LTP. Rats were implanted with electrodes to enable chronic measurement of evoked potentials from medial perforant path-dentate gyrus synapses. Neither the selective mGluR3 agonist, N-acetylaspartylglutamate (NAAG), nor the antagonist beta-NAAG, given intracerebrally, affected basal synaptic transmission. beta-NAAG significantly inhibited LTD expression. NAAG exhibited transient inhibitory effects on the intermediate phase of LTD. Whereas NAAG altered paired-pulse responses, beta-NAAG had no effect, suggesting that antagonism of mGluR3 prevents LTD via a postsynaptic mechanism, whereas agonist activation of mGluR3 modulates LTD at a presynaptic locus. NAAG impaired the expression of LTP, whereas beta-NAAG had no effect. NAAG effects on LTP were blocked by EGLU, a selective group II mGluR antagonist. Our data suggest an essential role for mGluR3 in LTD, and a modulatory role for mGluR3 in LTP, with effects being mediated by distinct pre- and post-synaptic loci.

[Postsynaptic reactions of cerebral cortex neurons, activated by nociceptive afferents during stimulation of the Raphe nuclei].

PubMed

Labakhua, T Sh; Dzhanashiia, T K; Gedevanishvili, G I; Dzhokhadze, L D; Tkemaladze, T T; Abzianidze, I V

2012-01-01

On cats, we studied the influence of stimulation of the Raphe nuclei (RN) on postsynaptic processes evoked in neurons of the somatosensory cortex by stimulation of nociceptive (intensive stimulation of the tooth pulp) and non-nociceptive (moderate stimulation of the ventroposteromedial--VPN--nucleus of the thalamus) afferent inputs. 6 cells, selectively excited by stimulation of nocciceptors and 9 cells, activated by both the above nociceptive and non-nociceptive influences (nociceptive and convergent neurons, respectively) were recorded intracellular. In neurons of both groups, responses to nociceptive stimulation (of sufficient intensity) looked like an EPSP-spike-IPSP (the letter of significant duration, up to 200-300 ms) compleх. Conditioning stimulation of the RN which preceded test stimulus applied to the tooth pulp or VPM nucleus by 100 to 800 ms, induced 40-60 % decrease of the IPSP amplitude only, while maхimal effect of influence, in both cases, was noted within intervals of 300-800 ms between conditioning and test stimulus. During stimulation of the RN, serotonin released via receptor and second messengers, provides postsynaptic modulation of GABAergic system, decreasing the IPSP amplitude which occurs after stimulation of both the tooth pulp and VPM thalamic nucleus. This process may be realized trough either pre- or postsynaptic mechanisms.

Cationic influences upon synaptic transmission at the hair cell-afferent fiber synapse of the frog

NASA Technical Reports Server (NTRS)

Cochran, S. L.

1995-01-01

The concentrations of inorganic cations (K+, Na+, and Ca2+) bathing the isolated frog labyrinth were varied in order to assess their role in influencing and mediating synaptic transmission at the hair cell-afferent fiber synapse. Experiments employed intracellular recordings of synaptic activity from VIIIth nerve afferents. Recordings were digitized continuously at 50 kHz, and excitatory postsynaptic potentials were detected and parameters quantified by computer algorithms. Particular attention was focused on cationic effects upon excitatory postsynaptic potential frequency of occurrence and excitatory postsynaptic potential amplitude, in order to discriminate between pre- and postsynaptic actions. Because the small size of afferents preclude long term stable recordings, alterations in cationic concentrations were applied transiently and their peak effects on synaptic activity were assessed. Increases in extracellular K+ concentration of a few millimolar produced a large increase in the frequency of occurrence of excitatory postsynaptic potentials with little change in amplitude, indicating that release of transmitter from the hair cell is tightly coupled to its membrane potential. Increasing extracellular Na+ concentration resulted in an increase in excitatory postsynaptic potential amplitude with no significant change in excitatory postsynaptic potential frequency of occurrence, suggesting that the transmitter-gated subsynaptic channel conducts Na+ ions. Decreases in extracellular Ca2+ concentration had little effect upon excitatory postsynaptic potential frequency, but increased excitatory postsynaptic potential frequency and amplitude. These findings suggest that at higher concentrations Ca2+ act presynaptically to prevent transmitter release and postsynaptically to prevent Na+ influx during the generation of the excitatory postsynaptic potential. The influences of these ions on synaptic activity at this synapse are remarkably similar to those reported at the vertebrate neuromuscular junction. The major differences between these two synapses are the neurotransmitters and the higher resting release rate and higher sensitivity of release to increased K+ concentrations of the hair cells over that of motor nerve terminals. These differences reflect the functional roles of the two synapses: the motor nerve terminal response in an all-or-nothing signal consequent from action potential invasion, while the hair cell releases transmitter in a graded fashion, proportionate to the extent of stereocilial deflection. Despite these differences between the two junctions, the similar actions of these elemental cations upon synaptic function at each implies that these ions may participate similarly in the operations of other synapses, independent of the neurotransmitter type.(ABSTRACT TRUNCATED AT 400 WORDS).

Characterization of spontaneous excitatory synaptic currents in salamander retinal ganglion cells.

PubMed Central

Taylor, W R; Chen, E; Copenhagen, D R

1995-01-01

1. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded under voltage-clamp conditions. Consistent with activation of non-NMDA-type glutamate receptors, the sEPSCs reversed at potentials above 0 mV, were blocked by 1 microM CNQX and prolonged by 2 mM aniracetam. 2. The peak conductance of the averaged sEPSCs (n = 70-400) was 130 +/- 60 pS (mean +/- S.D.; 17 cells, ranging from 70 to 290 pS). Amplitude distributions were skewed towards larger amplitudes. 3. The decay of individual and mean sEPSCs was exponential with a mean time constant (tau d) of 3.75 +/- 0.84 ms (n = 13), which was voltage independent. The 10-90% rise time of the sEPSCs was 1.30 +/- 0.44 ms (n = 13). There was no correlation between sEPSC rise time and tau d suggesting that dendritic filtering alone did not shape the time course of sEPSCs. 4. Light-evoked EPSCs in these retinal ganglion cells are mediated by concomitant activation of NMDA and non-NMDA receptors; however, no NMDA component was discerned in the sEPSCs, even when recording at -96 mV in Mg(2+)-free solutions. The decay time course was not altered by 20 microM AP7, an NMDA antagonist, nor was an NMDA component unmasked by adding glycine or D-serine. These results suggest that NMDA and non-NMDA receptors are not coactivated by a single vesicle of transmitter during spontaneous release, and thus are probably not colocalized in the postsynaptic membrane at the sites of spontaneous release. 5. The sEPSCs were an order of magnitude faster than the non-NMDA receptor-mediated EPSCs evoked by light stimuli, and it is proposed that the EPSC time course is determined largely by the extended time course of release of synaptic vesicles from bipolar cells. The quantal content of a light-evoked non-NMDA receptor-mediated EPSC in an on-off cell is about 200 quanta. Images Figure 6 PMID:7562636

Glutamatergic postsynaptic block by Pamphobeteus spider venoms in crayfish.

PubMed

Araque, A; Ferreira, W; Lucas, S; Buño, W

1992-01-31

The effects of toxins from venom glands of two south american spiders (Pamphobeteus platyomma and P. soracabae) on glutamatergic excitatory synaptic transmission were studied in the neuromuscular junction of the opener muscle of crayfish. The toxins selectively and reversibly blocked both excitatory postsynaptic currents and potentials in a dose-dependent manner. They also reversibly abolished glutamate-induced postsynaptic membrane depolarization. They had no effect on resting postsynaptic membrane conductance nor on postsynaptic voltage-gated currents. The synaptic facilitation and the frequency of miniature postsynaptic potentials were unaffected by the toxins, indicating that presynaptic events were not modified. Picrotoxin, a selective antagonist of the gamma-aminobutyric acid (GABA)A receptor, did not modify toxin effects. We conclude that both toxins specifically block the postsynaptic glutamate receptor-channel complex.

Actions of (-)-baclofen on rat dorsal horn neurons.

PubMed

Kangrga, I; Jiang, M C; Randić, M

1991-10-25

The actions of a gamma-aminobutyric acid B (GABAB) agonist, (-)-baclofen, on the electrophysiological properties of neurons and synaptic transmission in the spinal dorsal horn (laminae I-IV) were examined by using intracellular recordings in spinal cord slice from young rats. In addition, the effects of baclofen on the dorsal root stimulation-evoked outflow of glutamate and aspartate from the spinal dorsal horn were examined by using high performance liquid chromatography (HPLC) with flourimetric detection. Superfusion of baclofen (5 nM to 10 microM) hyperpolarized, in a stereoselective and bicuculline-insensitive manner, the majority (86%) of tested neurons. The hyperpolarization was associated with a decrease in membrane resistance and persisted in a nominally zero-Ca2+, 10 mM Mg(2+)- or a TTX-containing solution. Our findings indicate that the hyperpolarizing effect of baclofen is probably due to an increase in conductance to potassium ions. Baclofen decreased the direct excitability of dorsal horn neurons, enhanced accommodation of spike discharge, and reduced the duration of Ca(2+)-dependent action potentials. Baclofen depressed, or blocked, excitatory postsynaptic potentials evoked by electrical stimulation of the dorsal roots. Spontaneously occurring synaptic potentials were also reversibly depressed by baclofen. Whereas baclofen did not produce any consistent change in the rate of the basal outflow of glutamate and aspartate, the stimulation-evoked release of the amino acids was blocked. The present results suggest that baclofen, by activating GABAB receptors, may modulate spinal afferent processing in the superficial dorsal horn by at least two mechanisms: (1) baclofen depresses excitatory synaptic transmission primarily by a presynaptic mechanism involving a decrease in the release of excitatory amino acids, and (2) at higher concentrations, the hyperpolarization and increased membrane conductance may contribute to the depressant effect of baclofen on excitatory synaptic transmission in the rat spinal dorsal horn.

Tachykininergic slow depolarization of motoneurones evoked by descending fibres in the neonatal rat spinal cord.

PubMed

Kurihara, T; Yoshioka, K; Otsuka, M

1995-06-15

1. In the isolated spinal cord of the neonatal rat, repetitive electrical stimulation of the upper cervical region elicited a prolonged depolarization of lumbar motoneurones (L3-5) lasting 1-2 min, which was recorded extracellularly from ventral roots, or intracellularly. 2. This depolarizing response was markedly depressed by the excitatory amino acid receptor antagonists D-(-)-2-amino-5-phosphonovaleric acid (D-APV, 30 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). The remaining response was further depressed by a 5-hydroxytryptamine (5-HT) receptor antagonist, ketanserin (3 microM). 3. In the presence of these antagonists, a small part of the depolarizing response of slow time course remained, and this response was partially blocked by the tachykinin NK1 receptor antagonists GR71251 (0.3-5 microM) and RP67580 (0.3-1 microM). In contrast, RP68651 (0.3-1 microM), the inactive enantiomer of RP67580, had no effect on the depolarizing response. 4. The slow depolarizing response in the presence of D-APV, CNQX and ketanserin was markedly potentiated by a peptidase inhibitor, thiorphan (1 microM). 5. This descending fibre-evoked slow depolarization became smaller after prolonged treatment (5-7 h) with 5,7-dihydroxytryptamine (10 microM), a neurotoxin for 5-HT neurones. Under such conditions, the effects of thiorphan and GR71251 on the slow depolarization were virtually absent. 6. Under the action of D-APV, CNQX and ketanserin, applications of tachykinins, substance P and neurokinin A produced depolarizing responses of lumbar motoneurones, and the responses were depressed by GR71251 and potentiated by thiorphan. 7. These results suggest that tachykinins contained in serotonergic fibres serve as neurotransmitters mediating the descending fibre-evoked slow excitatory postsynaptic potentials in motoneurones.

BK channels are required for multisensory plasticity in the oculomotor system

PubMed Central

Nelson, Alexandra; Faulstich, Michael; Moghadam, Setareh; Onori, Kimberly; Meredith, Andrea; du Lac, Sascha

2017-01-01

SUMMARY Neural circuits are endowed with several forms of intrinsic and synaptic plasticity that could contribute to adaptive changes in behavior, but circuit complexities have hindered linking specific cellular mechanisms with their behavioral consequences. Eye movements generated by simple brainstem circuits provide a means for relating cellular plasticity to behavioral gain control. Here we show that firing rate potentiation, a form of intrinsic plasticity mediated by reductions in BK-type calcium activated potassium currents in spontaneously firing neurons, is engaged during optokinetic reflex compensation for inner ear dysfunction. Vestibular loss triggers transient increases in postsynaptic excitability, occlusion of firing rate potentiation, and reductions in BK currents in vestibular nucleus neurons. Concurrently, adaptive increases in visually-evoked eye movements rapidly restore oculomotor function in wildtype mice but are profoundly impaired in BK channel null mice. Activity-dependent regulation of intrinsic excitability may be a general mechanism for adaptive control of behavioral output in multisensory circuits. PMID:27989457

Platelet-activating factor and group I metabotropic glutamate receptors interact for full development and maintenance of long-term potentiation in the rat medial vestibular nuclei.

PubMed

Grassi, S; Francescangeli, E; Goracci, G; Pettorossi, V E

1999-01-01

In rat brainstem slices, we investigated the interaction between platelet-activating factor and group I metabotropic glutamate receptors in mediating long-term potentiation within the medial vestibular nuclei. We analysed the N1 field potential wave evoked in the ventral portion of the medial vestibular nuclei by primary vestibular afferent stimulation. The group I metabotropic glutamate receptor antagonist, (R,S)-1-aminoindan-1,5-dicarboxylic acid, prevented long-term potentiation induced by a platelet-activating factor analogue [1-O-hexadecyl-2-O-(methylcarbamyl)-sn-glycero-3-phosphocholine], as well as the full development of potentiation, induced by high-frequency stimulation under the blocking agent for synaptosomal platelet-activating factor receptors (ginkolide B), at drug washout. However, potentiation directly induced by the group I glutamate metabotropic receptor agonist, (R,S)-3,5-dihydroxyphenylglycine, was reduced by ginkolide B. These findings suggest that platelet-activating factor, whether exogenous or released following potentiation induction, exerts its effect through presynaptic group I metabotropic glutamate receptors, mediating the increase of glutamate release. In addition, we found that this mechanism, which led to full potentiation through presynaptic group I metabotropic glutamate receptor activation, was inactivated soon after application of potentiation-inducing stimulus. In fact, the long-lasting block of the platelet-activating factor and metabotropic glutamate receptors prevented the full potentiation development and the induced potentiation progressively declined to null. Moreover, ginkolide B, given when high-frequency-dependent potentiation was established, only reduced it within 5 min after potentiation induction. We conclude that to fully develop vestibular long-term potentiation requires presynaptic events. Platelet-activating factor, released after the activation of postsynaptic mechanisms which induce potentiation, is necessary for coupling postsynaptic and presynaptic phenomena, through the activation of group I metabotropic glutamate receptors, and its action lasts only for a short period. If this coupling does not occur, a full and long-lasting potentiation cannot develop.

Choline induces opposite changes in pyramidal neuron excitability and synaptic transmission through a nicotinic receptor-independent process in hippocampal slices.

PubMed

Albiñana, E; Luengo, J G; Baraibar, A M; Muñoz, M D; Gandía, L; Solís, J M; Hernández-Guijo, J M

2017-06-01

Choline is present at cholinergic synapses as a product of acetylcholine degradation. In addition, it is considered a selective agonist for α5 and α7 nicotinic acetylcholine receptors (nAChRs). In this study, we determined how choline affects action potentials and excitatory synaptic transmission using extracellular and intracellular recording techniques in CA1 area of hippocampal slices obtained from both mice and rats. Choline caused a reversible depression of evoked field excitatory postsynaptic potentials (fEPSPs) in a concentration-dependent manner that was not affected by α7 nAChR antagonists. Moreover, this choline-induced effect was not mimicked by either selective agonists or allosteric modulators of α7 nAChRs. Additionally, this choline-mediated effect was not prevented by either selective antagonists of GABA receptors or hemicholinium, a choline uptake inhibitor. The paired pulse facilitation paradigm, which detects whether a substance affects presynaptic release of glutamate, was not modified by choline. On the other hand, choline induced a robust increase of population spike evoked by orthodromic stimulation but did not modify that evoked by antidromic stimulation. We also found that choline impaired recurrent inhibition recorded in the pyramidal cell layer through a mechanism independent of α7 nAChR activation. These choline-mediated effects on fEPSP and population spike observed in rat slices were completely reproduced in slices obtained from α7 nAChR knockout mice, which reinforces our conclusion that choline modulates synaptic transmission and neuronal excitability by a mechanism independent of nicotinic receptor activation.

Trafficking of presynaptic AMPA receptors mediating neurotransmitter release: neuronal selectivity and relationships with sensitivity to cyclothiazide.

PubMed

Pittaluga, Anna; Feligioni, Marco; Longordo, Fabio; Luccini, Elisa; Raiteri, Maurizio

2006-03-01

Postsynaptic glutamate AMPA receptors (AMPARs) can recycle between plasma membrane and intracellular pools. In contrast, trafficking of presynaptic AMPARs has not been investigated. AMPAR surface expression involves interactions between the GluR2 carboxy tail and various proteins including glutamate receptor-interacting protein (GRIP), AMPA receptor-binding protein (ABP), protein interacting with C kinase 1 (PICK1), N-ethyl-maleimide-sensitive fusion protein (NSF). Here, peptides known to selectively block the above interactions were entrapped into synaptosomes to study the effects on the AMPA-evoked release of [3H]noradrenaline ([3H]NA) and [3H]acetylcholine ([3H]ACh) from rat hippocampal and cortical synaptosomes, respectively. Internalization of pep2-SVKI to prevent GluR2-GRIP/ABP/PICK1 interactions potentiated the AMPA-evoked release of [3H]NA but left unmodified that of [3H]ACh. Similar potentiation was caused by pep2-AVKI, the blocker of GluR2-PICK1 interaction. Conversely, a decrease in the AMPA-evoked release of [3H]NA, but not of [3H]ACh, was caused by pep2m, a selective blocker of the GluR2-NSF interaction. In the presence of pep2-SVKI the presynaptic AMPARs on noradrenergic terminals lost sensitivity to cyclothiazide. AMPARs releasing [3H]ACh, but not those releasing [3H]NA, were sensitive to spermine, suggesting that they are GluR2-lacking AMPARs. To conclude: (i) release-regulating presynaptic AMPARs constitutively cycle in isolated nerve terminals; (ii) the process exhibits neuronal selectivity; (iii) AMPAR trafficking and desensitization may be interrelated.

Developmental profile of SK2 channel expression and function in CA1 neurons

PubMed Central

Ballesteros-Merino, Carmen; Lin, Mike; Wu, Wendy W.; Ferrandiz-Huertas, Clotilde; Cabañero, María J.; Watanabe, Masahiko; Fukazawa, Yugo; Shigemoto, Ryuichi; Maylie, James; Adelman, John P.; Luján, Rafael

2012-01-01

We investigated the temporal and spatial expression of SK2 in the developing mouse hippocampus using molecular and biochemical techniques, quantitative immunogold electron microscopy and electrophysiology. The mRNA encoding SK2 was expressed in the developing and adult hippocampus. Western blotting and immunohistochemistry showed that SK2 protein increased with age. This was accompanied by a shift in subcellular localization. Early in development (P5), SK2 was predominantly localized to the endoplasmic reticulum in the pyramidal cell layer. But by P30 SK2 was almost exclusively expressed in the dendrites and spines. The level of SK2 at the postsynaptic density (PSD) also increased during development. In the adult, SK2 expression on the spine plasma membrane showed a proximal-to-distal gradient. Consistent with this redistribution and gradient of SK2, the selective SK channel blocker apamin increased evoked excitatory postsynaptic potentials (EPSPs) only in CA1 pyramidal neurons from mice older than P15. However, the effect of apamin on EPSPs was not different between synapses in proximal or distal stratum radiatum or stratum lacunosum-moleculare in adult. These results show a developmental increase and gradient in SK2-containing channel surface expression that underlie their influence on neurotransmission, and that may contribute to increased memory acquisition during early development. PMID:22072564

Influence of hypoxia on excitation and GABAergic inhibition in mature and developing rat neocortex.

PubMed

Luhmann, H J; Kral, T; Heinemann, U

1993-01-01

To analyze the functional consequences of hypoxia on the efficacy of intracortical inhibitory mechanisms mediated by gamma-aminobutyric acid (GABA), extra- and intracellular recordings were obtained from rat primary somatosensory cortex in vitro. Hypoxia, induced by transient N2 aeration, caused a decrease in stimulus-evoked inhibitory postsynaptic potentials (IPSPs), followed by a pronounced anoxic depolarization. Upon reoxygenation, the fast (f-) and long-latency (l-) IPSP showed a positive shift in the reversal potential by 24.4 and 14.9 mV, respectively. The peak conductance of the f- and l-IPSP was reversibly reduced in the postanoxic period by 72% and 94%, respectively. Extracellular field potential recordings and application of a paired-pulse inhibition protocol confirmed the enhanced sensitivity of inhibitory synaptic transmission for transient oxygen deprivation. Intracellular recordings from morphologically or electrophysiologically identified interneurons did not reveal any enhanced susceptibility for hypoxia as compared to pyramidal cells, suggesting that inhibitory neurons are not selectively impaired in their functional properties. Intracellularly recorded spontaneous IPSPs were transiently augmented in the postanoxic period, indicating that presynaptic GABA release was not suppressed. Developmental studies in adult (older than postnatal day 28), juvenile (P14-18), and young (P5-8) neocortical slices revealed a prominent functional resistance of immature tissue for hypoxia. In comparison with adult cortex, the hypoxia-induced reduction in excitatory and inhibitory synaptic transmission was significantly smaller in immature cortex. Our data indicate a hypoxia-induced distinct reduction of postsynaptic GABAergic mechanisms, leading to the manifestation of intracortical hyperexcitability as a possible functional consequence.

Quantal mEPSCs and residual glutamate: how horizontal cell responses are shaped at the photoreceptor ribbon synapse

PubMed Central

Cadetti, Lucia; Bartoletti, Theodore M.; Thoreson, Wallace B.

2012-01-01

At the photoreceptor ribbon synapse, glutamate released from vesicles at different positions along the ribbon reaches the same postsynaptic receptors. Thus, vesicles may not exert entirely independent effects. We examined whether responses of salamander retinal horizontal cells evoked by light or direct depolarization during paired recordings could be predicted by summation of individual miniature excitatory postsynaptic currents (mEPSCs). For EPSCs evoked by depolarization of rods or cones, linear convolution of mEPSCs with photoreceptor release functions predicted EPSC waveforms and changes caused by inhibiting glutamate receptor desensitization. A low-affinity glutamate antagonist, kynurenic acid (KynA), preferentially reduced later components of rod-driven EPSCs, suggesting lower levels of glutamate are present during the later sustained component of the EPSC. A glutamate-scavenging enzyme, glutamic-pyruvic transaminase, did not inhibit mEPSCs or the initial component of rod-driven EPSCs, but reduced later components of the EPSC. Inhibiting glutamate uptake with a low concentration of dl-threo-β-benzoyloxyaspartate (TBOA) also did not alter mEPSCs or the initial component of rod-driven EPSCs, but enhanced later components of the EPSC. Low concentrations of TBOA and KynA did not affect the kinetics of fast cone-driven EPSCs. Under both rod- and cone-dominated conditions, light-evoked currents (LECs) were enhanced considerably by TBOA. LECs were more strongly inhibited than EPSCs by KynA, suggesting the presence of lower glutamate levels. Collectively, these results indicate that the initial EPSC component can be largely predicted from a linear sum of individual mEPSCs, but with sustained release, residual amounts of glutamate from multiple vesicles pool together, influencing LECs and later components of EPSCs. PMID:18547244

Lack of effect of mossy fiber-released zinc on granule cell GABA(A) receptors in the pilocarpine model of epilepsy.

PubMed

Molnár, P; Nadler, J V

2001-05-01

The recurrent mossy fiber pathway of the dentate gyrus expands dramatically in the epileptic brain and serves as a mechanism for synchronization of granule cell epileptiform activity. It has been suggested that this pathway also promotes epileptiform activity by inhibiting GABA(A) receptor function through release of zinc. Hippocampal slices from pilocarpine-treated rats were used to evaluate this hypothesis. The rats had developed status epilepticus after pilocarpine administration, followed by robust recurrent mossy fiber growth. The ability of exogenously applied zinc to depress GABA(A) receptor function in dentate granule cells depended on removal of polyvalent anions from the superfusion medium. Under these conditions, 200 microM zinc reduced the amplitude of the current evoked by applying muscimol to the proximal portion of the granule cell dendrite (23%). It also reduced the mean amplitude (31%) and frequency (36%) of miniature inhibitory postsynaptic currents. Nevertheless, repetitive mossy fiber stimulation (10 Hz for 1 s, 100 Hz for 1 s, or 10 Hz for 5 min) at maximal intensity did not affect GABA(A) receptor-mediated currents evoked by photorelease of GABA onto the proximal portion of the dendrite, where recurrent mossy fiber synapses were located. These results could not be explained by stimulation-induced depletion of zinc from the recurrent mossy fiber boutons. Negative results were obtained even during exposure to conditions that promoted transmitter release and synchronized granule cell activity (6 mM [K(+)](o), nominally Mg(2+)-free medium, 33 degrees C). These results suggest that zinc released from the recurrent mossy fiber pathway did not reach a concentration at postsynaptic GABA(A) receptors sufficient to inhibit agonist-evoked activation.

Development of excitatory synaptic transmission to the superior paraolivary and lateral superior olivary nuclei optimizes differential decoding strategies.

PubMed

Felix, Richard A; Magnusson, Anna K

2016-10-15

The superior paraolivary nucleus (SPON) is a prominent structure in the mammalian auditory brainstem with a proposed role in encoding transient broadband sounds such as vocalized utterances. Currently, the source of excitatory pathways that project to the SPON and how these inputs contribute to SPON function are poorly understood. To shed light on the nature of these inputs, we measured evoked excitatory postsynaptic currents (EPSCs) in the SPON originating from the intermediate acoustic stria and compared them with the properties of EPSCs in the lateral superior olive (LSO) originating from the ventral acoustic stria during auditory development from postnatal day 5 to 22 in mice. Before hearing onset, EPSCs in the SPON and LSO are very similar in size and kinetics. After the onset of hearing, SPON excitation is refined to extremely few (2:1) fibers, with each strengthened by an increase in release probability, yielding fast and strong EPSCs. LSO excitation is recruited from more fibers (5:1), resulting in strong EPSCs with a comparatively broader stimulus-response range after hearing onset. Evoked SPON excitation is comparatively weaker than evoked LSO excitation, likely due to a larger fraction of postsynaptic GluR2-containing Ca 2+ -impermeable AMPA receptors after hearing onset. Taken together, SPON excitation develops synaptic properties that are suited for transmitting single events with high temporal reliability and the strong, dynamic LSO excitation is compatible with high rate-level sensitivity. Thus, the excitatory input pathways to the SPON and LSO mature to support different decoding strategies of respective coarse temporal and sound intensity information at the brainstem level. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Dopamine depresses excitatory synaptic transmission onto rat subicular neurons via presynaptic D1-like dopamine receptors.

PubMed

Behr, J; Gloveli, T; Schmitz, D; Heinemann, U

2000-07-01

Schizophrenia is considered to be associated with an abnormal functioning of the hippocampal output. The high clinical potency of antipsychotics that act as antagonists at dopamine (DA) receptors indicate a hyperfunction of the dopaminergic system. The subiculum obtains information from area CA1 and the entorhinal cortex and represents the major output region of the hippocampal complex. To clarify whether an enhanced dopaminergic activity alters the hippocampal output, the effect of DA on alveus- and perforant path-evoked excitatory postsynaptic currents (EPSCs) in subicular neurons was examined using conventional intracellular and whole cell voltage-clamp recordings. Dopamine (100 microM) depressed alveus-elicited (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated EPSCs to 56 +/- 8% of control while perforant path-evoked EPSCs were attenuated to only 76 +/- 7% of control. Dopamine had no effect on the EPSC kinetics. Dopamine reduced the frequency of spontaneous miniature EPSCs without affecting their amplitudes. The sensitivity of subicular neurons to the glutamate receptor agonist (S)-alpha-amino-3-hydoxy-5-methyl-4-isoxazolepropionic acid was unchanged by DA pretreatment, excluding a postsynaptic mechanism for the observed reduction of excitatory synaptic transmission. The effect of DA on evoked EPSCs was mimicked by the D1 receptor agonist SFK 38393 and partially antagonized by the D1 receptor antagonist SCH 23390. While the D2 receptor agonist quinelorane failed to reduce the EPSCs, the D2 receptor antagonist sulpiride did not block the action of DA. The results indicate that DA strongly depresses the hippocampal and the entorhinal excitatory input onto subicular neurons by decreasing the glutamate release following activation of presynaptic D1-like DA receptors.

Glutamate spillover drives endocannabinoid production and inhibits GABAergic transmission in the Substantia Nigra pars compacta.

PubMed

Freestone, Peter S; Guatteo, Ezia; Piscitelli, Fabiana; di Marzo, Vincenzo; Lipski, Janusz; Mercuri, Nicola B

2014-04-01

Endocannabinoids (eCBs) modulate synaptic transmission in the brain, but little is known of their regulatory role in nigral dopaminergic neurons, and whether transmission to these neurons is tonically inhibited by eCBs as seen in some other brain regions. Using whole-cell recording in midbrain slices, we observed potentiation of evoked IPSCs (eIPSCs) in these neurons after blocking CB1 receptors with rimonabant or LY-320,135, indicating the presence of an eCB tone reducing inhibitory synaptic transmission. Increased postsynaptic calcium buffering and block of mGluR1 or postsynaptic G-protein coupled receptors prevented this potentiation. Increasing spillover of endogenous glutamate by inhibiting uptake attenuated eIPSC amplitude, while enhancing the potentiation by rimonabant. Group I mGluR activation transiently inhibited eIPSCs, which could be prevented by GDP-β-S, increased calcium buffering or rimonabant. We explored the possibility that the dopamine-derived eCB N-arachidonoyl dopamine (NADA) is involved. The eCB tone was abolished by preventing dopamine synthesis, and enhanced by l-DOPA. It was not detected in adjacent non-dopaminergic neurons. Preventing 2-AG synthesis did not affect the tone, while inhibition of NADA production abolished it. Quantification of ventral midbrain NADA suggested a basal level that increased following prolonged depolarization or mGluR activation. Since block of the tone was not always accompanied by attenuation of depolarization-induced suppression of inhibition (DSI) and vice versa, our results indicate DSI and the eCB tone are mediated by distinct eCBs. This study provides evidence that dopamine modulates the activity of SNc neurons not only by conventional dopamine receptors, but also by CB1 receptors, potentially via NADA. Copyright © 2013 Elsevier Ltd. All rights reserved.

Electrophysiological actions of GABAB agonists and antagonists in rat dorso-lateral septal neurones in vitro.

PubMed

Bon, C; Galvan, M

1996-06-01

1. The actions of GABAB-receptor agonists and antagonists on rat dorso-lateral septal neurones in vitro were recorded with intracellular microelectrodes. 2. In the presence of 1 microM tetrodotoxin to prevent indirect neuronal effects caused by action potential-dependent neurotransmitter release, bath application of baclofen (0.1-30 microM) or SK&F 97541 (0.01-3 microM) evoked concentration-dependent hyperpolarizations which reversed close to the potassium equilibrium potential; the EC50S were 0.55 and 0.05 microM, respectively. No significant desensitization was observed during prolonged agonist exposure (< or = 10 min). 3. Hyperpolarizations induced by baclofen were antagonized in a competitive manner by the following GABAB-receptors antagonists (calculated pA2 values in parentheses): CGP 36742 (4.0), 2-OH saclofen (4.2), CGP 35348 (4.5), CGP 52432 (6.7) and CGP 55845A (8.3). Responses to SK&F 97541 were also antagonized by CGP 55845A (pA2 = 8.4). 4. The amplitude of the late, GABAB receptor-mediated inhibitory postsynaptic potential (i.p.s.p.) was reduced by the GABAB antagonists as follows (means +/- s.e.mean): CGP 55845A (1 microM) 91 +/- 5%, CGP 52432 (1 microM) 64 +/- 5%, CGP 35348 (100 microM) 82 +/- 5%, CGP 36742 (100 microM) 76 +/- 8%, and 2-OH saclofen (100 microM) 68 +/- 3%. 5. It is concluded that neurones in the rat dorso-lateral septal nucleus express conventional GABAB receptors, which are involved in the generation of slow inhibitory postsynaptic potentials. CGP 55845A is the most potent GABAB receptor antagonist described in this brain area.

Excitatory synapse in the rat hippocampus in tissue culture and effects of aniracetam.

PubMed

Ozawa, S; Iino, M; Abe, M

1991-10-01

Excitatory synaptic connections between rat hippocampal neurons were established in tissue culture. The electrophysiological and pharmacological properties of these synapses were studied with the use of the tight-seal whole-cell recording technique. The excitatory postsynaptic current (EPSC) in a dissociated CA1 neuron evoked by stimulation of an explant from the CA3/CA4 region of the hippocampus had two distinct components in Mg(2+)-free medium. The fast component was abolished by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (2 microM), whereas the slow component was abolished by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonovalerate (D-APV) (50 microM). In solution containing 1 mM Mg2+, the peak amplitude of the fast component was almost linearly related to the membrane potential. In contrast, the conductance change underlying the slow component of the EPSC was voltage-dependent with a region of negative-slope conductance in the range of -80 to -20 mV. A nootropic drug, aniracetam, increased both the amplitude and duration of the fast component of the EPSC in a concentration-dependent manner in the range of 0.1-5 mM, whereas it had no potentiating effect on the slow component. Aniracetam (0.1-5 mM) similarly increased current responses of the postsynaptic neuron to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). Current responses to quisqualate and glutamate in the presence of D-APV were also potentiated by aniracetam. However, neither NMDA- nor kainate-induced current was potentiated by 1 mM aniracetam.

Regeneration of synapses in the olfactory pathway of locusts after antennal deafferentation.

PubMed

Wasser, Hannah; Stern, Michael

2017-10-01

The olfactory pathway of the locust is capable of fast and precise regeneration on an anatomical level. Following deafferentation of the antenna either of young adult locusts, or of fifth instar nymphs, severed olfactory receptor neurons (ORNs) reinnervate the antennal lobe (AL) and arborize in AL microglomeruli. In the present study we tested whether these regenerated fibers establish functional synapses again. Intracellular recordings from AL projection neurons revealed that the first few odor stimulus evoked postsynaptic responses from regenerated ORNs from day 4-7 post crush on. On average, synaptic connections of regenerated afferents appeared faster in younger locusts operated as fifth instar nymphs than in adults. The proportions of response categories (excitatory vs. inhibitory) changed during regeneration, but were back to normal within 21 days. Odor-evoked oscillating extracellular local field potentials (LFP) were recorded in the mushroom body. These responses, absent after antennal nerve crush, reappeared, in a few animals as soon as 4 days post crush. Odor-induced oscillation patterns were restored within 7 days post crush. Both intra- and extracellular recordings indicate the capability of the locust olfactory system to re-establish synaptic contacts in the antennal lobe after antennal nerve lesion.

Electrophysical properties, synaptic transmission and neuromodulation in serotonergic caudal raphe neurons.

PubMed

Li, Y W; Bayliss, D A

1998-06-01

1. We studied electrophysiological properties, synaptic transmission and modulation by 5-hydroxytryptamine (5-HT) of caudal raphe neurons using whole-cell recording in a neonatal rat brain slice preparation; recorded neurons were identified as serotonergic by post-hoc immunohistochemical detection of tryptophan hydroxylase, the 5-HT-synthesizing enzyme. 2. Serotonergic neurons fired spontaneously (approximately 1 Hz), with maximal steady state firing rates of < 4 Hz. 5-Hydroxytryptamine caused hyperpolarization and cessation of spike activity in these neurons by activating inwardly rectifying K+ conductance via somatodendritic 5-HT1A receptors. 3. Unitary glutamatergic excitatory post-synaptic potentials (EPSP) and currents (EPSC) were evoked in serotonergic neurons by local electrical stimulation. Evoked EPSC were potently inhibited by 5-HT, an effect mediated by presynaptic 5-HT1B receptors. 4. In conclusion, serotonergic caudal raphe neurons are spontaneously active in vitro; they receive prominent glutamatergic synaptic inputs. 5-Hydroxytryptamine regulates serotonergic neuronal activity of the caudal raphe by decreasing spontaneous activity via somatodendritic 5-HT1A receptors and by inhibiting excitatory synaptic transmission onto these neurons via presynaptic 5-HT1B receptors. These local modulatory mechanisms provide multiple levels of feedback autoregulation of serotonergic raphe neurons by 5-HT.

Inhibition of muscle spindle afferent activity during masseter muscle fatigue in the rat.

PubMed

Brunetti, Orazio; Della Torre, Giovannella; Lucchi, Maria Luisa; Chiocchetti, Roberto; Bortolami, Ruggero; Pettorossi, Vito Enrico

2003-09-01

The influence of muscle fatigue on the jaw-closing muscle spindle activity has been investigated by analyzing: (1) the field potentials evoked in the trigeminal motor nucleus (Vmot) by trigeminal mesencephalic nucleus (Vmes) stimulation, (2) the orthodromic and antidromic responses evoked in the Vmes by stimulation of the peripheral and central axons of the muscle proprioceptive afferents, and (3) the extracellular unitary discharge of masseter muscle spindles recorded in the Vmes. The masseter muscle was fatigued by prolonged tetanic masseter nerve electrical stimulation. Pre- and postsynaptic components of the potentials evoked in the Vmot showed a significant reduction in amplitude following muscle fatigue. Orthodromic and antidromic potentials recorded in the Vmes also showed a similar amplitude decrease. Furthermore, muscle fatigue caused a decrease of the discharge frequency of masseter muscle spindle afferents in most of the examined units. The inhibition of the potential amplitude and discharge frequency was strictly correlated with the extent of muscle fatigue and was mediated by the group III and IV afferent muscle fibers activated by fatigue. In fact, the inhibitory effect was abolished by capsaicin injection in the masseter muscle that provokes selective degeneration of small afferent muscle fibers containing neurokinins. We concluded that fatigue signals originating from the muscle and traveling through capsaicin-sensitive fibers are able to diminish the proprioceptive input by a central presynaptic influence. In the second part of the study, we examined the central projection of the masseter small afferents sensitive to capsaicin at the electron-microscopic level. Fiber degeneration was induced by injecting capsaicin into the masseter muscle. Degenerating terminals were found on the soma and stem process in Vmes and on the dendritic tree of neurons in Vmot. This suggests that small muscle afferents may influence the muscle spindle activity through direct synapses on somata in Vmes and on dendrites of neurons in Vmot.

Adrenoceptor-Mediated Post- and Pre-Synaptic Regulations of the Reticulospinal Neurons in Rat Caudal Pontine Reticular Nucleus.

PubMed

Yang, Nian; Qiao, Qi-Cheng; Liu, Yu-Hui; Zhang, Ji-Qiang; Hu, Zhi-An; Zhang, Jun

2016-12-01

The central noradrenergic system participates in diverse nervous functions. Nevertheless, our knowledge of the action of adrenoceptors in motor regulation is still lacking. Intriguingly, reticulospinal neurons in the caudal pontine reticular nucleus (PnC) receive fairly dense noradrenergic innervation and play an important role in motor control. Here, after demonstrating the expression of α1- and α2-adrenoceptors in the PnC, we found that noradrenaline elicited a post-synaptic effect (inward or outward whole-cell current at -70 mV holding) on PnC reticulospinal neurons. The α1- and α2-adrenoceptors were co-expressed in individual PnC reticulospinal neurons to mediate an inward and an outward current component at -70 mV holding, respectively, which, when superposed, produced the overall post-synaptic effects of noradrenaline (NA). More importantly, the activation of post-synaptic α1- or α2-adrenoceptors indeed exerted opposing modulations (excitation vs. inhibition) on the firing activities of individual PnC reticulospinal neurons. Furthermore, the activation and inhibition of the Na + -permeable non-selective cationic conductance (NSCC) were demonstrated to be coupled to α1- and α2-adrenoceptors, respectively. Additionally, the activation of α2-adrenoceptors activated K + conductance. Pre-synaptically, the α2-adrenoceptors were expressed to attenuate the miniature excitatory postsynaptic current (mEPSC) in PnC reticulospinal neurons, but not to affect the miniature inhibitory postsynaptic current (mIPSC). Consistently, the evoked EPSC in PnC reticulospinal neurons was suppressed after the activation of pre-synaptic α2-adrenoceptors. Thus, the excitatory input and post-synaptic dynamics of PnC reticulospinal neurons are indeed intricately modulated by the activation of α1- and α2-adrenoceptors, through which motor control may be regulated in an adaptive manner by the central noradrenergic system.

Calcium-induced calcium release in rod photoreceptor terminals boosts synaptic transmission during maintained depolarization

PubMed Central

Cadetti, Lucia; Bryson, Eric J.; Ciccone, Cory A.; Rabl, Katalin; Thoreson, Wallace B.

2008-01-01

We examined the contribution of calcium-induced calcium release (CICR) to synaptic transmission from rod photoreceptor terminals. Whole-cell recording and confocal calcium imaging experiments were conducted on rods with intact synaptic terminals in a retinal slice preparation from salamander. Low concentrations of ryanodine stimulated calcium increases in rod terminals, consistent with the presence of ryanodine receptors. Application of strong depolarizing steps (−70 to −10 mV) exceeding 200 ms or longer in duration evoked a wave of calcium that spread across the synaptic terminals of voltage-clamped rods. This secondary calcium increase was blocked by high concentrations of ryanodine, indicating it was due to CICR. Ryanodine (50 μM) had no significant effect on rod calcium current (Ica) although it slightly diminished rod light-evoked voltage responses. Bath application of 50 μM ryanodine strongly inhibited light-evoked currents in horizontal cells. Whether applied extracellularly or delivered into the rod cell through the patch pipette, ryanodine (50 μM) also inhibited excitatory post-synaptic currents (EPSCs) evoked in horizontal cells by depolarizing steps applied to rods. Ryanodine caused a preferential reduction in the later portions of EPSCs evoked by depolarizing steps of 200 ms or longer. These results indicate that CICR enhances calcium increases in rod terminals evoked by sustained depolarization, which in turn acts to boost synaptic exocytosis from rods. PMID:16819987

Regulation of synaptic acetylcholine concentrations by acetylcholine transport in rat striatal cholinergic transmission.

PubMed

Muramatsu, Ikunobu; Uwada, Junsuke; Masuoka, Takayoshi; Yoshiki, Hatsumi; Sada, Kiyonao; Lee, Kung-Shing; Nishio, Matomo; Ishibashi, Takaharu; Taniguchi, Takanobu

2017-10-01

In addition to hydrolysis by acetylcholine esterase (AChE), acetylcholine (ACh) is also directly taken up into brain tissues. In this study, we examined whether the uptake of ACh is involved in the regulation of synaptic ACh concentrations. Superfusion experiments with rat striatal segments pre-incubated with [ 3 H]choline were performed using an ultra-mini superfusion vessel, which was developed to minimize superfusate retention within the vessel. Hemicholinium-3 (HC-3) at concentrations less than 1 μM, selectively inhibited the uptake of [ 3 H]choline by the high affinity-choline transporter 1 and had no effect on basal and electrically evoked [ 3 H]efflux in superfusion experiments. In contrast, HC-3 at higher concentrations, as well as tetraethylammonium (>10 μM), which inhibited the uptake of both [ 3 H]choline and [ 3 H]ACh, increased basal [ 3 H]overflow and potentiated electrically evoked [ 3 H]efflux. These effects of HC-3 and tetraethylammonium were also observed under conditions where tissue AChE was irreversibly inactivated by diisopropylfluorophosphate. Specifically, the potentiation of evoked [ 3 H]efflux was significantly higher in AChE-inactivated preparations and was attenuated by atropine. On the other hand, striatal segments pre-incubated with [ 3 H]ACh failed to increase [ 3 H]overflow in response to electrical stimulation. These results show that synaptic ACh concentrations are significantly regulated by the postsynaptic uptake of ACh, as well as by AChE hydrolysis and modulation of ACh release mediated through presynaptic muscarinic ACh receptors. In addition, these data suggest that the recycling of ACh-derived choline may be minor in cholinergic terminals. This study reveals a new mechanism of cholinergic transmission in the central nervous system. © 2017 International Society for Neurochemistry.

Phasic dopamine release drives rapid activation of striatal D2-receptors

PubMed Central

Marcott, Pamela F; Mamaligas, Aphroditi A; Ford, Christopher P

2014-01-01

Summary Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G-protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory post-synaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals. PMID:25242218

Enhanced GABAergic transmission in the central nucleus of the amygdala of genetically selected Marchigian Sardinian rats: alcohol and CRF effects

PubMed Central

Herman, Melissa; Kallupi, Marsida; Luu, George; Oleata, Christopher; Heilig, Markus; Koob, George F.; Ciccocioppo, Roberto; Roberto, Marisa

2012-01-01

The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and the anxiogenic-like response to ethanol withdrawal. Alcohol dependence is associated with increased corticotropin releasing factor (CRF) influence on CeA GABA release and CRF type 1 receptor (CRF1) antagonists prevent the excessive alcohol consumption associated with dependence. Genetically-selected Marchigian Sardinian (msP) rats have an overactive extrahypothalamic CRF1 system, are highly sensitive to stress, and display an innate preference for alcohol. The present study examined differences in CeA GABAergic transmission and the effects of ethanol, CRF and a CRF1 antagonist in msP, Sprague-Dawley, and Wistar rats using an electrophysiological approach. We found no significant differences in membrane properties or mean amplitude of evoked GABAA-inhibitory postsynaptic potentials (IPSPs). However, paired-pulse facilitation (PPF) ratios of evoked IPSPs were significantly lower and spontaneous miniature inhibitory postsynaptic current (mIPSC) frequencies were higher in msP rats, suggesting increased CeA GABA release in msP as compared to Sprague-Dawley and Wistar rats. The sensitivity of spontaneous GABAergic transmission to ethanol (44 mM), CRF (200 nM) and CRF1 antagonist (R121919, 1 μM) was comparable in msP, Sprague Dawley, and Wistar rats. However, a history of ethanol drinking significantly increased the baseline mIPSC frequency and decreased the effects of a CRF1 antagonist in msP rats, suggesting increased GABA release and decreased CRF1 sensitivity. These results provide electrophysiological evidence that msP rats display distinct CeA GABAergic activity as compared to Sprague Dawley and Wistar rats. The elevated GABAergic transmission observed in naïve mSP rats is consistent with the neuroadaptations reported in Sprague Dawley rats after the development of ethanol dependence. PMID:23220399

Kinetics of Exocytosis Is Faster in Cones Than in Rods

PubMed Central

Rabl, Katalin; Cadetti, Lucia; Thoreson, Wallace B.

2006-01-01

Cone-driven responses of second-order retinal neurons are considerably faster than rod-driven responses. We examined whether differences in the kinetics of synaptic transmitter release from rods and cones may contribute to differences in postsynaptic response kinetics. Exocytosis from rods and cones was triggered by membrane depolarization and monitored in two ways: (1) by measuring EPSCs evoked in second-order neurons by depolarizing steps applied to presynaptic rods or cones during simultaneous paired whole-cell recordings or (2) by direct measurements of exocytotic increases in membrane capacitance. The kinetics of release was assessed by varying the length of the depolarizing test step. Both measures of release revealed two kinetic components to the increase in exocytosis as a function of the duration of a step depolarization. In addition to slow sustained components in both cell types, the initial fast component of exocytosis had a time constant of <5 ms in cones, >10-fold faster than that of rods. Rod/cone differences in the kinetics of release were substantiated by a linear correlation between depolarization-evoked capacitance increases and EPSC charge transfer. Experiments on isolated rods indicate that the slower kinetics of exocytosis from rods was not a result of rod–rod coupling. The initial rapid release of vesicles from cones can shape the postsynaptic response and may contribute to the faster responses of cone-driven cells observed at light offset. PMID:15872111

Sub- and suprathreshold receptive field properties of pyramidal neurones in layers 5A and 5B of rat somatosensory barrel cortex

PubMed Central

Manns, Ian D; Sakmann, Bert; Brecht, Michael

2004-01-01

Layer 5 (L5) pyramidal neurones constitute a major sub- and intracortical output of the somatosensory cortex. This layer 5 is segregated into layers 5A and 5B which receive and distribute relatively independent afferent and efferent pathways. We performed in vivo whole-cell recordings from L5 neurones of the somatosensory (barrel) cortex of urethane-anaesthetized rats (aged 27–31 days). By delivering 6 deg single whisker deflections, whisker pad receptive fields were mapped for 16 L5A and 11 L5B neurones located below the layer 4 whisker-barrels. Average resting membrane potentials were −75.6±1.1 mV, and spontaneous action potential (AP) rates were 0.54± 0.14 APs s−1. Principal whisker (PW) evoked responses were similar in L5A and L5B neurones, with an average 5.0 ± 0.6 mV postsynaptic potential (PSP) and 0.12 ± 0.03 APs per stimulus. The layer 5A sub- and suprathreshold receptive fields (RFs) were more confined to the principle whisker than those of layer 5B. The basal dendritic arbors of layer 5A and 5B cells were located below both layer 4 barrels and septa, and the cell bodies were biased towards the barrel walls. Responses in both L5A and L5B developed slowly, with onset latencies of 10.1 ± 0.5 ms and peak latencies of 33.9 ± 3.3 ms. Contralateral multi-whisker stimulation evoked PSPs similar in amplitude to those of PW deflections; whereas, ipsilateral stimulation evoked smaller and longer latency PSPs. We conclude that in L5 a whisker deflection is represented in two ways: focally by L5A pyramids and more diffusely by L5B pyramids as a result of combining different inputs from lemniscal and paralemniscal pathways. The relevant output evoked by a whisker deflection could be the ensemble activity in the anatomically defined cortical modules associated with a single or a few barrel-columns. PMID:14724202

Computational Modeling of Single Neuron Extracellular Electric Potentials and Network Local Field Potentials using LFPsim.

PubMed

Parasuram, Harilal; Nair, Bipin; D'Angelo, Egidio; Hines, Michael; Naldi, Giovanni; Diwakar, Shyam

2016-01-01

Local Field Potentials (LFPs) are population signals generated by complex spatiotemporal interaction of current sources and dipoles. Mathematical computations of LFPs allow the study of circuit functions and dysfunctions via simulations. This paper introduces LFPsim, a NEURON-based tool for computing population LFP activity and single neuron extracellular potentials. LFPsim was developed to be used on existing cable compartmental neuron and network models. Point source, line source, and RC based filter approximations can be used to compute extracellular activity. As a demonstration of efficient implementation, we showcase LFPs from mathematical models of electrotonically compact cerebellum granule neurons and morphologically complex neurons of the neocortical column. LFPsim reproduced neocortical LFP at 8, 32, and 56 Hz via current injection, in vitro post-synaptic N2a, N2b waves and in vivo T-C waves in cerebellum granular layer. LFPsim also includes a simulation of multi-electrode array of LFPs in network populations to aid computational inference between biophysical activity in neural networks and corresponding multi-unit activity resulting in extracellular and evoked LFP signals.

Effects of 17beta-estradiol on glutamate synaptic transmission and neuronal excitability in the rat medial vestibular nuclei.

PubMed

Grassi, S; Frondaroli, A; Scarduzio, M; Dutia, M B; Dieni, C; Pettorossi, V E

2010-02-17

We investigated the effects of the neurosteroid 17beta-estradiol (E(2)) on the evoked and spontaneous activity of rat medial vestibular nucleus (MVN) neurons in brainstem slices. E(2) enhances the synaptic response to vestibular nerve stimulation in type B neurons and depresses the spontaneous discharge in both type A and B neurons. The amplitude of the field potential, as well as the excitatory post-synaptic potential (EPSP) and current (EPSC), in type B neurons, are enhanced by E(2). Both effects are long-term phenomena since they outlast the drug washout. The enhancement of synaptic response is mainly due to facilitation of glutamate release mediated by pre-synaptic N-methyl-D-aspartate receptors (NMDARs), since the reduction of paired pulse ratio (PPR) and the increase of miniature EPSC frequency after E(2) are abolished under D-(-)-2-amino-5-phosphonopentanoic acid (AP-5). E(2) also facilitates post-synaptic NMDARs, but it does not affect directly alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and group I-metabotropic glutamate receptors (mGluRs-I). In contrast, the depression of the spontaneous discharge of type A and type B neurons appears to depend on E(2) modulation of intrinsic ion conductances, as the effect remains after blockade of glutamate, GABA and glycine receptors (GlyRs). The net effect of E(2) is to enhance the signal-to-noise ratio of the synaptic response in type B neurons, relative to resting activity of all MVN neurons. These findings provide evidence for a novel potential mechanism to modulate the responsiveness of vestibular neurons to afferent inputs, and so regulate vestibular function in vivo.

Adenosine inhibits activity of hypocretin/orexin neurons via A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect

PubMed Central

Liu, Zhong-Wu; Gao, Xiao-Bing

2006-01-01

Neurons in the lateral hypothalamus (LH) that contain hypocretin/orexin have been established as important promoters of arousal. Deficiencies in the hypocretin/orexin system lead to narcolepsy. The inhibition of hypocretin/orexin neurons by sleep-promoting neurotransmitters has been suggested as one part of the sleep regulation machinery. Adenosine has been identified as a sleep promoter and its role in sleep regulation in the basal forebrain has been well documented. However, the effect of adenosine on arousal-promoting hypocretin/orexin neurons has not been addressed, despite recent evidence that immunocytochemical visualization of adenosine receptors was detected in these neurons. In this study, we examined the hypothesis that adenosine inhibits the activity of hypocretin/orexin neurons by using electrophysiological methods in brain slices from mice expressing green fluorescent protein in hypocretin/orexin neurons. We found that adenosine significantly attenuated the frequency of action potentials without a change in membrane potential in hypocretin/orexin neurons. The adenosine-mediated inhibition is due to depression of excitatory synaptic transmission to hypocretin/orexin neurons, since adenosine depresses the amplitude of evoked excitatory postsynaptic potential and the frequency of spontaneous and miniature excitatory postsynaptic currents in these neurons. At the cell body of the hypocretin/orexin neurons, adenosine inhibits voltage-dependent calcium currents without the induction of GIRK current. The inhibitory effect of adenosine is dose-dependent, pertussis toxin-sensitive and mediated via A1 receptors. In summary, our data suggest that in addition to its effect in the basal forebrain, adenosine exerts its sleep-promoting effect in the LH via inhibition of hypocretin/orexin neurons. PMID:17093123

K+-induced alterations in airway muscle responsiveness to electrical field stimulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murlas, C.; Ehring, G.; Suszkiw, J.

1986-07-01

We investigated possible pre- and postsynaptic effects of K+-induced depolarization on ferret tracheal smooth muscle (TSM) responsiveness to cholinergic stimulation. To assess electromechanical activity, cell membrane potential (Em) and tension (Tm) were simultaneously recorded in buffer containing 6, 12, 18, or 24 mM K+ before and after electrical field stimulation (EFS) or exogenous acetylcholine (ACh). In 6 mM K+, Em was -58.1 +/- 1.0 mV (mean +/- SE). In 12 mM K+, Em was depolarized to -52.3 +/- 0.9 mV, basal Tm did not change, and both excitatory junctional potentials and contractile responses to EFS at short stimulus duration weremore » larger than in 6 mM K+. No such potentiation occurred at a higher K+, although resting Em and Tm increased progressively above 12 mM K+. The sensitivity of ferret TSM to exogenous ACh appeared unaffected by K+. To determine whether the hyperresponsiveness in 12 mM K+ was due, in part, to augmented ACh release from intramural airway nerves, experiments were done using TSM preparations incubated with (3H)choline to measure (3H)ACh release at rest and during EFS. Although resting (3H)ACh release increased progressively in higher K+, release evoked by EFS was maximal in 12 mM K+ and declined in higher concentrations. We conclude that small elevations in the extracellular K+ concentration augment responsiveness of the airways, by increasing the release of ACh both at rest and during EFS from intramural cholinergic nerve terminals. Larger increases in K+ appear to be inhibitory, possibly due to voltage-dependent effects that occur both pre- and postsynaptically.« less

Spike-timing-dependent plasticity in the human dorso-lateral prefrontal cortex.

PubMed

Casula, Elias Paolo; Pellicciari, Maria Concetta; Picazio, Silvia; Caltagirone, Carlo; Koch, Giacomo

2016-12-01

Changes in the synaptic strength of neural connections are induced by repeated coupling of activity of interconnected neurons with precise timing, a phenomenon known as spike-timing-dependent plasticity (STDP). It is debated if this mechanism exists in large-scale cortical networks in humans. We combined transcranial magnetic stimulation (TMS) with concurrent electroencephalography (EEG) to directly investigate the effects of two paired associative stimulation (PAS) protocols (fronto-parietal and parieto-frontal) of pre and post-synaptic inputs within the human fronto-parietal network. We found evidence that the dorsolateral prefrontal cortex (DLPFC) has the potential to form robust STDP. Long-term potentiation/depression of TMS-evoked cortical activity is prompted after that DLPFC stimulation is followed/preceded by posterior parietal stimulation. Such bidirectional changes are paralleled by sustained increase/decrease of high-frequency oscillatory activity, likely reflecting STDP responsivity. The current findings could be important to drive plasticity of damaged cortical circuits in patients with cognitive or psychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

BK Channels Are Required for Multisensory Plasticity in the Oculomotor System.

PubMed

Nelson, Alexandra B; Faulstich, Michael; Moghadam, Setareh; Onori, Kimberly; Meredith, Andrea; du Lac, Sascha

2017-01-04

Neural circuits are endowed with several forms of intrinsic and synaptic plasticity that could contribute to adaptive changes in behavior, but circuit complexities have hindered linking specific cellular mechanisms with their behavioral consequences. Eye movements generated by simple brainstem circuits provide a means for relating cellular plasticity to behavioral gain control. Here we show that firing rate potentiation, a form of intrinsic plasticity mediated by reductions in BK-type calcium-activated potassium currents in spontaneously firing neurons, is engaged during optokinetic reflex compensation for inner ear dysfunction. Vestibular loss triggers transient increases in postsynaptic excitability, occlusion of firing rate potentiation, and reductions in BK currents in vestibular nucleus neurons. Concurrently, adaptive increases in visually evoked eye movements rapidly restore oculomotor function in wild-type mice but are profoundly impaired in BK channel-null mice. Activity-dependent regulation of intrinsic excitability may be a general mechanism for adaptive control of behavioral output in multisensory circuits. Copyright © 2017 Elsevier Inc. All rights reserved.

A new and specific non-NMDA receptor antagonist, FG 9065, blocks L-AP4-evoked depolarization in rat cerebral cortex.

PubMed

Sheardown, M J

1988-04-13

L(+)-AP4 (2-amino-4-phosphonobutyrate) depolarized slices of rat cerebral cortex, when applied following a 2 min priming application of quisqualate. This response diminishes with time and is not seen after NMDA application. A new selective non-N-methyl-D-aspartate (NMDA) antagonist, 6-cyano-7-nitro-2,3-dihydroxyquinoxaline (FG 9065), inhibits the L(+)-AP4 depolarization. It is argued that the response is mediated indirectly by postsynaptic quisqualate receptors.

Acute hyperbilirubinaemia induces presynaptic neurodegeneration at a central glutamatergic synapse

PubMed Central

Haustein, Martin D; Read, David J; Steinert, Joern R; Pilati, Nadia; Dinsdale, David; Forsythe, Ian D

2010-01-01

There is a well-established link between hyperbilirubinaemia and hearing loss in paediatrics, but the cellular mechanisms have not been elucidated. Here we used the Gunn rat model of hyperbilirubinaemia to investigate bilirubin-induced hearing loss. In vivo auditory brainstem responses revealed that Gunn rats have severe auditory deficits within 18 h of exposure to high bilirubin levels. Using an in vitro preparation of the auditory brainstem from these rats, extracellular multi-electrode array recording from the medial nucleus of the trapezoid body (MNTB) showed longer latency and decreased amplitude of evoked field potentials following bilirubin exposure, suggestive of transmission failure at this synaptic relay. Whole-cell patch-clamp recordings confirmed that the electrophysiological properties of the postsynaptic MNTB neurons were unaffected by bilirubin, with no change in action potential waveforms or current–voltage relationships. However, stimulation of the trapezoid body was unable to elicit large calyceal EPSCs in MNTB neurons of hyperbilirubinaemic rats, indicative of damage at a presynaptic site. Multi-photon imaging of anterograde-labelled calyceal projections revealed axonal staining and presynaptic profiles around MNTB principal neuron somata. Following induction of hyperbilirubinaemia the giant synapses were largely destroyed. Electron microscopy confirmed loss of presynaptic calyceal terminals and supported the electrophysiological evidence for healthy postsynaptic neurons. MNTB neurons express high levels of neuronal nitric oxide synthase (nNOS). Nitric oxide has been implicated in mechanisms of bilirubin toxicity elsewhere in the brain, and antagonism of nNOS by 7-nitroindazole protected hearing during bilirubin exposure. We conclude that bilirubin-induced deafness is caused by degeneration of excitatory synaptic terminals in the auditory brainstem. PMID:20937712

Acute hyperbilirubinaemia induces presynaptic neurodegeneration at a central glutamatergic synapse.

PubMed

Haustein, Martin D; Read, David J; Steinert, Joern R; Pilati, Nadia; Dinsdale, David; Forsythe, Ian D

2010-12-01

There is a well-established link between hyperbilirubinaemia and hearing loss in paediatrics, but the cellular mechanisms have not been elucidated. Here we used the Gunn rat model of hyperbilirubinaemia to investigate bilirubin-induced hearing loss. In vivo auditory brainstem responses revealed that Gunn rats have severe auditory deficits within 18 h of exposure to high bilirubin levels. Using an in vitro preparation of the auditory brainstem from these rats, extracellular multi-electrode array recording from the medial nucleus of the trapezoid body (MNTB) showed longer latency and decreased amplitude of evoked field potentials following bilirubin exposure, suggestive of transmission failure at this synaptic relay. Whole-cell patch-clamp recordings confirmed that the electrophysiological properties of the postsynaptic MNTB neurons were unaffected by bilirubin, with no change in action potential waveforms or current-voltage relationships. However, stimulation of the trapezoid body was unable to elicit large calyceal EPSCs in MNTB neurons of hyperbilirubinaemic rats, indicative of damage at a presynaptic site. Multi-photon imaging of anterograde-labelled calyceal projections revealed axonal staining and presynaptic profiles around MNTB principal neuron somata. Following induction of hyperbilirubinaemia the giant synapses were largely destroyed. Electron microscopy confirmed loss of presynaptic calyceal terminals and supported the electrophysiological evidence for healthy postsynaptic neurons. MNTB neurons express high levels of neuronal nitric oxide synthase (nNOS). Nitric oxide has been implicated in mechanisms of bilirubin toxicity elsewhere in the brain, and antagonism of nNOS by 7-nitroindazole protected hearing during bilirubin exposure. We conclude that bilirubin-induced deafness is caused by degeneration of excitatory synaptic terminals in the auditory brainstem.

The non-competitive acetylcholinesterase inhibitor APS12-2 is a potent antagonist of skeletal muscle nicotinic acetylcholine receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grandič, Marjana; Aráoz, Romulo; Molgó, Jordi

APS12-2, a non-competitive acetylcholinesterase inhibitor, is one of the synthetic analogs of polymeric alkylpyridinium salts (poly-APS) isolated from the marine sponge Reniera sarai. In the present work the effects of APS12-2 were studied on isolated mouse phrenic nerve–hemidiaphragm muscle preparations, using twitch tension measurements and electrophysiological recordings. APS12-2 in a concentration-dependent manner blocked nerve-evoked isometric muscle contraction (IC{sub 50} = 0.74 μM), without affecting directly-elicited twitch tension up to 2.72 μM. The compound (0.007–3.40 μM) decreased the amplitude of miniature endplate potentials until a complete block by concentrations higher than 0.68 μM, without affecting their frequency. Full size endplate potentials,more » recorded after blocking voltage-gated muscle sodium channels, were inhibited by APS12-2 in a concentration-dependent manner (IC{sub 50} = 0.36 μM) without significant change in the resting membrane potential of the muscle fibers up to 3.40 μM. The compound also blocked acetylcholine-evoked inward currents in Xenopus oocytes in which Torpedo (α1{sub 2}β1γδ) muscle-type nicotinic acetylcholine receptors (nAChRs) have been incorporated (IC{sub 50} = 0.0005 μM), indicating a higher affinity of the compound for Torpedo (α1{sub 2}β1γδ) than for the mouse (α1{sub 2}β1γε) nAChR. Our data show for the first time that APS12-2 blocks neuromuscular transmission by a non-depolarizing mechanism through an action on postsynaptic nAChRs of the skeletal neuromuscular junction. -- Highlights: ► APS12-2 produces concentration-dependent inhibition of nerve-evoked muscle contraction in vitro. ► APS12-2 blocks MEPPs and EPPs at the neuromuscular junction. APS12-2 blocks ACh-activated current in Xenopus oocytes incorporated with Torpedo nAChRs.« less

Tachykininergic slow depolarization of motoneurones evoked by descending fibres in the neonatal rat spinal cord.

PubMed Central

Kurihara, T; Yoshioka, K; Otsuka, M

1995-01-01

1. In the isolated spinal cord of the neonatal rat, repetitive electrical stimulation of the upper cervical region elicited a prolonged depolarization of lumbar motoneurones (L3-5) lasting 1-2 min, which was recorded extracellularly from ventral roots, or intracellularly. 2. This depolarizing response was markedly depressed by the excitatory amino acid receptor antagonists D-(-)-2-amino-5-phosphonovaleric acid (D-APV, 30 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). The remaining response was further depressed by a 5-hydroxytryptamine (5-HT) receptor antagonist, ketanserin (3 microM). 3. In the presence of these antagonists, a small part of the depolarizing response of slow time course remained, and this response was partially blocked by the tachykinin NK1 receptor antagonists GR71251 (0.3-5 microM) and RP67580 (0.3-1 microM). In contrast, RP68651 (0.3-1 microM), the inactive enantiomer of RP67580, had no effect on the depolarizing response. 4. The slow depolarizing response in the presence of D-APV, CNQX and ketanserin was markedly potentiated by a peptidase inhibitor, thiorphan (1 microM). 5. This descending fibre-evoked slow depolarization became smaller after prolonged treatment (5-7 h) with 5,7-dihydroxytryptamine (10 microM), a neurotoxin for 5-HT neurones. Under such conditions, the effects of thiorphan and GR71251 on the slow depolarization were virtually absent. 6. Under the action of D-APV, CNQX and ketanserin, applications of tachykinins, substance P and neurokinin A produced depolarizing responses of lumbar motoneurones, and the responses were depressed by GR71251 and potentiated by thiorphan. 7. These results suggest that tachykinins contained in serotonergic fibres serve as neurotransmitters mediating the descending fibre-evoked slow excitatory postsynaptic potentials in motoneurones. PMID:7562617

Actions of brain-derived neurotrophic factor on evoked and spontaneous EPSCs dissociate with maturation of neurones cultured from rat visual cortex

PubMed Central

Taniguchi, Nobuaki; Takada, Naoki; Kimura, Fumitaka; Tsumoto, Tadaharu

2000-01-01

To address the question of whether brain-derived neurotrophic factor (BDNF) directly enhances excitatory synaptic transmission, we recorded excitatory postsynaptic currents (EPSCs) from solitary neurones cultured on glial microislands for 7–38 days, and observed changes in EPSCs after the application of BDNF. In this preparation the possible action of BDNF on GABAergic inhibition was not involved, and evoked and spontaneous (miniature) EPSCs were derived from the same group of synapses (autapses). The application of BDNF at a concentration of 200 ng ml−1 rapidly enhanced the frequency of miniature EPSCs (mEPSCs) in almost all the neurones tested. On the other hand, the amplitude of mEPSCs did not change at all, suggesting that the site of BDNF action is presynaptic. In contrast to the enhanced frequency of mEPSCs, evoked EPSCs were not potentiated in 61 % of the cells tested. Most of these BDNF-insensitive EPSCs had a peak amplitude larger than 1 nA, while most of the other BDNF-sensitive EPSCs had a smaller amplitude. The former EPSCs had smaller coefficients of variation (CVs) of amplitude, while the latter had larger CVs, suggesting the possibility that the presynaptic release probability for the former groups of EPSCs might have beeen saturated so that the BDNF action was occluded. To test this possibility we applied a low Ca2+ solution to 17 cells and reduced the amplitude of their evoked EPSCs to less than or near to 1 nA. It was found, however, that BDNF did not enhance these EPSCs. Rather, evoked EPSCs of almost all the cells cultured for less than 15 days were enhanced by BDNF, while those of most of the cells cultured for longer than 16 days were not enhanced. These results suggest that BDNF enhances transmitter release from presynaptic sites through its action on the release machinery, which can be differentiated into a BDNF-insensitive form for evoked release and a BDNF-sensitive form for spontaneous release with maturation of synapses. PMID:10990542

Specialized postsynaptic morphology enhances neurotransmitter dilution and high-frequency signaling at an auditory synapse.

PubMed

Graydon, Cole W; Cho, Soyoun; Diamond, Jeffrey S; Kachar, Bechara; von Gersdorff, Henrique; Grimes, William N

2014-06-11

Sensory processing in the auditory system requires that synapses, neurons, and circuits encode information with particularly high temporal and spectral precision. In the amphibian papillia, sound frequencies up to 1 kHz are encoded along a tonotopic array of hair cells and transmitted to afferent fibers via fast, repetitive synaptic transmission, thereby promoting phase locking between the presynaptic and postsynaptic cells. Here, we have combined serial section electron microscopy, paired electrophysiological recordings, and Monte Carlo diffusion simulations to examine novel mechanisms that facilitate fast synaptic transmission in the inner ear of frogs (Rana catesbeiana and Rana pipiens). Three-dimensional anatomical reconstructions reveal specialized spine-like contacts between individual afferent fibers and hair cells that are surrounded by large, open regions of extracellular space. Morphologically realistic diffusion simulations suggest that these local enlargements in extracellular space speed transmitter clearance and reduce spillover between neighboring synapses, thereby minimizing postsynaptic receptor desensitization and improving sensitivity during prolonged signal transmission. Additionally, evoked EPSCs in afferent fibers are unaffected by glutamate transporter blockade, suggesting that transmitter diffusion and dilution, and not uptake, play a primary role in speeding neurotransmission and ensuring fidelity at these synapses. Copyright © 2014 the authors 0270-6474/14/348358-15$15.00/0.

Postsynaptic ERG potassium channels limit muscle excitability to allow distinct egg-laying behavior states in C. elegans

PubMed Central

Collins, Kevin M.; Koelle, Michael R.

2013-01-01

C. elegans regulates egg laying by alternating between an inactive phase and a serotonin-triggered active phase. We found that the conserved ERG potassium channel UNC-103 enables this two-state behavior by limiting excitability of the egg-laying muscles. Using both high-speed video recording and calcium imaging of egg-laying muscles in behaving animals, we found that the muscles appear to be excited at a particular phase of each locomotor body bend. During the inactive phase, this rhythmic excitation infrequently evokes calcium transients or contraction of the egg-laying muscles. During the serotonin-triggered active phase, however, these muscles are more excitable and each body bend is accompanied by a calcium transient that drives twitching or full contraction of the egg-laying muscles. We found that ERG null mutants lay eggs too frequently, and that ERG function is necessary and sufficient in the egg-laying muscles to limit egg laying. ERG K+ channels localize to postsynaptic sites in the egg-laying muscle, and mutants lacking ERG have more frequent calcium transients and contractions of the egg-laying muscles even during the inactive phase. Thus ERG channels set postsynaptic excitability at a threshold so that further adjustments of excitability by serotonin generate two distinct behavioral states. PMID:23303953

Regulation of Hypothalamic Presympathetic Neurons and Sympathetic Outflow by Group II Metabotropic Glutamate Receptors in Spontaneously Hypertensive Rats.

PubMed

Ye, Zeng-You; Li, De-Pei; Pan, Hui-Lin

2013-08-01

Increased glutamatergic input in the hypothalamic paraventricular nucleus (PVN) plays an important role in the development of hypertension. Group II metabotropic glutamate receptors are expressed in the PVN, but their involvement in regulating synaptic transmission and sympathetic outflow in hypertension is unclear. Here, we show that the group II metabotropic glutamate receptors agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) produced a significantly greater reduction in the frequency of spontaneous and miniature excitatory postsynaptic currents and in the amplitude of electrically evoked excitatory postsynaptic currents in retrogradely labeled spinally projecting PVN neurons in spontaneously hypertensive rats (SHRs) than in normotensive control rats. DCG-IV similarly decreased the frequency of GABAergic inhibitory postsynaptic currents of labeled PVN neurons in the 2 groups of rats. Strikingly, DCG-IV suppressed the firing of labeled PVN neurons only in SHRs. DCG-IV failed to inhibit the firing of PVN neurons of SHRs in the presence of ionotropic glutamate receptor antagonists. Lowering blood pressure with celiac ganglionectomy in SHRs normalized the DCG-IV effect on excitatory postsynaptic currents to the same level seen in control rats. Furthermore, microinjection of DCG-IV into the PVN significantly reduced blood pressure and sympathetic nerve activity in SHRs. Our findings provide new information that presynaptic group II metabotropic glutamate receptor activity at the glutamatergic terminals increases in the PVN in SHRs. Activation of group II metabotropic glutamate receptors in the PVN inhibits sympathetic vasomotor tone through attenuation of increased glutamatergic input and neuronal hyperactivity in SHRs.

Acetyl-L-carnitine improves aged brain function.

PubMed

Kobayashi, Satoru; Iwamoto, Machiko; Kon, Kazuo; Waki, Hatsue; Ando, Susumu; Tanaka, Yasukazu

2010-07-01

The effects of acetyl-L-carnitine (ALCAR), an acetyl derivative of L-carnitine, on memory and learning capacity and on brain synaptic functions of aged rats were examined. Male Fischer 344 rats were given ALCAR (100 mg/kg bodyweight) per os for 3 months and were subjected to the Hebb-Williams tasks and AKON-1 task to assess their learning capacity. Cholinergic activities were determined with synaptosomes isolated from brain cortices of the rats. Choline parameters, the high-affinity choline uptake, acetylcholine (ACh) synthesis and depolarization-evoked ACh release were all enhanced in the ALCAR group. An increment of depolarization-induced calcium ion influx into synaptosomes was also evident in rats given ALCAR. Electrophysiological studies using hippocampus slices indicated that the excitatory postsynaptic potential slope and population spike size were both increased in ALCAR-treated rats. These results indicate that ALCAR increases synaptic neurotransmission in the brain and consequently improves learning capacity in aging rats.

Feed-back modulation of cone synapses by L-horizontal cells of turtle retina.

PubMed

Gerschenfeld, H M; Piccolino, M; Neyton, J

1980-12-01

Light stimulation of the periphery of the receptive field of turtle cones can evoke both transient and sustained increases of the cone Ca2+ conductance, which may become regenerative. Such increase in the cone Ca2+ conductance evoked by peripheral illumination results from the activation of a polysynaptic pathway involving a feed-back connexion from the L-horizontal cells (L-HC) to the cones. Thus the hyperpolarization of a L-HC by inward current injection can evoke a Ca2+ conductance increase in neighbouring cones. The cone Ca2+ channels thus activated are likely located at its synaptic endings and probably intervene in the cone transmitter release. Therefore the feed-back connexion between L-HC and cones by modifying the Ca2+ conductance of cones could actually modulate the transmitter release from cone synapses. Such feed-back modulation of cone synapses plays a role in the organization of the colour-coded responses of the chromaticity type-horizontal cells and probably of other second order neurones, post-synaptic to the cones. The mechanisms operating the feed-back connexion from L-HC to cones are discussed.

Control of the subthalamic innervation of substantia nigra pars reticulata by D1 and D2 dopamine receptors.

PubMed

Ibañez-Sandoval, Osvaldo; Hernández, Adán; Florán, Benjamin; Galarraga, Elvira; Tapia, Dagoberto; Valdiosera, Rene; Erlij, David; Aceves, Jorge; Bargas, José

2006-03-01

The effects of activating dopaminergic D1 and D2 class receptors of the subthalamic projections that innervate the pars reticulata of the subtantia nigra (SNr) were explored in slices of the rat brain using the whole cell patch-clamp technique. Excitatory postsynaptic currents (EPSCs) that could be blocked by 6-cyano-7-nitroquinoxalene-2,3-dione and D-(-)-2-amino-5-phosphonopentanoic acid were evoked onto reticulata GABAergic projection neurons by local field stimulation inside the subthalamic nucleus in the presence of bicuculline. Bath application of (RS)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF-38393), a dopaminergic D1-class receptor agonist, increased evoked EPSCs by approximately 30% whereas the D2-class receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo(3,4-g)quinoline (quinpirole), reduced EPSCs by approximately 25%. These apparently opposing actions were blocked by the specific D1- and D2-class receptor antagonists: R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepinehydrochloride (SCH 23390) and S-(-)-5-amino-sulfonyl-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride), respectively. Both effects were accompanied by changes in the paired-pulse ratio, indicative of a presynaptic site of action. The presynaptic location of dopamine receptors at the subthalamonigral projections was confirmed by mean-variance analysis. The effects of both SKF-38393 and quinpirole could be observed on terminals contacting the same postsynaptic neuron. Sulpiride and SCH 23390 enhanced and reduced the evoked EPSC, respectively, suggesting a constitutive receptor activation probably arising from endogenous dopamine. These data suggest that dopamine presynaptically modulates the subthalamic projection that targets GABAergic neurons of the SNr. Implications of this modulation for basal ganglia function are discussed.

Long-term potentiation of synaptic response and intrinsic excitability in neurons of the rat medial vestibular nuclei.

PubMed

Pettorossi, V E; Dieni, C V; Scarduzio, M; Grassi, S

2011-07-28

Using intracellular recordings, we investigated the effects of high frequency stimulation (HFS) of the primary vestibular afferents on the evoked excitatory postsynaptic potential (EPSP) and intrinsic excitability (IE) of type-A and type-B neurons of the medial vestibular nucleus (MVN), in male rat brainstem slices. HFS induces long-term potentiation (LTP) of both EPSP and IE, which may occur in combination or separately. Synaptic LTP is characterized by an increase in the amplitude, slope and decay time constant of EPSP and IE-LTP through enhancements of spontaneous and evoked neuron firing and of input resistance (Rin). Moreover, IE-LTP is associated with a decrease in action potential afterhyperpolarization (AHP) amplitude and an increase in interspike slope steepness (ISS). The more frequent effects of HFS are EPSP-LTP in type-B neurons and IE-LTP in type-A neurons. In addition, the development of EPSP-LTP is fast in type-B neurons but slow in type-A, whereas IE-LTP develops slowly in both types. We have demonstrated that activation of N-methyl-d aspartate receptors (NMDARs) is only required for EPSP-LTP induction, whereas metabotropic glutamate receptors type-1 (mGluR1) are necessary for IE-LTP induction as well as the full development and maintenance of EPSP-LTP. Taken together, these findings demonstrate that brief and intense activation of vestibular afferent input to the MVN neurons may provoke synaptic LTP and/or IE-LTP that, induced in combination or separately, may assure the different selectivity of the MVN neuron response enhancement to the afferent signals. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Acetaminophen Metabolite N-Acylphenolamine Induces Analgesia via Transient Receptor Potential Vanilloid 1 Receptors Expressed on the Primary Afferent Terminals of C-fibers in the Spinal Dorsal Horn.

PubMed

Ohashi, Nobuko; Uta, Daisuke; Sasaki, Mika; Ohashi, Masayuki; Kamiya, Yoshinori; Kohno, Tatsuro

2017-08-01

The widely used analgesic acetaminophen is metabolized to N-acylphenolamine, which induces analgesia by acting directly on transient receptor potential vanilloid 1 or cannabinoid 1 receptors in the brain. Although these receptors are also abundant in the spinal cord, no previous studies have reported analgesic effects of acetaminophen or N-acylphenolamine mediated by the spinal cord dorsal horn. We hypothesized that clinical doses of acetaminophen induce analgesia via these spinal mechanisms. We assessed our hypothesis in a rat model using behavioral measures. We also used in vivo and in vitro whole cell patch-clamp recordings of dorsal horn neurons to assess excitatory synaptic transmission. Intravenous acetaminophen decreased peripheral pinch-induced excitatory responses in the dorsal horn (53.1 ± 20.7% of control; n = 10; P < 0.01), while direct application of acetaminophen to the dorsal horn did not reduce these responses. Direct application of N-acylphenolamine decreased the amplitudes of monosynaptic excitatory postsynaptic currents evoked by C-fiber stimulation (control, 462.5 ± 197.5 pA; N-acylphenolamine, 272.5 ± 134.5 pA; n = 10; P = 0.022) but not those evoked by stimulation of Aδ-fibers. These phenomena were mediated by transient receptor potential vanilloid 1 receptors, but not cannabinoid 1 receptors. The analgesic effects of acetaminophen and N-acylphenolamine were stronger in rats experiencing an inflammatory pain model compared to naïve rats. Our results suggest that the acetaminophen metabolite N-acylphenolamine induces analgesia directly via transient receptor potential vanilloid 1 receptors expressed on central terminals of C-fibers in the spinal dorsal horn and leads to conduction block, shunt currents, and desensitization of these fibers.

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

PubMed Central

Cruz, Maureen T; Herman, Melissa A; Cote, Dawn M; Ryabinin, Andrey E; Roberto, Marisa

2013-01-01

The neural circuitry that processes natural rewards converges with that engaged by addictive drugs. Because of this common neurocircuitry, drugs of abuse have been able to engage the hedonic mechanisms normally associated with the processing of natural rewards. Ghrelin is an orexigenic peptide that stimulates food intake by activating GHS-R1A receptors in the hypothalamus. However, ghrelin also activates GHS-R1A receptors on extrahypothalamic targets that mediate alcohol reward. The central nucleus of the amygdala (CeA) has a critical role in regulating ethanol consumption and the response to ethanol withdrawal. We previously demonstrated that rat CeA GABAergic transmission is enhanced by acute and chronic ethanol treatment. Here, we used quantitative RT-PCR (qRT-PCR) to detect Ghsr mRNA in the CeA and performed electrophysiological recordings to measure ghrelin effects on GABA transmission in this brain region. Furthermore, we examined whether acute or chronic ethanol treatment would alter these electrophysiological effects. Our qRT-PCR studies show the presence of Ghsr mRNA in the CeA. In naive animals, superfusion of ghrelin increased the amplitude of evoked inhibitory postsynaptic potentials (IPSPs) and the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Coapplication of ethanol further increased the ghrelin-induced enhancement of IPSP amplitude, but to a lesser extent than ethanol alone. When applied alone, ethanol significantly increased IPSP amplitude, but this effect was attenuated by the application of ghrelin. In neurons from chronic ethanol-treated (CET) animals, the magnitude of ghrelin-induced increases in IPSP amplitude was not significantly different from that in naive animals, but the ethanol-induced increase in amplitude was abolished. Superfusion of the GHS-R1A antagonists 𝒟-Lys3-GHRP-6 and JMV 3002 decreased evoked IPSP and mIPSC frequency, revealing tonic ghrelin activity in the CeA. 𝒟-Lys3-GHRP-6 and JMV 3002 also blocked ghrelin-induced increases in GABAergic responses. Furthermore, 𝒟-Lys3-GHRP-6 did not affect ethanol-induced increases in IPSP amplitude. These studies implicate a potential role for the ghrelin system in regulating GABAergic transmission and a complex interaction with ethanol at CeA GABAergic synapses. PMID:22968812

Role of AMPA and NMDA receptors and back-propagating action potentials in spike timing-dependent plasticity.

PubMed

Fuenzalida, Marco; Fernández de Sevilla, David; Couve, Alejandro; Buño, Washington

2010-01-01

The cellular mechanisms that mediate spike timing-dependent plasticity (STDP) are largely unknown. We studied in vitro in CA1 pyramidal neurons the contribution of AMPA and N-methyl-d-aspartate (NMDA) components of Schaffer collateral (SC) excitatory postsynaptic potentials (EPSPs; EPSP(AMPA) and EPSP(NMDA)) and of the back-propagating action potential (BAP) to the long-term potentiation (LTP) induced by a STDP protocol that consisted in pairing an EPSP and a BAP. Transient blockade of EPSP(AMPA) with 7-nitro-2,3-dioxo-1,4-dihydroquinoxaline-6-carbonitrile (CNQX) during the STDP protocol prevented LTP. Contrastingly LTP was induced under transient inhibition of EPSP(AMPA) by combining SC stimulation, an imposed EPSP(AMPA)-like depolarization, and BAP or by coupling the EPSP(NMDA) evoked under sustained depolarization (approximately -40 mV) and BAP. In Mg(2+)-free solution EPSP(NMDA) and BAP also produced LTP. Suppression of EPSP(NMDA) or BAP always prevented LTP. Thus activation of NMDA receptors and BAPs are needed but not sufficient because AMPA receptor activation is also obligatory for STDP. However, a transient depolarization of another origin that unblocks NMDA receptors and a BAP may also trigger LTP.

Radiation-induced alterations in synaptic neurotransmission of dentate granule cells depend on the dose and species of charged particles.

PubMed

Marty, V N; Vlkolinsky, R; Minassian, N; Cohen, T; Nelson, G A; Spigelman, I

2014-12-01

The evaluation of potential health risks associated with neuronal exposure to space radiation is critical for future long duration space travel. The purpose of this study was to evaluate and compare the effects of low-dose proton and high-energy charged particle (HZE) radiation on electrophysiological parameters of the granule cells in the dentate gyrus (DG) of the hippocampus and its associated functional consequences. We examined excitatory and inhibitory neurotransmission in DG granule cells (DGCs) in dorsal hippocampal slices from male C57BL/6 mice at 3 months after whole body irradiation with accelerated proton, silicon or iron particles. Multielectrode arrays were used to investigate evoked field synaptic potentials, an extracellular measurement of synaptic excitability in the perforant path to DG synaptic pathway. Whole-cell patch clamp recordings were used to measure miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in DGCs. Exposure to proton radiation increased synaptic excitability and produced dose-dependent decreases in amplitude and charge transfer of mIPSCs, without affecting the expression of γ-aminobutyric acid type A receptor α2, β3 and γ2 subunits determined by Western blotting. Exposure to silicon radiation had no significant effects on synaptic excitability, mEPSCs or mIPSCs of DGCs. Exposure to iron radiation had no effect on synaptic excitability and mIPSCs, but significantly increased mEPSC frequency at 1 Gy, without changes in mEPSC kinetics, suggesting a presynaptic mechanism. Overall, the data suggest that proton and HZE exposure results in radiation dose- and species-dependent long-lasting alterations in synaptic neurotransmission, which could cause radiation-induced impairment of hippocampal-dependent cognitive functions.

Tolerance to the antinociceptive effect of morphine in the absence of short-term presynaptic desensitization in rat periaqueductal gray neurons.

PubMed

Fyfe, Leon W; Cleary, Daniel R; Macey, Tara A; Morgan, Michael M; Ingram, Susan L

2010-12-01

Opioids activate the descending antinociceptive pathway from the ventrolateral periaqueductal gray (vlPAG) by both pre- and postsynaptic inhibition of tonically active GABAergic neurons (i.e., disinhibition). Previous research has shown that short-term desensitization of postsynaptic μ-opioid receptors (MOPrs) in the vlPAG is increased with the development of opioid tolerance. Given that pre- and postsynaptic MOPrs are coupled to different signaling mechanisms, the present study tested the hypothesis that short-term desensitization of presynaptic MOPrs also contributes to opioid tolerance. Twice-daily injections of morphine (5 mg/kg s.c.) for 2 days caused a rightward shift in the morphine dose-response curve on the hot plate test (D(50) = 9.9 mg/kg) compared with saline-pretreated (5.3 mg/kg) male Sprague-Dawley rats. In vitro whole-cell patch-clamp recordings from vlPAG slices revealed that inhibition of evoked inhibitory postsynaptic currents (eIPSCs) by the MOPr-selective agonist [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin was decreased in morphine-tolerant (EC(50) = 708 nM) compared with saline-pretreated rats (EC(50) = 163 nM). However, short-term desensitization of MOPr inhibition of eIPSCs was not observed in either saline- or morphine-pretreated rats. Reducing the number of available MOPrs with the irreversible opioid receptor antagonist, β-chlornaltrexamine decreased maximal MOPr inhibition with no evidence of desensitization, indicating that the lack of observed desensitization is not caused by receptor reserve. These results demonstrate that tolerance to the antinociceptive effect of morphine is associated with a decrease in presynaptic MOPr sensitivity or coupling to effectors, but this change is independent of short-term MOPr desensitization.

Tolerance to the Antinociceptive Effect of Morphine in the Absence of Short-Term Presynaptic Desensitization in Rat Periaqueductal Gray Neurons

PubMed Central

Fyfe, Leon W.; Cleary, Daniel R.; Macey, Tara A.; Morgan, Michael M.

2010-01-01

Opioids activate the descending antinociceptive pathway from the ventrolateral periaqueductal gray (vlPAG) by both pre- and postsynaptic inhibition of tonically active GABAergic neurons (i.e., disinhibition). Previous research has shown that short-term desensitization of postsynaptic μ-opioid receptors (MOPrs) in the vlPAG is increased with the development of opioid tolerance. Given that pre- and postsynaptic MOPrs are coupled to different signaling mechanisms, the present study tested the hypothesis that short-term desensitization of presynaptic MOPrs also contributes to opioid tolerance. Twice-daily injections of morphine (5 mg/kg s.c.) for 2 days caused a rightward shift in the morphine dose-response curve on the hot plate test (D50 = 9.9 mg/kg) compared with saline-pretreated (5.3 mg/kg) male Sprague-Dawley rats. In vitro whole-cell patch-clamp recordings from vlPAG slices revealed that inhibition of evoked inhibitory postsynaptic currents (eIPSCs) by the MOPr-selective agonist [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin was decreased in morphine-tolerant (EC50 = 708 nM) compared with saline-pretreated rats (EC50 = 163 nM). However, short-term desensitization of MOPr inhibition of eIPSCs was not observed in either saline- or morphine-pretreated rats. Reducing the number of available MOPrs with the irreversible opioid receptor antagonist, β-chlornaltrexamine decreased maximal MOPr inhibition with no evidence of desensitization, indicating that the lack of observed desensitization is not caused by receptor reserve. These results demonstrate that tolerance to the antinociceptive effect of morphine is associated with a decrease in presynaptic MOPr sensitivity or coupling to effectors, but this change is independent of short-term MOPr desensitization. PMID:20739455

Frequency-selective augmenting responses by short-term synaptic depression in cat neocortex

PubMed Central

Houweling, Arthur R; Bazhenov, Maxim; Timofeev, Igor; Grenier, François; Steriade, Mircea; Sejnowski, Terrence J

2002-01-01

Thalamic stimulation at frequencies between 5 and 15 Hz elicits incremental or ‘augmenting’ cortical responses. Augmenting responses can also be evoked in cortical slices and isolated cortical slabs in vivo. Here we show that a realistic network model of cortical pyramidal cells and interneurones including short-term plasticity of inhibitory and excitatory synapses replicates the main features of augmenting responses as obtained in isolated slabs in vivo. Repetitive stimulation of synaptic inputs at frequencies around 10 Hz produced postsynaptic potentials that grew in size and carried an increasing number of action potentials resulting from the depression of inhibitory synaptic currents. Frequency selectivity was obtained through the relatively weak depression of inhibitory synapses at low frequencies, and strong depression of excitatory synapses together with activation of a calcium-activated potassium current at high frequencies. This network resonance is a consequence of short-term synaptic plasticity in a network of neurones without intrinsic resonances. These results suggest that short-term plasticity of cortical synapses could shape the dynamics of synchronized oscillations in the brain. PMID:12122156

Vesicle Pool Size at the Salamander Cone Ribbon Synapse

PubMed Central

Bartoletti, Theodore M.; Babai, Norbert

2010-01-01

Cone light responses are transmitted to postsynaptic neurons by changes in the rate of synaptic vesicle release. Vesicle pool size at the cone synapse constrains the amount of release and can thus shape contrast detection. We measured the number of vesicles in the rapidly releasable and reserve pools at cone ribbon synapses by performing simultaneous whole cell recording from cones and horizontal or off bipolar cells in the salamander retinal slice preparation. We found that properties of spontaneously occurring miniature excitatory postsynaptic currents (mEPSCs) are representative of mEPSCs evoked by depolarizing presynaptic stimulation. Strong, brief depolarization of the cone stimulated release of the entire rapidly releasable pool (RRP) of vesicles. Comparing charge transfer of the EPSC with mEPSC charge transfer, we determined that the fast component of the EPSC reflects release of ∼40 vesicles. Comparing EPSCs with simultaneous presynaptic capacitance measurements, we found that horizontal cell EPSCs constitute 14% of the total number of vesicles released from a cone terminal. Using a fluorescent ribeye-binding peptide, we counted ∼13 ribbons per cone. Together, these results suggest each cone contacts a single horizontal cell at ∼2 ribbons. The size of discrete components in the EPSC amplitude histogram also suggested ∼2 ribbon contacts per cell pair. We therefore conclude there are ∼20 vesicles per ribbon in the RRP, similar to the number of vesicles contacting the plasma membrane at the ribbon base. EPSCs evoked by lengthy depolarization suggest a reserve pool of ∼90 vesicles per ribbon, similar to the number of additional docking sites further up the ribbon. PMID:19923246

Synaptic physiology of the flow of information in the cat's visual cortex in vivo

PubMed Central

Hirsch, Judith A; Martinez, Luis M; Alonso, José-Manuel; Desai, Komal; Pillai, Cinthi; Pierre, Carhine

2002-01-01

Each stage of the striate cortical circuit extracts novel information about the visual environment. We asked if this analytic process reflected laminar variations in synaptic physiology by making whole-cell recording with dye-filled electrodes from the cat's visual cortex and thalamus; the stimuli were flashed spots. Thalamic afferents terminate in layer 4, which contains two types of cell, simple and complex, distinguished by the spatial structure of the receptive field. Previously, we had found that the postsynaptic and spike responses of simple cells reliably followed the time course of flash-evoked thalamic activity. Here we report that complex cells in layer 4 (or cells intermediate between simple and complex) similarly reprised thalamic activity (response/trial, 99 ± 1.9 %; response duration 159 ± 57 ms; latency 25 ± 4 ms; average ± standard deviation; n = 7). Thus, all cells in layer 4 share a common synaptic physiology that allows secure integration of thalamic input. By contrast, at the second cortical stage (layer 2+3), where layer 4 directs its output, postsynaptic responses did not track simple patterns of antecedent activity. Typical responses to the static stimulus were intermittent and brief (response/trial, 31 ± 40 %; response duration 72 ± 60 ms, latency 39 ± 7 ms; n = 11). Only richer stimuli like those including motion evoked reliable responses. All told, the second level of cortical processing differs markedly from the first. At that later stage, ascending information seems strongly gated by connections between cortical neurons. Inputs must be combined in newly specified patterns to influence intracortical stages of processing. PMID:11927691

Neuropeptide y gates a stress-induced, long-lasting plasticity in the sympathetic nervous system.

PubMed

Wang, Qian; Wang, Manqi; Whim, Matthew D

2013-07-31

Acute stress evokes the fight-or-flight reflex, which via release of the catecholamine hormones affects the function of every major organ. Although the reflex is transient, it has lasting consequences that produce an exaggerated response when stress is reexperienced. How this change is encoded is not known. We investigated whether the reflex affects the adrenal component of the sympathetic nervous system, a major branch of the stress response. Mice were briefly exposed to the cold-water forced swim test (FST) which evoked an increase in circulating catecholamines. Although this hormonal response was transient, the FST led to a long-lasting increase in the catecholamine secretory capacity measured amperometrically from chromaffin cells and in the expression of tyrosine hydroxylase. A variety of approaches indicate that these changes are regulated postsynaptically by neuropeptide Y (NPY), an adrenal cotransmitter. Using immunohistochemistry, RT-PCR, and NPY(GFP) BAC mice, we find that NPY is synthesized by all chromaffin cells. Stress failed to increase secretory capacity in NPY knock-out mice. Genetic or pharmacological interference with NPY and Y1 (but not Y2 or Y5) receptor signaling attenuated the stress-induced change in tyrosine hydroxylase expression. These results indicate that, under basal conditions, adrenal signaling is tonically inhibited by NPY, but stress overrides this autocrine negative feedback loop. Because acute stress leads to a lasting increase in secretory capacity in vivo but does not alter sympathetic tone, these postsynaptic changes appear to be an adaptive response. We conclude that the sympathetic limb of the stress response exhibits an activity-dependent form of long-lasting plasticity.

Excitatory and inhibitory synaptic connectivity to layer V fast-spiking interneurons in the freeze lesion model of cortical microgyria

PubMed Central

Jin, Xiaoming; Jiang, Kewen

2014-01-01

A variety of major developmental cortical malformations are closely associated with clinically intractable epilepsy. Pathophysiological aspects of one such disorder, human polymicrogyria, can be modeled by making neocortical freeze lesions (FL) in neonatal rodents, resulting in the formation of microgyri. Previous studies showed enhanced excitatory and inhibitory synaptic transmission and connectivity in cortical layer V pyramidal neurons in the paramicrogyral cortex. In young adult transgenic mice that express green fluorescent protein (GFP) specifically in parvalbumin positive fast-spiking (FS) interneurons, we used laser scanning photostimulation (LSPS) of caged glutamate to map excitatory and inhibitory synaptic connectivity onto FS interneurons in layer V of paramicrogyral cortex in control and FL groups. The proportion of uncaging sites from which excitatory postsynaptic currents (EPSCs) could be evoked (hotspot ratio) increased slightly but significantly in FS cells of the FL vs. control cortex, while the mean amplitude of LSPS-evoked EPSCs at hotspots did not change. In contrast, the hotspot ratio of inhibitory postsynaptic currents (IPSCs) was significantly decreased in FS neurons of the FL cortex. These alterations in synaptic inputs onto FS interneurons may result in an enhanced inhibitory output. We conclude that alterations in synaptic connectivity to cortical layer V FS interneurons do not contribute to hyperexcitability of the FL model. Instead, the enhanced inhibitory output from these neurons may partially offset an earlier demonstrated increase in synaptic excitation of pyramidal cells and thereby maintain a relative balance between excitation and inhibition in the affected cortical circuitry. PMID:24990567

Long-term plasticity in identified hippocampal GABAergic interneurons in the CA1 area in vivo.

PubMed

Lau, Petrina Yau-Pok; Katona, Linda; Saghy, Peter; Newton, Kathryn; Somogyi, Peter; Lamsa, Karri P

2017-05-01

Long-term plasticity is well documented in synapses between glutamatergic principal cells in the cortex both in vitro and in vivo. Long-term potentiation (LTP) and -depression (LTD) have also been reported in glutamatergic connections to hippocampal GABAergic interneurons expressing parvalbumin (PV+) or nitric oxide synthase (NOS+) in brain slices, but plasticity in these cells has not been tested in vivo. We investigated synaptically-evoked suprathreshold excitation of identified hippocampal neurons in the CA1 area of urethane-anaesthetized rats. Neurons were recorded extracellularly with glass microelectrodes, and labelled with neurobiotin for anatomical analyses. Single-shock electrical stimulation of afferents from the contralateral CA1 elicited postsynaptic action potentials with monosynaptic features showing short delay (9.95 ± 0.41 ms) and small jitter in 13 neurons through the commissural pathway. Theta-burst stimulation (TBS) generated LTP of the synaptically-evoked spike probability in pyramidal cells, and in a bistratified cell and two unidentified fast-spiking interneurons. On the contrary, PV+ basket cells and NOS+ ivy cells exhibited either LTD or LTP. An identified axo-axonic cell failed to show long-term change in its response to stimulation. Discharge of the cells did not explain whether LTP or LTD was generated. For the fast-spiking interneurons, as a group, no correlation was found between plasticity and local field potential oscillations (1-3 or 3-6 Hz components) recorded immediately prior to TBS. The results demonstrate activity-induced long-term plasticity in synaptic excitation of hippocampal PV+ and NOS+ interneurons in vivo. Physiological and pathological activity patterns in vivo may generate similar plasticity in these interneurons.

The facilitating effect of systemic administration of Kv7/M channel blocker XE991 on LTP induction in the hippocampal CA1 area independent of muscarinic activation.

PubMed

Song, Ming-Ke; Cui, Yong-Yao; Zhang, Wei-Wei; Zhu, Liang; Lu, Yang; Chen, Hong-Zhuan

2009-09-11

A large amount of in vitro studies demonstrate suppression of M-current in hippocampal neurons by Kv7/M channel blocker results in depolarization of membrane potential and release of neurotransmitters, such as acetylcholine and glutamate, suggesting that Kv7/M channel may play important roles in regulating synaptic plasticity. In the present study, we examined the in vivo effect of Kv7/M channel inhibition on the long-term potentiation (LTP) induction at basal dendrites in hippocampal CA1 area of urethane-anaesthetized rats. The Kv7/M channel was inhibited by intraperitoneal injection of XE991 (10mg/kg) and the LTP of field excitatory postsynaptic potential (fEPSP) was induced by supra-threshold high frequency stimulation (S1 HFS). A weak protocol which was just below the threshold for evoking LTP was used as sub-threshold high frequency stimulation (S2 HFS). XE991 did not significantly alter the slope of fEPSP and the magnitude of LTP induced by S1 HFS, suggesting that Kv7/M channel inhibition had little or no effect on glutamatergic transmission under basal conditions. However, XE991 could make S2 HFS evoke LTP even after the application of the muscarinic cholinergic (mACh) receptor antagonist scopolamine, suggesting that Kv7/M channel inhibition lowered the threshold for LTP induction and the effect was independent of muscarinic activation. Based on the above findings, we concluded that the facilitating effect of XE991 on LTP induction is not mediated by its ability to enhance the release of acetylcholine; therefore, Kv7/M channel blockers may provide a therapeutic benefit to cholinergic deficiency-related cognitive impairment, e.g., Alzheimer's disease.

Interactions between superficial and deep dorsal horn spinal cord neurons in the processing of nociceptive information.

PubMed

Petitjean, Hugues; Rodeau, Jean-Luc; Schlichter, Rémy

2012-12-01

In acute rat spinal cord slices, the application of capsaicin (5 μm, 90 s), an agonist of transient receptor potential vanilloid 1 receptors expressed by a subset of nociceptors that project to laminae I-II of the spinal cord dorsal horn, induced an increase in the frequency of spontaneous excitatory and spontaneous inhibitory postsynaptic currents in about half of the neurons in laminae II, III-IV and V. In the presence of tetrodotoxin, which blocks action potential generation and polysynaptic transmission, capsaicin increased the frequency of miniature excitatory postsynaptic currents in only 30% of lamina II neurons and had no effect on the frequency of miniature excitatory postsynaptic currents in laminae III-V or on the frequency of miniature inhibitory postsynaptic currents in laminae II-V. When the communication between lamina V and more superficial laminae was interrupted by performing a mechanical section between laminae IV and V, capsaicin induced an increase in spontaneous excitatory postsynaptic current frequency in laminae II-IV and an increase in spontaneous inhibitory postsynaptic current frequency in lamina II that were similar to those observed in intact slices. However, in laminae III-IV of transected slices, the increase in spontaneous inhibitory postsynaptic current frequency was virtually abolished. Our results indicate that nociceptive information conveyed by transient receptor potential vanilloid 1-expressing nociceptors is transmitted from lamina II to deeper laminae essentially by an excitatory pathway and that deep laminae exert a 'feedback' control over neurons in laminae III-IV by increasing inhibitory synaptic transmission in these laminae. Moreover, we provide evidence that laminae III-IV might play an important role in the processing of nociceptive information in the dorsal horn. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Modulatory Action by the Serotonergic System: Behavior and Neurophysiology in Drosophila melanogaster

PubMed Central

Majeed, Zana R.; Abdeljaber, Esraa; Soveland, Robin; Cornwell, Kristin; Bankemper, Aubrey; Koch, Felicitas; Cooper, Robin L.

2016-01-01

Serotonin modulates various physiological processes and behaviors. This study investigates the role of 5-HT in locomotion and feeding behaviors as well as in modulation of sensory-motor circuits. The 5-HT biosynthesis was dysregulated by feeding Drosophila larvae 5-HT, a 5-HT precursor, or an inhibitor of tryptophan hydroxylase during early stages of development. The effects of feeding fluoxetine, a selective serotonin reuptake inhibitor, during early second instars were also examined. 5-HT receptor subtypes were manipulated using RNA interference mediated knockdown and 5-HT receptor insertional mutations. Moreover, synaptic transmission at 5-HT neurons was blocked or enhanced in both larvae and adult flies. The results demonstrate that disruption of components within the 5-HT system significantly impairs locomotion and feeding behaviors in larvae. Acute activation of 5-HT neurons disrupts normal locomotion activity in adult flies. To determine which 5-HT receptor subtype modulates the evoked sensory-motor activity, pharmacological agents were used. In addition, the activity of 5-HT neurons was enhanced by expressing and activating TrpA1 channels or channelrhodopsin-2 while recording the evoked excitatory postsynaptic potentials (EPSPs) in muscle fibers. 5-HT2 receptor activation mediates a modulatory role in a sensory-motor circuit, and the activation of 5-HT neurons can suppress the neural circuit activity, while fluoxetine can significantly decrease the sensory-motor activity. PMID:26989517

The effect of propofol on CA1 pyramidal cell excitability and GABAA-mediated inhibition in the rat hippocampal slice.

PubMed

Albertson, T E; Walby, W F; Stark, L G; Joy, R M

1996-05-24

An in vitro paired-pulse orthodromic stimulation technique was used to examine the effects of propofol on excitatory afferent terminals, CA1 pyramidal cells and recurrent collateral evoked inhibition in the rat hippocampal slice. Hippocampal slices 400 microns thick were perfused with oxygenated artificial cerebrospinal fluid, and electrodes were placed in the CA1 region to record extracellular field population spike (PS) or excitatory postsynaptic potential (EPSP) responses to stimulation of Schaffer collateral/commissural fibers. Gamma-aminobutyric acid (GABA)-mediated recurrent inhibition was measured using a paired-pulse technique. The major effect of propofol (7-28 microM) was a dose and time dependent increase in the intensity and duration of GABA-mediated inhibition. This propofol effect could be rapidly and completely reversed by exposure to known GABAA antagonists, including picrotoxin, bicuculline and pentylenetetrazol. It was also reversed by the chloride channel antagonist, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). It was not antagonized by central (flumazenil) or peripheral (PK11195) benzodiazepine antagonists. Reversal of endogenous inhibition was also noted with the antagonists picrotoxin and pentylenetetrazol. Input/output curves constructed using stimulus propofol caused only a small enhancement of EPSPs at higher stimulus intensities but had no effect on PS amplitudes. These studies are consistent with propofol having a GABAA-chloride channel mechanism causing its effect on recurrent collateral evoked inhibition in the rat hippocampal slice.

Characteristics of mucosally projecting myenteric neurones in the guinea-pig proximal colon

PubMed Central

Neunlist, Michel; Dobreva, Gisela; Schemann, Michael

1999-01-01

Using retrograde tracing with 1,1′-didodecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) in combination with electrophysiological and immunohistochemical techniques we determined the properties of the putative intrinsic primary afferent myenteric neurones with mucosal projections in the guinea-pig proximal colon. Eighty-four out of eighty-five DiI-labelled myenteric neurones were AH neurones with a late after-hyperpolarization. Thirty-three per cent of them exhibited atropine- and tetrodotoxin-resistant spontaneously occurring hyperpolarizing potentials (SHPs) during which the membrane resistance and excitability decreased. DiI-labelled AH neurones had multipolar Dogiel type II morphology, primarily of the dendritic type. Sixty-one per cent of the neurones were immunoreactive for choline acetyltransferase (ChAT) and calbindin (Calb) and 23% were ChAT positive but Calb negative. DiI-labelled neurones did not receive fast excitatory postsynaptic potentials but 94% (34/36) received slow excitatory postsynaptic potentials (sEPSPs). The neurokinin-3 (NK-3) agonist (MePhe7)-NKB but not the NK-1 agonist [(SAR9,Met(O2)11]-SP mimicked this response. The NK-3 receptor antagonist SR 142801 (1 μm) significantly decreased the amplitude and duration of the sEPSPs; the NK-1 receptor antagonist CP-99,994 (1 μm) was ineffective. Atropine (0.5 μm) increased the duration but not the amplitude of the sEPSPs. Microejection of 100 mM sodium butyrate onto the neurones induced in 90% of the DiI-labelled neurones a transient depolarization associated with an increased excitability. In neurones with SHPs sodium butyrate evoked, additionally, a late onset hyperpolarization. Perfusion of 0.1-10 mM sodium butyrate induced a dose-dependent increase in neuronal excitability. Sodium butyrate was ineffective when applied directly onto the mucosa. Mucosally projecting myenteric neurones of the colon are multipolar AH neurones with NK-3-mediated slow EPSPs and somal butyrate sensitivity. PMID:10332100

K/sup +/-induced alterations in airway muscle responsiveness to electrical field stimulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murlas, C.; Ehring, G.; Suszkiw, J.

1986-07-01

The authors investigated possible pre- and postsynaptic effects of K/sup +/-induced depolarization on ferret tracheal smooth muscle (TSM) responsiveness to cholinergic stimulation. To assess electromechanical activity, cell membrane potential (E/sub m/) and tension (T/sub m/) were simultaneously recorded in buffer containing 6, 12, 18, or 24 mM K/sup +/ before and after electrical field stimulation (EFS) or exogenous acetylcholine (ACh). In 6 mM K/sup +/ E/sub m/ was -58.1 +/- 1.0 m V (mean +/- SE). In 12 mM K/sup +/, E/sub m/ was depolarized to -52.3 +/- 0.9 mV, basal T/sub m/ did not change, and both excitatory junctionalmore » potentials and contractile responses to EFS at short stimulus duration were larger than in 6 mM K/sup +/. No such potentiation occurred at a higher K/sup +/, although resting E/sub m/ and T/sub m/ increased progressively above 12 mM K/sup +/. The sensitivity of ferret TSM to exogenous ACh appeared unaffected by K/sup +/. To determine whether the hyperresponsiveness in 12 mM K/sup +/ was due, in part, to augmented ACh release from intramural airway nerves, experiments were done using TSM preparations incubated with (/sup 3/H)choline to measure (/sup 3/H)ACh release at rest and during EFS. Although resting (/sup 3/H)ACh release increased progressively in higher K/sup +/, release evoked by EFS was maximal in 12 mM K/sup +/ and declined in higher concentrations. They conclude that small elevations in the extracellular K/sup +/ concentration augment responsiveness of the airways, by increasing the release of ACh both at rest and during EFS from intramural cholinergic nerve terminals. Larger increases in K/sup +/ appear to be inhibitory, possibly due to voltage-dependent effects that occur both pre- and postsynaptically.« less

Input- and subunit-specific AMPA receptor trafficking underlying long-term potentiation at hippocampal CA3 synapses.

PubMed

Kakegawa, Wataru; Tsuzuki, Keisuke; Yoshida, Yukari; Kameyama, Kimihiko; Ozawa, Seiji

2004-07-01

Hippocampal CA3 pyramidal neurons receive synaptic inputs from both mossy fibres (MFs) and associational fibres (AFs). Long-term potentiation (LTP) at these synapses differs in its induction sites and N-methyl-D-aspartate receptor (NMDAR) dependence. Most evidence favours the presynaptic and postsynaptic mechanisms for induction of MF LTP and AF LTP, respectively. This implies that molecular and functional properties differ between MF and AF synapses at both presynaptic and postsynaptic sites. In this study, we focused on the difference in the postsynaptic trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) between these synapses. To trace the subunit-specific trafficking of AMPARs at each synapse, GluR1 and GluR2 subunits were introduced into CA3 pyramidal neurons in hippocampal organotypic cultures using the Sindbis viral expression system. The electrophysiologically-tagged GluR2 AMPARs, produced by the viral-mediated transfer of the unedited form of GluR2 (GluR2Q), were inserted into both MF and AF postsynaptic sites in a neuronal activity-independent manner. Endogenous Ca(2+)-impermeable AMPARs at these synapses were replaced with exogenous Ca(2+)-permeable receptors, and Ca(2+) influx via the newly expressed postsynaptic AMPARs induced NMDAR-independent LTP at AF synapses. In contrast, no GluR1 AMPAR produced by the gene transfer was constitutively incorporated into AF postsynaptic sites, and only a small amount into MF postsynaptic sites. The synaptic trafficking of GluR1 AMPARs was triggered by the activity of Ca(2+)/calmodulin-dependent kinase II or high-frequency stimulation to induce LTP at AF synapses, but not at MF synapses. These results indicate that MF and AF postsynaptic sites possess distinct properties for AMPAR trafficking in CA3 pyramidal neurons.

Processing Semblances Induced through Inter-Postsynaptic Functional LINKs, Presumed Biological Parallels of K-Lines Proposed for Building Artificial Intelligence

PubMed Central

Vadakkan, Kunjumon I.

2011-01-01

The internal sensation of memory, which is available only to the owner of an individual nervous system, is difficult to analyze for its basic elements of operation. We hypothesize that associative learning induces the formation of functional LINK between the postsynapses. During memory retrieval, the activation of either postsynapse re-activates the functional LINK evoking a semblance of sensory activity arriving at its opposite postsynapse, nature of which defines the basic unit of internal sensation – namely, the semblion. In neuronal networks that undergo continuous oscillatory activity at certain levels of their organization re-activation of functional LINKs is expected to induce semblions, enabling the system to continuously learn, self-organize, and demonstrate instantiation, features that can be utilized for developing artificial intelligence (AI). This paper also explains suitability of the inter-postsynaptic functional LINKs to meet the expectations of Minsky’s K-lines, basic elements of a memory theory generated to develop AI and methods to replicate semblances outside the nervous system. PMID:21845180

Cholinergic Interneurons Mediate Fast VGluT3-Dependent Glutamatergic Transmission in the Striatum

PubMed Central

Higley, Michael J.; Balthasar, Nina; Seal, Rebecca P.; Edwards, Robert H.; Lowell, Bradford B.; Kreitzer, Anatol C.; Sabatini, Bernardo L.

2011-01-01

The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity. PMID:21544206

Selectively driving cholinergic fibers optically in the thalamic reticular nucleus promotes sleep

PubMed Central

Ni, Kun-Ming; Hou, Xiao-Jun; Yang, Ci-Hang; Dong, Ping; Li, Yue; Zhang, Ying; Jiang, Ping; Berg, Darwin K; Duan, Shumin; Li, Xiao-Ming

2016-01-01

Cholinergic projections from the basal forebrain and brainstem are thought to play important roles in rapid eye movement (REM) sleep and arousal. Using transgenic mice in which channelrhdopsin-2 is selectively expressed in cholinergic neurons, we show that optical stimulation of cholinergic inputs to the thalamic reticular nucleus (TRN) activates local GABAergic neurons to promote sleep and protect non-rapid eye movement (NREM) sleep. It does not affect REM sleep. Instead, direct activation of cholinergic input to the TRN shortens the time to sleep onset and generates spindle oscillations that correlate with NREM sleep. It does so by evoking excitatory postsynaptic currents via α7-containing nicotinic acetylcholine receptors and inducing bursts of action potentials in local GABAergic neurons. These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal. Our results provide new insight into the mechanisms controlling sleep. DOI: http://dx.doi.org/10.7554/eLife.10382.001 PMID:26880556

A linear model fails to predict orientation selectivity of cells in the cat visual cortex.

PubMed Central

Volgushev, M; Vidyasagar, T R; Pei, X

1996-01-01

1. Postsynaptic potentials (PSPs) evoked by visual stimulation in simple cells in the cat visual cortex were recorded using in vivo whole-cell technique. Responses to small spots of light presented at different positions over the receptive field and responses to elongated bars of different orientations centred on the receptive field were recorded. 2. To test whether a linear model can account for orientation selectivity of cortical neurones, responses to elongated bars were compared with responses predicted by a linear model from the receptive field map obtained from flashing spots. 3. The linear model faithfully predicted the preferred orientation, but not the degree of orientation selectivity or the sharpness of orientation tuning. The ratio of optimal to non-optimal responses was always underestimated by the model. 4. Thus non-linear mechanisms, which can include suppression of non-optimal responses and/or amplification of optimal responses, are involved in the generation of orientation selectivity in the primary visual cortex. PMID:8930828

Somato-dendritic Synaptic Plasticity and Error-backpropagation in Active Dendrites

PubMed Central

Schiess, Mathieu; Urbanczik, Robert; Senn, Walter

2016-01-01

In the last decade dendrites of cortical neurons have been shown to nonlinearly combine synaptic inputs by evoking local dendritic spikes. It has been suggested that these nonlinearities raise the computational power of a single neuron, making it comparable to a 2-layer network of point neurons. But how these nonlinearities can be incorporated into the synaptic plasticity to optimally support learning remains unclear. We present a theoretically derived synaptic plasticity rule for supervised and reinforcement learning that depends on the timing of the presynaptic, the dendritic and the postsynaptic spikes. For supervised learning, the rule can be seen as a biological version of the classical error-backpropagation algorithm applied to the dendritic case. When modulated by a delayed reward signal, the same plasticity is shown to maximize the expected reward in reinforcement learning for various coding scenarios. Our framework makes specific experimental predictions and highlights the unique advantage of active dendrites for implementing powerful synaptic plasticity rules that have access to downstream information via backpropagation of action potentials. PMID:26841235

Intrinsic neuromodulation in the Tritonia swim CPG: serotonin mediates both neuromodulation and neurotransmission by the dorsal swim interneurons.

PubMed

Katz, P S; Frost, W N

1995-12-01

1. Neuromodulation has previously been shown to be intrinsic to the central pattern generator (CPG) circuit that generates the escape swim of the nudibranch mollusk Tritonia diomedea; the dorsal swim interneurons (DSIs) make conventional monosynaptic connections and evoke neuromodulatory effects within the swim motor circuit. The conventional synaptic potentials evoked by a DSI onto cerebral neuron 2 (C2) and onto the dorsal flexion neurons (DFNs) consist of a fast excitatory postsynaptic potential (EPSP) followed by a prolonged slow EPSP. In their neuromodulatory role, the DSIs produce an enhancement of the monosynaptic connections made by C2 onto other CPG circuit interneurons and onto efferent flexion neurons. Previous work showed that the DSIs are immunoreactive for serotonin. Here we provide evidence that both the neurotransmission and the neuromodulation evoked by the DSIs are produced by serotonin, and that these effects may be pharmacologically separable. 2. Previously it was shown that bath-applied serotonin both mimics and occludes the modulation of the C2 synapses by the DSIs. Here we find that pressure-applied puffs of serotonin mimic both the fast and slow EPSPs evoked by a DSI onto a DFN, whereas high concentrations of bath-applied serotonin occlude both of these synaptic components. 3. Consistent with the hypothesis that serotonin mediates the actions of the DSIs, the serotonin reuptake inhibitor imipramine prolongs the duration of the fast DSI-DFN EPSP, increases the amplitude of the slow DSI-DFN EPSP, and increases both the amplitude and duration of the modulation of the C2-DFN synapse by the DSIs. 4. Two serotonergic antagonists were found that block the actions of the DSIs. Gramine blocks the fast DSI-DFN EPSP, and has far less of an effect on the slow EPSP and the modulation. Gramine also diminishes the depolarization evoked by pressure-applied serotonin, showing that it is a serotonin antagonist in this system. In contrast, methysergide greatly reduces both the slow EPSP and the modulation evoked by the DSIs, but has mixed effects on the fast EPSP. Methysergide also blocks the ability of exogenous serotonin to enhance the C2-DFN EPSP, demonstrating that it antagonizes the serotonin receptors responsible for this modulation. 5. Taken together with previous work, these results indicate that serotonin is likely to be responsible for all three actions of the DSIs that were examined: the fast and slow DSI-DFN EPSPs and the neuromodulation of the C2-DFN synapse. These results also indicate that the conventional and neuromodulatory effects of the DSIs may be pharmacologically separable. In future work it may be possible to determine the functional role of each in the swim circuit.

Paired-Pulse Depression at Photoreceptor Synapses

PubMed Central

Rabl, Katalin; Cadetti, Lucia; Thoreson, Wallace B.

2011-01-01

Synaptic depression produced by repetitive stimulation is likely to be particularly important in shaping responses of second-order retinal neurons at the tonically active photoreceptor synapse. We analyzed the time course and mechanisms of synaptic depression at rod and cone synapses using paired-pulse protocols involving two complementary measurements of exocytosis: (1) paired whole-cell recordings of the postsynaptic current (PSC) in second-order retinal neurons and (2) capacitance measurements of vesicular membrane fusion in rods and cones. PSCs in ON bipolar, OFF bipolar, and horizontal cells evoked by stimulation of either rods or cones recovered from paired-pulse depression (PPD) at rates similar to the recovery of exocytotic capacitance changes in rods and cones. Correlation between presynaptic and postsynaptic measures of recovery from PPD suggests that 80 –90% of the depression at these synapses is presynaptic in origin. Consistent with a predominantly presynaptic mechanism, inhibiting desensitization of postsynaptic glutamate receptors had little effect on PPD. The depression of exocytotic capacitance changes exceeded depression of the presynaptic calcium current, suggesting that it is primarily caused by a depletion of synaptic vesicles. In support of this idea, limiting Ca2+ influx by using weaker depolarizing stimuli promoted faster recovery from PPD. Although cones exhibit much faster exocytotic kinetics than rods, exocytotic capacitance changes recovered from PPD at similar rates in both cell types. Thus, depression of release is not likely to contribute to differences in the kinetics of transmission from rods and cones. PMID:16510733

Simultaneous monitoring of presynaptic transmitter release and postsynaptic receptor trafficking reveals an enhancement of presynaptic activity in metabotropic glutamate receptor-mediated long-term depression.

PubMed

Xu, Wei; Tse, Yiu Chung; Dobie, Frederick A; Baudry, Michel; Craig, Ann Marie; Wong, Tak Pan; Wang, Yu Tian

2013-03-27

Although the contribution of postsynaptic mechanisms to long-term synaptic plasticity has been studied extensively, understanding the contribution of presynaptic modifications to this process lags behind, primarily because of a lack of techniques with which to directly and quantifiably measure neurotransmitter release from synaptic terminals. Here, we developed a method to measure presynaptic activity through the biotinylation of vesicular transporters in vesicles fused with presynaptic membranes during neurotransmitter release. This method allowed us for the first time to selectively quantify the spontaneous or evoked release of glutamate or GABA at their respective synapses. Using this method to investigate presynaptic changes during the expression of group I metabotropic glutamate receptor (mGluR1/5)-mediated long-term depression (LTD) in cultured rat hippocampal neurons, we discovered that this form of LTD was associated with increased presynaptic release of glutamate, despite reduced miniature EPSCs measured with whole-cell recording. Moreover, we found that specific blockade of AMPA receptor (AMPAR) endocytosis with a membrane-permeable GluR2-derived peptide not only prevented the expression of LTD but also eliminated LTD-associated increase in presynaptic release. Thus, our work not only demonstrates that mGluR1/5-mediated LTD is associated with increased endocytosis of postsynaptic AMPARs but also reveals an unexpected homeostatic/compensatory increase in presynaptic release. In addition, this study indicates that biotinylation of vesicular transporters in live cultured neurons is a valuable tool for studying presynaptic function.

Urban air pollutants reduce synaptic function of CA1 neurons via an NMDA/NO• pathway in vitro

PubMed Central

Davis, David A.; Akopian, Garnik; Walsh, John P.; Sioutas, Constantinos; Morgan, Todd E.; Finch, Caleb E.

2013-01-01

Airborne particulate matter (PM) from urban vehicular aerosols altered glutamate receptor functions and induced glial inflammatory responses in rodent models after chronic exposure. Potential neurotoxic mechanisms were analyzed in vitro. In hippocampal slices, 2 h exposure to aqueous nanosized PM (nPM) selectively altered postsynaptic proteins in CA1 neurons: increased GluA1, GluN2A, and GluN2B, but not GluA2, GluN1 or mGlur5; increased PSD95 and spinophilin, but not synaptophysin, while dentate gyrus (DG) neurons were unresponsive. In hippocampal slices and neurons, MitoSOX red fluorescence was increased by nPM, implying free radical production. Specifically, NO• production by slices was increased within 15 min of exposure to nPM with dose dependence, 1–10 µg/ml. Correspondingly, CA1 neurons exhibited increased nitrosylation of the GluN2A receptor and dephosphorylation of GluN2B (S1303) and of GluA1 (S831 & S845). Again, DG neurons were unresponsive to nPM. The induction of NO• and nitrosylation were inhibited by AP5, an NMDA receptor antagonist, which also protects neurite outgrowth in vitro from inhibition by nPM. Membrane injury (EthidiumD-1 uptake) showed parallel specificity. Finally, nPM decreased evoked excitatory postsynaptic currents (EPSCs) of CA1 neurons. These findings further document the selective impact of nPM on glutamatergic functions and identify novel responses of NMDA receptor-stimulated NO• production and nitrosylation reactions during nPM-mediated neurotoxicity. PMID:23927064

Visual patch clamp recording of neurons in thick portions of the adult spinal cord.

PubMed

Munch, Anders Sonne; Smith, Morten; Moldovan, Mihai; Perrier, Jean-François

2010-07-15

The study of visually identified neurons in slice preparations from the central nervous system offers considerable advantages over in vivo preparations including high mechanical stability in the absence of anaesthesia and full control of the extracellular medium. However, because of their relative thinness, slices are not appropriate for investigating how individual neurons integrate synaptic inputs generated by large numbers of neurons. Here we took advantage of the exceptional resistance of the turtle to anoxia to make slices of increasing thicknesses (from 300 to 3000 microm) from the lumbar enlargement of the spinal cord. With a conventional upright microscope in which the light condenser was carefully adjusted, we could visualize neurons present at the surface of the slice and record them with the whole-cell patch clamp technique. We show that neurons present in the middle of the preparation remain alive and capable of generating action potentials. By stimulating the lateral funiculus we can evoke intense synaptic activity associated with large increases in conductance of the recorded neurons. The conductance increases substantially more in neurons recorded in thick slices suggesting that the size of the network recruited with the stimulation increases with the thickness of the slices. We also find that that the number of spontaneous excitatory postsynaptic currents (EPSCs) is higher in thick slices compared with thin slices while the number of spontaneous inhibitory postsynaptic currents (IPSCs) remains constant. These preliminary data suggest that inhibitory and excitatory synaptic connections are balanced locally while excitation dominates long-range connections in the spinal cord. Copyright 2010 Elsevier B.V. All rights reserved.

The Endocannabinoid System Tonically Regulates Inhibitory Transmission and Depresses the Effect of Ethanol in Central Amygdala

PubMed Central

Roberto, Marisa; Cruz, Maureen; Bajo, Michal; Siggins, George R; Parsons, Loren H; Schweitzer, Paul

2010-01-01

The central amygdala (CeA) has a major role in alcohol dependence and reinforcement, and behavioral and neurochemical evidence suggests a role for the endocannabinoid (eCB) system in ethanol binging and dependence. We used a slice preparation to investigate the physiological role of cannabinoids and their interaction with ethanol on inhibitory synaptic transmission in CeA. Superfusion of the cannabinoid receptor (CB1) agonist WIN55212-2 (WIN2) onto CeA neurons decreased evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the CB1 antagonists Rimonabant (SR141716, SR1) and AM251. SR1 or AM251 applied alone augmented IPSPs, revealing a tonic eCB activity that decreased inhibitory transmission in CeA. Paired-pulse analysis suggested a presynaptic CB1 mechanism. Intracellular BAPTA abolished the ability of AM251 to augment IPSPs, demonstrating the eCB-driven nature and postsynaptic origin of the tonic CB1-dependent control of GABA release. Superfusion of ethanol increased IPSPs and addition of WIN2 reversed the ethanol effect. Similarly, previous superfusion of WIN2 prevented subsequent ethanol effects on GABAergic transmission. The ethanol-induced augmentation of IPSPs was additive to CB1 blockade, ruling out a participation of CB1 in the action of acute ethanol. Our study points to an important role of CB1 in CeA in which the eCBs tonically regulate neuronal activity, and suggests a potent mechanism for modulating CeA tone during challenge with ethanol. PMID:20463657

Transesophageal versus transcranial motor evoked potentials to monitor spinal cord ischemia.

PubMed

Tsuda, Kazumasa; Shiiya, Norihiko; Takahashi, Daisuke; Ohkura, Kazuhiro; Yamashita, Katsushi; Kando, Yumi; Arai, Yoshifumi

2016-02-01

We have previously reported that transesophageal motor evoked potential is feasible and more stable than transcranial motor evoked potential. This study aimed to investigate the efficacy of transesophageal motor evoked potential to monitor spinal cord ischemia. Transesophageal and transcranial motor evoked potentials were recorded in 13 anesthetized dogs at the bilateral forelimbs, anal sphincters, and hindlimbs. Spinal cord ischemia was induced by aortic balloon occlusion at the 8th to 10th thoracic vertebra level. In the 12 animals with motor evoked potential disappearance, occlusion was maintained for 10 minutes (n = 6) or 40 minutes (n = 6) after motor evoked potential disappearance. Neurologic function was evaluated by Tarlov score at 24 and 48 hours postoperatively. Time to disappearance of bilateral motor evoked potentials was quicker in transesophageal motor evoked potentials than in transcranial motor evoked potentials at anal sphincters (6.9 ± 3.1 minutes vs 8.3 ± 3.4 minutes, P = .02) and hindlimbs (5.7 ± 1.9 minutes vs 7.1 ± 2.7 minutes, P = .008). Hindlimb function was normal in all dogs in the 10-minute occlusion group, and motor evoked potentials recovery (>75% on both sides) after reperfusion was quicker in transesophageal motor evoked potentials than transcranial motor evoked potentials at hindlimbs (14.8 ± 5.6 minutes vs 24.7 ± 8.2 minutes, P = .001). At anal sphincters, transesophageal motor evoked potentials always reappeared (>25%), but transcranial motor evoked potentials did not in 3 of 6 dogs. In the 40-minute occlusion group, hindlimb motor evoked potentials did not reappear in 4 dogs with paraplegia. Among the 2 remaining dogs, 1 with paraparesis (Tarlov 3) showed delayed recovery (>75%) of hindlimb motor evoked potentials without reappearance of anal sphincter motor evoked potentials. In another dog with spastic paraplegia, transesophageal motor evoked potentials from the hindlimbs remained less than 20%, whereas transcranial motor evoked potentials showed recovery (>75%). Transesophageal motor evoked potentials may be superior to transcranial motor evoked potentials in terms of quicker response to spinal cord ischemia and better prognostic value. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Transient release kinetics of rod bipolar cells revealed by capacitance measurement of exocytosis from axon terminals in rat retinal slices.

PubMed

Oltedal, Leif; Hartveit, Espen

2010-05-01

Presynaptic transmitter release has mostly been studied through measurements of postsynaptic responses, but a few synapses offer direct access to the presynaptic terminal, thereby allowing capacitance measurements of exocytosis. For mammalian rod bipolar cells, synaptic transmission has been investigated in great detail by recording postsynaptic currents in AII amacrine cells. Presynaptic measurements of the dynamics of vesicular cycling have so far been limited to isolated rod bipolar cells in dissociated preparations. Here, we first used computer simulations of compartmental models of morphologically reconstructed rod bipolar cells to adapt the 'Sine + DC' technique for capacitance measurements of exocytosis at axon terminals of intact rod bipolar cells in retinal slices. In subsequent physiological recordings, voltage pulses that triggered presynaptic Ca(2+) influx evoked capacitance increases that were proportional to the pulse duration. With pulse durations 100 ms, the increase saturated at 10 fF, corresponding to the size of a readily releasable pool of vesicles. Pulse durations 400 ms evoked additional capacitance increases, probably reflecting recruitment from additional pools of vesicles. By using Ca(2+) tail current stimuli, we separated Ca(2+) influx from Ca(2+) channel activation kinetics, allowing us to estimate the intrinsic release kinetics of the readily releasable pool, yielding a time constant of 1.1 ms and a maximum release rate of 2-3 vesicles (release site)(1) ms(1). Following exocytosis, we observed endocytosis with time constants ranging from 0.7 to 17 s. Under physiological conditions, it is likely that release will be transient, with the kinetics limited by the activation kinetics of the voltage-gated Ca(2+) channels.

Quantal amplitude at the cone ribbon synapse can be adjusted by changes in cytosolic glutamate

PubMed Central

Bartoletti, Theodore M.

2011-01-01

Purpose Vision is encoded at photoreceptor synapses by the number of released vesicles and size of the post-synaptic response. We hypothesized that elevating cytosolic glutamate could enhance quantal size by increasing glutamate in vesicles. Methods We introduced glutamate (10–40 mM) into cone terminals through a patch pipette and recorded excitatory post-synaptic currents (EPSCs) from horizontal or OFF bipolar cells in the Ambystoma tigrinum retinal slice preparation. Results Elevating cytosolic glutamate in cone terminals enhanced EPSCs as well as quantal miniature EPSCs (mEPSCs). Enhancement was prevented by inhibiting vesicular glutamate transport with 1S,3R-1-aminocyclopentane-1,3-dicarboxylate in the patch pipette. A low affinity glutamate receptor antagonist, γD-glutamylglycine (1 mM), less effectively inhibited EPSCs evoked from cones loaded with glutamate than control cones indicating that release from cones with supplemental glutamate produced higher glutamate levels in the synaptic cleft. Raising presynaptic glutamate did not alter exocytotic capacitance responses and exocytosis was observed after inhibiting glutamate loading with the vesicular ATPase inhibitor, concanamycin A, suggesting that release capability is not restricted by low vesicular glutamate levels. Variance-mean analysis of currents evoked by flash photolysis of caged glutamate indicated that horizontal cell AMPA receptors have a single channel conductance of 10.1 pS suggesting that ~8.7 GluRs contribute to each mEPSC. Conclusions Quantal amplitude at the cone ribbon synapse is capable of adjustment by changes in cytosolic glutamate levels. The small number of channels contributing to each mEPSC suggests that stochastic variability in channel opening could be an important source of quantal variability. PMID:21541265

Comparison of glomerular activity patterns by fMRI and wide-field calcium imaging: implications for principles underlying odor mapping

PubMed Central

Sanganahalli, Basavaraju G.; Rebello, Michelle R.; Herman, Peter; Papademetris, Xenophon; Shepherd, Gordon M.; Verhagen, Justus V.; Hyder, Fahmeed

2015-01-01

Functional imaging signals arise from distinct metabolic and hemodynamic events at the neuropil, but how these processes are influenced by pre- and post-synaptic activities need to be understood for quantitative interpretation of stimulus-evoked mapping data. The olfactory bulb (OB) glomeruli, spherical neuropil regions with well-defined neuronal circuitry, can provide insights into this issue. Optical calcium-sensitive fluorescent dye imaging (OICa2+) reflects dynamics of pre-synaptic input to glomeruli, whereas high-resolution functional magnetic resonance imaging (fMRI) using deoxyhemoglobin contrast reveals neuropil function within the glomerular layer where both pre- and post-synaptic activities contribute. We imaged odor-specific activity patterns of the dorsal OB in the same anesthetized rats with fMRI and OICa2+ and then co-registered the respective maps to compare patterns in the same space. Maps by each modality were very reproducible as trial-to-trial patterns for a given odor, overlapping by ~80%. Maps evoked by ethyl butyrate and methyl valerate for a given modality overlapped by ~80%, suggesting activation of similar dorsal glomerular networks by these odors. Comparison of maps generated by both methods for a given odor showed ~70% overlap, indicating similar odor-specific maps by each method. These results suggest that odor-specific glomerular patterns by high-resolution fMRI primarily tracks pre-synaptic input to the OB. Thus combining OICa2+ and fMRI lays the framework for studies of OB processing over a range of spatiotemporal scales, where OICa2+ can feature the fast dynamics of dorsal glomerular clusters and fMRI can map the entire glomerular sheet in the OB. PMID:26631819

Activation of the sigma receptor 1 modulates AMPA receptor-mediated light-evoked excitatory postsynaptic currents in rat retinal ganglion cells.

PubMed

Liu, Lei-Lei; Deng, Qin-Qin; Weng, Shi-Jun; Yang, Xiong-Li; Zhong, Yong-Mei

2016-09-22

Sigma receptor (σR), a unique receptor family, is classified into three subtypes: σR1, σR2 and σR3. It was previously shown that σR1 activation induced by 1μM SKF10047 (SKF) suppressed N-methyl-d-aspartate (NMDA) receptor-mediated responses of rat retinal ganglion cells (GCs) and the suppression was mediated by a distinct Ca(2+)-dependent phospholipase C (PLC)-protein kinase C (PKC) pathway. In the present work, using whole-cell patch-clamp techniques in rat retinal slice preparations, we further demonstrate that SKF of higher dosage (50μM) significantly suppressed AMPA receptor (AMPAR)-mediated light-evoked excitatory postsynaptic currents (L-EPSCs) of retinal ON-type GCs (ON GCs), and the effect was reversed by the σR1 antagonist BD1047, suggesting the involvement of σR1. The SKF (50μM) effect was unlikely due to a change in glutamate release from bipolar cells, as suggested by the unaltered paired-pulse ratio (PPR) of AMPAR-mediated EPSCs of ON GCs. SKF (50μM) did not change L-EPSCs of ON GCs when the G protein inhibitor GDP-β-S or the protein kinase G (PKG) inhibitor KT5823 was intracellularly infused. Calcium imaging further revealed that SKF (50μM) did not change intracellular calcium concentration in GCs and persisted to suppress L-EPSCs when intracellular calcium was chelated by BAPTA. The SKF (50μM) effect was intact when protein kinase A (PKA) and phosphatidylinostiol (PI)-PLC signaling pathways were both blocked. We conclude that the SKF (50μM) effect is Ca(2+)-independent, PKG-dependent, but not involving PKA, PI-PLC pathways. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Cannabinoids suppress synaptic input to neurones of the rat dorsal motor nucleus of the vagus nerve

PubMed Central

Derbenev, Andrei V; Stuart, Thomas C; Smith, Bret N

2004-01-01

Cannabinoids bind central type 1 receptors (CB1R) and modify autonomic functions, including feeding and anti-emetic behaviours, when administered peripherally or into the dorsal vagal complex. Western blots and immunohistochemistry indicated the expression of CB1R in the rat dorsal vagal complex, and tissue polymerase chain reaction confirmed that CB1R message was made within the region. To identify a cellular substrate for the central autonomic effects of cannabinoids, whole-cell patch-clamp recordings were made in brainstem slices to determine the effects of CB1R activation on synaptic transmission to neurones of the dorsal motor nucleus of the vagus (DMV). A subset of these neurones was identified as gastric related after being labelled retrogradely from the stomach. The CB1R agonists WIN55,212-2 and anandamide decreased the frequency of spontaneous excitatory or inhibitory postsynaptic currents in a concentration-related fashion, an effect that persisted in the presence of tetrodotoxin. Paired pulse ratios of electrically evoked postsynaptic currents were also increased by WIN55,212-2. The effects of WIN55,212-2 were sensitive to the selective CB1R antagonist AM251. Cannabinoid agonist effects on synaptic input originating from neurones in the nucleus tractus solitarius (NTS) were determined by evoking activity in the NTS with local glutamate application. Excitatory and inhibitory synaptic inputs arising from the NTS were attenuated by WIN55,212-2. Our results indicate that cannabinoids inhibit transfer of synaptic information to the DMV, including that arising from the NTS, in part by acting at receptors located on presynaptic terminals contacting DMV neurones. Inhibition of synaptic input to DMV neurones is likely to contribute to the suppression of visceral motor responses by cannabinoids. PMID:15272041

The Effects of Nicotinic and Muscarinic Receptor Activation on Patch-Clamped Cells in the Optic Tectum of Rana Pipiens

PubMed Central

Yu, C.-J.; Debski, E. A.

2008-01-01

Both nicotinic and muscarinic cholinergic receptors are present in the optic tectum. To begin to understand how the activation of these receptors affects visual activity patterns, we have determined the types of physiological responses induced by their activation. Using tectal brain slices from the leopard frog, we found that application of nicotine (100 μM) evoked long-lasting responses in 60% of patch-clamped tectal cells. Thirty percent of these responses consisted of an increase in spontaneous postsynaptic currents (sPSCs) and had both a glutamatergic and GABAergic component as determined by the use of 6-cyano-7-nitroquinoxaline-2,3-dione (50 μM) and bicuculline (25 μM), respectively. Remaining response types consisted of an inward membrane current (16%) and an increase in sPSCs combined with an inward membrane current (14%). All responses could be elicited in the presence of tetrodotoxin (0.5 μM). Muscarinic receptor-mediated responses, induced by carbachol (100 μM) application after nicotinic receptor desensitization, produced responses in 70% of tectal cells. In contrast to responses elicited by nicotine, carbachol-induced responses could be evoked multiple times without significant decrement. Responses consisted of either an outward current (57%), a decrease in sPSCs (5%) or an increase in sPSCs, with (almost 6%) or without (almost 3%) an outward current. The response elicited by carbachol was not predicted by the response of the cell to nicotine. Our results suggest that nicotinic receptors are found predominantly at presynaptic locations in the optic tectum while muscarinic receptors are most often present at postsynaptic sites. We conclude that both of these receptor types could substantially modulate visual activity by changing either the input to tectal neurons or the level of their response to that input. PMID:12676145

The effects of nicotinic and muscarinic receptor activation on patch-clamped cells in the optic tectum of Rana pipiens.

PubMed

Yu, C-J; Debski, E A

2003-01-01

Both nicotinic and muscarinic cholinergic receptors are present in the optic tectum. To begin to understand how the activation of these receptors affects visual activity patterns, we have determined the types of physiological responses induced by their activation. Using tectal brain slices from the leopard frog, we found that application of nicotine (100 microM) evoked long-lasting responses in 60% of patch-clamped tectal cells. Thirty percent of these responses consisted of an increase in spontaneous postsynaptic currents (sPSCs) and had both a glutamatergic and GABAergic component as determined by the use of 6-cyano-7-nitroquinoxaline-2,3-dione (50 microM) and bicuculline (25 microM), respectively. Remaining response types consisted of an inward membrane current (16%) and an increase in sPSCs combined with an inward membrane current (14%). All responses could be elicited in the presence of tetrodotoxin (0.5 microM). Muscarinic receptor-mediated responses, induced by carbachol (100 microM) application after nicotinic receptor desensitization, produced responses in 70% of tectal cells. In contrast to responses elicited by nicotine, carbachol-induced responses could be evoked multiple times without significant decrement. Responses consisted of either an outward current (57%), a decrease in sPSCs (5%) or an increase in sPSCs, with (almost 6%) or without (almost 3%) an outward current. The response elicited by carbachol was not predicted by the response of the cell to nicotine. Our results suggest that nicotinic receptors are found predominantly at presynaptic locations in the optic tectum while muscarinic receptors are most often present at postsynaptic sites. We conclude that both of these receptor types could substantially modulate visual activity by changing either the input to tectal neurons or the level of their response to that input.

Peptidergic CGRPα primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold

PubMed Central

McCoy, Eric S.; Taylor-Blake, Bonnie; Street, Sarah E.; Pribisko, Alaine L.; Zheng, Jihong; Zylka, Mark J.

2013-01-01

SUMMARY Calcitonin gene-related peptide (CGRP) is a classic molecular marker of peptidergic primary somatosensory neurons. Despite years of research, it is unknown if these neurons are required to sense pain or other sensory stimuli. Here, we found that genetic ablation of CGRPα-expressing sensory neurons reduced sensitivity to noxious heat, capsaicin and itch (histamine and chloroquine) and impaired thermoregulation but did not impair mechanosensation or β-alanine itch—stimuli associated with nonpeptidergic sensory neurons. Unexpectedly, ablation enhanced behavioral responses to cold stimuli and cold mimetics without altering peripheral nerve responses to cooling. Mechanistically, ablation reduced tonic and evoked activity in postsynaptic spinal neurons associated with TRPV1/heat, while profoundly increasing tonic and evoked activity in spinal neurons associated with TRPM8/cold. Our data reveal that CGRPα sensory neurons encode heat and itch and tonically cross-inhibit cold-responsive spinal neurons. Disruption of this crosstalk unmasks cold hypersensitivity, with mechanistic implications for neuropathic pain and temperature perception. PMID:23523592

Potentiation in the first visual synapse of the fly compound eye.

PubMed

Uusitalo, R O; Weckström, M

2000-04-01

In the first visual synapse of the insect compound eye, both the presynaptic and postsynaptic signals are graded, nonspiking changes in membrane voltage. The synapse exhibits tonic transmitter release (even in dark) and strong adaptation to long-lasting light backgrounds, leading to changes also in the dynamics of signal transmission. We have studied these adaptational properties of the first visual synapse of the blowfly Calliphora vicina. Investigations were done in situ by intracellular recordings from the presynaptic photoreceptors, photoreceptor axon terminals, and the postsynaptic first order visual interneurons (LMCs). The dark recovery, the shifts in intensity dependence, and the underlying processes were studied by stimulating the visual system with various adapting stimuli while observing the recovery (i.e., dark adaptation). The findings show a transient potentiation in the postsynaptic responses after intense light adaptation, and the underlying mechanisms seem to be the changes in the equilibrium potential of the transmitter-gated conductance (chloride) of the postsynaptic neurons. The potentiation by itself serves as a mechanism that after light adaptation rapidly recovers the sensitivity loss of the visual system. However, this kind of mechanism, being an intrinsic property of graded potential transmission, may be quite widespread among graded synapses, and the phenomenon demonstrates that functional plasticity is also a property of graded synaptic transmission.

Elevating Endogenous GABA Levels with GAT-1 Blockade Modulates Evoked but Not Induced Responses in Human Visual Cortex

PubMed Central

Muthukumaraswamy, Suresh D; Myers, Jim F M; Wilson, Sue J; Nutt, David J; Hamandi, Khalid; Lingford-Hughes, Anne; Singh, Krish D

2013-01-01

The electroencephalographic/magnetoencephalographic (EEG/MEG) signal is generated primarily by the summation of the postsynaptic currents of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons. Here we investigated the relative sensitivity of visual evoked and induced responses to altered levels of endogenous GABAergic inhibition. To do this, we pharmacologically manipulated the GABA system using tiagabine, which blocks the synaptic GABA transporter 1, and so increases endogenous GABA levels. In a single-blinded and placebo-controlled crossover study of 15 healthy participants, we administered either 15 mg of tiagabine or a placebo. We recorded whole-head MEG, while participants viewed a visual grating stimulus, before, 1, 3 and 5 h post tiagabine ingestion. Using beamformer source localization, we reconstructed responses from early visual cortices. Our results showed no change in either stimulus-induced gamma-band amplitude increases or stimulus-induced alpha amplitude decreases. However, the same data showed a 45% reduction in the evoked response component at ∼80 ms. These data demonstrate that, in early visual cortex the evoked response shows a greater sensitivity compared with induced oscillations to pharmacologically increased endogenous GABA levels. We suggest that previous studies correlating GABA concentrations as measured by magnetic resonance spectroscopy to gamma oscillation frequency may reflect underlying variations such as interneuron/inhibitory synapse density rather than functional synaptic GABA concentrations. PMID:23361120

Increased Excitatory Synaptic Transmission of Dentate Granule Neurons in Mice Lacking PSD-95-Interacting Adhesion Molecule Neph2/Kirrel3 during the Early Postnatal Period.

PubMed

Roh, Junyeop D; Choi, Su-Yeon; Cho, Yi Sul; Choi, Tae-Yong; Park, Jong-Sil; Cutforth, Tyler; Chung, Woosuk; Park, Hanwool; Lee, Dongsoo; Kim, Myeong-Heui; Lee, Yeunkum; Mo, Seojung; Rhee, Jeong-Seop; Kim, Hyun; Ko, Jaewon; Choi, Se-Young; Bae, Yong Chul; Shen, Kang; Kim, Eunjoon; Han, Kihoon

2017-01-01

Copy number variants and point mutations of NEPH2 (also called KIRREL3 ) gene encoding an immunoglobulin (Ig) superfamily adhesion molecule have been linked to autism spectrum disorders, intellectual disability and neurocognitive delay associated with Jacobsen syndrome, but the physiological roles of Neph2 in the mammalian brain remain largely unknown. Neph2 is highly expressed in the dentate granule (DG) neurons of the hippocampus and is localized in both dendrites and axons. It was recently shown that Neph2 is required for the formation of mossy fiber filopodia, the axon terminal structure of DG neurons forming synapses with GABAergic neurons of CA3. In contrast, however, it is unknown whether Neph2 also has any roles in the postsynaptic compartments of DG neurons. We here report that, through its C-terminal PDZ domain-binding motif, Neph2 directly interacts with postsynaptic density (PSD)-95, an abundant excitatory postsynaptic scaffolding protein. Moreover, Neph2 protein is detected in the brain PSD fraction and interacts with PSD-95 in synaptosomal lysates. Functionally, loss of Neph2 in mice leads to age-specific defects in the synaptic connectivity of DG neurons. Specifically, Neph2 -/- mice show significantly increased spontaneous excitatory synaptic events in DG neurons at postnatal week 2 when the endogenous Neph2 protein expression peaks, but show normal excitatory synaptic transmission at postnatal week 3. The evoked excitatory synaptic transmission and synaptic plasticity of medial perforant pathway (MPP)-DG synapses are also normal in Neph2 -/- mice at postnatal week 3, further confirming the age-specific synaptic defects. Together, our results provide some evidence for the postsynaptic function of Neph2 in DG neurons during the early postnatal period, which might be implicated in neurodevelopmental and cognitive disorders caused by NEPH2 mutations.

Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment.

PubMed

Scorza, M C; Lladó-Pelfort, L; Oller, S; Cortés, R; Puigdemont, D; Portella, M J; Pérez-Egea, R; Alvarez, E; Celada, P; Pérez, V; Artigas, F

2012-11-01

The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective. We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Etomidate evokes synaptic vesicle exocytosis without increasing miniature endplate potentials frequency at the mice neuromuscular junction.

PubMed

Valadão, Priscila Aparecida Costa; Naves, Lígia Araújo; Gomez, Renato Santiago; Guatimosim, Cristina

2013-11-01

Etomidate is an intravenous anesthetic used during anesthesia induction. This agent induces spontaneous movements, especially myoclonus after its administration suggesting a putative primary effect at the central nervous system or the periphery. Therefore, the aim of this study was to investigate the presynaptic and postsynaptic effects of etomidate at the mouse neuromuscular junction (NMJ). Diaphragm nerve muscle preparations were isolated and stained with the styryl dye FM1-43, a fluorescent tool that tracks synaptic vesicles exo-endocytosis that are key steps for neurotransmission. We observed that etomidate induced synaptic vesicle exocytosis in a dose-dependent fashion, an effect that was independent of voltage-gated Na(+) channels. By contrast, etomidate-evoked exocytosis was dependent on extracellular Ca(2+) because its effect was abolished in Ca(2+)-free medium and also inhibited by omega-Agatoxin IVA (30 and 200nM) suggesting the participation of P/Q-subtype Ca(2+) channels. Interestingly, even though etomidate induced synaptic vesicle exocytosis, we did not observe any significant difference in the frequency and amplitude of miniature end-plate potentials (MEPPs) in the presence of the anesthetic. We therefore investigated whether etomidate could act on nicotinic acetylcholine receptors labeled with α-bungarotoxin-Alexa 594 and we observed less fluorescence in preparations exposed to the anesthetic. In conclusion, our results suggest that etomidate exerts a presynaptic effect at the NMJ inducing synaptic vesicle exocytosis, likely through the activation of P-subtype voltage gated Ca(2+) channels without interfering with MEPPs frequency. The present data contribute to a better understanding about the effect of etomidate at the neuromuscular synapse and may help to explain some clinical effects of this agent. Copyright © 2013 Elsevier Ltd. All rights reserved.

Serotonin increases synaptic activity in olfactory bulb glomeruli

PubMed Central

Brill, Julia; Shao, Zuoyi; Puche, Adam C.; Wachowiak, Matt

2016-01-01

Serotoninergic fibers densely innervate olfactory bulb glomeruli, the first sites of synaptic integration in the olfactory system. Acting through 5HT2A receptors, serotonin (5HT) directly excites external tufted cells (ETCs), key excitatory glomerular neurons, and depolarizes some mitral cells (MCs), the olfactory bulb's main output neurons. We further investigated 5HT action on MCs and determined its effects on the two major classes of glomerular interneurons: GABAergic/dopaminergic short axon cells (SACs) and GABAergic periglomerular cells (PGCs). In SACs, 5HT evoked a depolarizing current mediated by 5HT2C receptors but did not significantly impact spike rate. 5HT had no measurable direct effect in PGCs. Serotonin increased spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) in PGCs and SACs. Increased sEPSCs were mediated by 5HT2A receptors, suggesting that they are primarily due to enhanced excitatory drive from ETCs. Increased sIPSCs resulted from elevated excitatory drive onto GABAergic interneurons and augmented GABA release from SACs. Serotonin-mediated GABA release from SACs was action potential independent and significantly increased miniature IPSC frequency in glomerular neurons. When focally applied to a glomerulus, 5HT increased MC spontaneous firing greater than twofold but did not increase olfactory nerve-evoked responses. Taken together, 5HT modulates glomerular network activity in several ways: 1) it increases ETC-mediated feed-forward excitation onto MCs, SACs, and PGCs; 2) it increases inhibition of glomerular interneurons; 3) it directly triggers action potential-independent GABA release from SACs; and 4) these network actions increase spontaneous MC firing without enhancing responses to suprathreshold sensory input. This may enhance MC sensitivity while maintaining dynamic range. PMID:26655822

Serotonin increases synaptic activity in olfactory bulb glomeruli.

PubMed

Brill, Julia; Shao, Zuoyi; Puche, Adam C; Wachowiak, Matt; Shipley, Michael T

2016-03-01

Serotoninergic fibers densely innervate olfactory bulb glomeruli, the first sites of synaptic integration in the olfactory system. Acting through 5HT2A receptors, serotonin (5HT) directly excites external tufted cells (ETCs), key excitatory glomerular neurons, and depolarizes some mitral cells (MCs), the olfactory bulb's main output neurons. We further investigated 5HT action on MCs and determined its effects on the two major classes of glomerular interneurons: GABAergic/dopaminergic short axon cells (SACs) and GABAergic periglomerular cells (PGCs). In SACs, 5HT evoked a depolarizing current mediated by 5HT2C receptors but did not significantly impact spike rate. 5HT had no measurable direct effect in PGCs. Serotonin increased spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) in PGCs and SACs. Increased sEPSCs were mediated by 5HT2A receptors, suggesting that they are primarily due to enhanced excitatory drive from ETCs. Increased sIPSCs resulted from elevated excitatory drive onto GABAergic interneurons and augmented GABA release from SACs. Serotonin-mediated GABA release from SACs was action potential independent and significantly increased miniature IPSC frequency in glomerular neurons. When focally applied to a glomerulus, 5HT increased MC spontaneous firing greater than twofold but did not increase olfactory nerve-evoked responses. Taken together, 5HT modulates glomerular network activity in several ways: 1) it increases ETC-mediated feed-forward excitation onto MCs, SACs, and PGCs; 2) it increases inhibition of glomerular interneurons; 3) it directly triggers action potential-independent GABA release from SACs; and 4) these network actions increase spontaneous MC firing without enhancing responses to suprathreshold sensory input. This may enhance MC sensitivity while maintaining dynamic range. Copyright © 2016 the American Physiological Society.

Electrophysiological and optical changes in slices of rat hippocampus during spreading depression.

PubMed

Snow, R W; Taylor, C P; Dudek, F E

1983-09-01

Spreading depression (SD) was studied with intracellular and extracellular recordings and with photometry in slices of rat hippocampus. Repetitive electrical stimulation could initiate SD in either normal medium or in low-Ca2+ medium containing Mn2+, especially during transient hypoxia. The extracellular voltage near CA1 pyramidal somata and dendrites became negative by approximately 18 mV during SD. This negativity peaked more slowly in low-Ca2+ medium containing Mn2+. The wave of negativity propagated across the slice in both media at approximately 6 mm/min. Input resistance of pyramidal neurons became undetectable during SD, and differential voltage recording between neurons and adjacent extracellular space demonstrated that transmembrane potential approached zero. Slices became more opaque during SD. Photometry revealed approximately 10% increase in reflectance and a similar decrease in transmittance of white light, which occurred with a time course similar to the extracellularly recorded voltage shift. These data support the hypothesis that SD represents a large increase in membrane permeability associated with substantial movements of water. The persistance of SD in a bathing solution that blocked electrically evoked postsynaptic potentials suggests that the contribution of synaptic transmitter release to the propagation of SD should be reappraised.

Generating synchrony from the asynchronous: compensation for cochlear traveling wave delays by the dendrites of individual brainstem neurons

PubMed Central

McGinley, Matthew J.; Liberman, M. Charles; Bal, Ramazan; Oertel, Donata

2012-01-01

Broadband transient sounds, such as clicks and consonants, activate a traveling wave in the cochlea. This wave evokes firing in auditory nerve fibers that are tuned to high frequencies several milliseconds earlier than in fibers tuned to low frequencies. Despite this substantial traveling wave delay, octopus cells in the brainstem receive broadband input and respond to clicks with submillisecond temporal precision. The dendrites of octopus cells lie perpendicular to the tonotopically organized array of auditory nerve fibers, placing the earliest arriving inputs most distally and the latest arriving closest to the soma. Here, we test the hypothesis that the topographic arrangement of synaptic inputs on dendrites of octopus cells allows octopus cells to compensate the traveling wave delay. We show that in mice the full cochlear traveling wave delay is 1.6 ms. Because the dendrites of each octopus cell spread across about one third of the tonotopic axis, a click evokes a soma directed sweep of synaptic input lasting 0.5 ms in individual octopus cells. Morphologically and biophysically realistic, computational models of octopus cells show that soma-directed sweeps with durations matching in vivo measurements result in the largest and sharpest somatic excitatory postsynaptic potentials (EPSPs). A low input resistance and activation of a low-voltage-activated potassium conductance that are characteristic of octopus cells are important determinants of sweep sensitivity. We conclude that octopus cells have dendritic morphologies and biophysics tailored to accomplish the precise encoding of broadband transient sounds. PMID:22764237

NR2A- and NR2B-NMDA receptors and drebrin within postsynaptic spines of the hippocampus correlate with hunger-evoked exercise.

PubMed

Chen, Yi-Wen; Actor-Engel, Hannah; Sherpa, Ang Doma; Klingensmith, Lauren; Chowdhury, Tara G; Aoki, Chiye

2017-07-01

Hunger evokes foraging. This innate response can be quantified as voluntary wheel running following food restriction (FR). Paradoxically, imposing severe FR evokes voluntary FR, as some animals choose to run rather than eat, even during limited periods of food availability. This phenomenon, called activity-based anorexia (ABA), has been used to identify brain changes associated with FR and excessive exercise (EX), two core symptoms of anorexia nervosa (AN), and to explore neurobiological bases of AN vulnerability. Previously, we showed a strong positive correlation between suppression of FR-evoked hyperactivity, i.e., ABA resilience, and levels of extra-synaptic GABA receptors in stratum radiatum (SR) of hippocampal CA1. Here, we tested for the converse: whether animals with enhanced expression of NMDA receptors (NMDARs) exhibit greater levels of FR-evoked hyperactivity, i.e., ABA vulnerability. Four groups of animals were assessed for NMDAR levels at CA1 spines: (1) ABA, in which 4 days of FR was combined with wheel access to allow voluntary EX; (2) FR only; (3) EX only; and (4) control (CON) that experienced neither EX nor FR. Electron microscopy revealed that synaptic NR2A-NMDARs and NR2B-NMDARs levels are significantly elevated, relative to CONs'. Individuals' ABA severity, based on weight loss, correlated with synaptic NR2B-NMDAR levels. ABA resilience, quantified as suppression of hyperactivity, correlated strongly with reserve pools of NR2A-NMDARs in spine cytoplasm. NR2A- and NR2B-NMDAR measurements correlated with spinous prevalence of an F-actin binding protein, drebrin, suggesting that drebrin enables insertion of NR2B-NMDAR to and retention of NR2A-NMDARs away from synaptic membranes, together influencing ABA vulnerability.

5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function.

PubMed

Wang, Xin; Dergacheva, Olga; Kamendi, Harriet; Gorini, Christopher; Mendelowitz, David

2007-08-01

Opioids evoke respiratory depression, bradycardia, and reduced respiratory sinus arrhythmia, whereas serotonin (5-HT) agonists stimulate respiration and cardiorespiratory interactions. This study tested whether serotonin agonists can prevent the inhibitory effects of opioids on cardiorespiratory function. Spontaneous and rhythmic inspiratory-related activity and gamma-aminobutyric acid (GABA) neurotransmission to premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus were recorded simultaneously in an in vitro thick slice preparation. The mu-opioid agonist fentanyl inhibited respiratory frequency. The 5-hydroxytryptamine 1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin increased respiratory frequency by itself and also prevented the fentanyl-induced respiratory depression. The 5-hydroxytryptamine 4alpha agonist BIMU-8 did not by itself change inspiratory activity but prevented the mu-opioid-mediated respiratory depression. Both spontaneous and inspiratory-evoked GABAergic neurotransmission to cardiac vagal neurons were inhibited by fentanyl. 8-Hydroxy-2-(di-n-propylamino)tetralin inhibited spontaneous but not inspiratory-evoked GABAergic activity to parasympathetic cardiac neurons. However, 8-hydroxy-2-(di-n-propylamino)tetralin differentially altered the opioid-mediated depression of inspiratory-evoked GABAergic activity but did not change the opioid-induced reduction in spontaneous GABAergic neurotransmission. In contrast, BIMU-8 did not alter GABAergic neurotransmission to cardiac vagal neurons by itself but prevented the fentanyl depression of both spontaneous and inspiratory-elicited GABAergic neurotransmission to cardiac vagal neurons. In the presence of tetrodotoxin, the inhibition of GABAergic inhibitory postsynaptic currents with fentanyl is prevented by coapplication of BIMU-8, indicating that BIMU-8 acts at presynaptic GABAergic terminals to prevent fentanyl-induced depression. These results suggest that activation of 5-hydroxytryptamine receptors, particularly 5-hydroxytryptamine 4alpha agonists, may be a useful therapeutic approach in preventing opioid-evoked cardiorespiratory depression.

Importance of Nitric Oxide for Local Increases of Blood Flow in Rat Cerebellar Cortex During Electrical Stimulation

NASA Astrophysics Data System (ADS)

Akgoren, Nuran; Fabricius, Martin; Lauritzen, Martin

1994-06-01

The endothelium-derived relaxing factor, probably nitric oxide (NO), is a potent vasodilator that regulates the vascular tone in several vascular beds, including the brain. We explored the possibility that NO might be of importance for the increase of cerebral blood flow (CBF) associated with activity of the well-defined neuronal circuits of the rat cerebellar cortex. Laser-Doppler flowmetry was used to measure increases of cerebellar blood flow evoked by trains of electrical stimulations of the dorsal surface. The evoked increases of CBF were frequency-dependent, being larger on than off the parallel fiber tracts, suggesting that conduction along parallel fibers and synaptic activation of target cells were important for the increase of CBF. This was verified experimentally since the evoked CBF increases were abolished by tetrodotoxin and reduced by 10 mM Mg2+ and selective antagonists for non-N-methyl-D-aspartate receptors. The cerebellar cortex contains high levels of NO synthase. This raised the possibility that NO was involved in the increase of CBF associated with neuronal activation. NO synthase inhibition by topical application of N^G-nitro-L-arginine attenuated the evoked CBF increase by about 50%. This effect was partially reversed by pretreatment with L-arginine, the natural substrate for the enzyme, while N^G-nitro-D-arginine, the inactive enantiomer, had no effect on the evoked CBF increases. Simultaneous blockade of non-N-methyl-D-aspartate receptors and NO synthase had no further suppressing effect on the blood flow increase than either substance alone, suggesting that the NO-dependent flow rise was dependent on postsynaptic mechanisms. These findings are consistent with the idea that local synthesis of NO is involved in the transduction mechanism between neuronal activity and increased CBF.

N-type Ca2+ channels mediate transmitter release at the electromotoneuron-electrocyte synapses of the weakly electric fish Gymnotus carapo.

PubMed

Sierra, F; Lorenzo, D; Macadar, O; Buño, W

1995-06-19

The effects of omega-conotoxin-GVIA (omega-CgTX) on synaptic transmission were studied in the electromotoneuron-electrocyte synapses of the electric organ (EO) of the weakly electric fish Gymnotus carapo. omega-CgTX selectively and irreversibly blocked excitatory postsynaptic potentials (EPSPs) in a dose dependent-manner. The toxin had no effect on: (a) resting postsynaptic membrane potential and conductance; (b) postsynaptic action potentials elicited by depolarizing transmembrane current pulses; (c) the action potential conduction in the presynaptic fiber; (d) acetylcholine (ACh)-induced postsynaptic responses. Nifedipine - a selective dihydropyridine antagonist of the L-type voltage-dependent Ca2+ channels (VDCCs) - did not affect synaptic transmission. Transmission was also undisturbed by the peptide omega-Agatoxin (omega-Aga-IVA), the low molecular weight polyamine, funnel-web toxin (FTX) - both included in the venom of the spider Agelenopsis aperta - and its synthetic analog sFTX, all selective blockers of P-type VDCCs. Since omega-CgTX irreversibly blocks the N-type VDCCs, we conclude that presynaptic N-type VDCCs mediate transmitter release at electromotoneuron terminals. The VDCCs involved in fish peripheral electromotoneuron-electrocyte presynaptic transmitter release are therefore similar to those in amphibian, reptilian and avian peripheral synapses, but differ from mammalian and invertebrate motoneuron terminals.

Ciproxifan, a histamine H{sub 3} receptor antagonist and inverse agonist, presynaptically inhibits glutamate release in rat hippocampus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Cheng-Wei; Lin, Tzu-Yu

2017-03-15

Ciproxifan is an H{sub 3} receptor antagonist and inverse agonist with antipsychotic effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus. In a synaptosomal preparation, ciproxifan reduced 4-aminopyridine (4-AP)-evoked Ca{sup 2+}-dependent glutamate release and cytosolic Ca{sup 2+} concentration elevation but did not affect the membrane potential. The inhibitory effect of ciproxifan on 4-AP-evoked glutamate release was prevented by the Gi/Go-protein inhibitor pertussis toxin and Ca{sub v}2.2 (N-type) and Ca{sub v}2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was not affected by the intracellular Ca{sup 2+}-release inhibitors dantrolene and CGP37157. Furthermore, the phospholipase A{submore » 2} (PLA{sub 2}) inhibitor OBAA, prostaglandin E{sub 2} (PGE{sub 2}), PGE2 subtype 2 (EP{sub 2}) receptor antagonist PF04418948, and extracellular signal-regulated kinase (ERK) inhibitor FR180204 eliminated the inhibitory effect of ciproxifan on glutamate release. Ciproxifan reduced the 4-AP-evoked phosphorylation of ERK and synapsin I, a presynaptic target of ERK. The ciproxifan-mediated inhibition of glutamate release was prevented in synaptosomes from synapsin I-deficient mice. Moreover, ciproxifan reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that ciproxifan, acting through the blockade of Gi/Go protein-coupled H{sub 3} receptors present on hippocampal nerve terminals, reduces voltage-dependent Ca{sup 2+} entry by diminishing PLA{sub 2}/PGE{sub 2}/EP{sub 2} receptor pathway, which subsequently suppresses the ERK/synapsin I cascade to decrease the evoked glutamate release. - Highlights: • Ciproxifan presynaptically reduces glutamate release in the hippocampus in vitro. • Decrease in voltage-dependent Ca{sup 2+} influx is involved. • A role for the PLA{sub 2}/PGE{sub 2}/EP{sub 2} pathway in the action of ciproxifan is suggested. • Decreased ERK and synapsin I activity is also involved. • This study provides new insight into the mode by which ciproxifan acts in the brain.« less

The Glutamatergic Aspects of Schizophrenia Molecular Pathophysiology: Role of the Postsynaptic Density, and Implications for Treatment

PubMed Central

Iasevoli, Felice; Tomasetti, Carmine; Buonaguro, Elisabetta F.; de Bartolomeis, Andrea

2014-01-01

Schizophrenia is one of the most debilitating psychiatric diseases with a lifetime prevalence of approximately 1%. Although the specific molecular underpinnings of schizophrenia are still unknown, evidence has long linked its pathophysiology to postsynaptic abnormalities. The postsynaptic density (PSD) is among the molecular structures suggested to be potentially involved in schizophrenia. More specifically, the PSD is an electron-dense thickening of glutamatergic synapses, including ionotropic and metabotropic glutamate receptors, cytoskeletal and scaffolding proteins, and adhesion and signaling molecules. Being implicated in the postsynaptic signaling of multiple neurotransmitter systems, mostly dopamine and glutamate, the PSD constitutes an ideal candidate for studying dopamine-glutamate disturbances in schizophrenia. Recent evidence suggests that some PSD proteins, such as PSD-95, Shank, and Homer are implicated in severe behavioral disorders, including schizophrenia. These findings, further corroborated by genetic and animal studies of schizophrenia, offer new insights for the development of pharmacological strategies able to overcome the limitations in terms of efficacy and side effects of current schizophrenia treatment. Indeed, PSD proteins are now being considered as potential molecular targets against this devastating illness. The current paper reviews the most recent hypotheses on the molecular mechanisms underlying schizophrenia pathophysiology. First, we review glutamatergic dysfunctions in schizophrenia and we provide an update on postsynaptic molecules involvement in schizophrenia pathophysiology by addressing both human and animal studies. Finally, the possibility that PSD proteins may represent potential targets for new molecular interventions in psychosis will be discussed. PMID:24851087

HttQ111/+ Huntington's Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic Dysfunction.

PubMed

Kovalenko, Marina; Milnerwood, Austen; Giordano, James; St Claire, Jason; Guide, Jolene R; Stromberg, Mary; Gillis, Tammy; Sapp, Ellen; DiFiglia, Marian; MacDonald, Marcy E; Carroll, Jeffrey B; Lee, Jong-Min; Tappan, Susan; Raymond, Lynn; Wheeler, Vanessa C

2018-01-01

Successful disease-modifying therapy for Huntington's disease (HD) will require therapeutic intervention early in the pathogenic process. Achieving this goal requires identifying phenotypes that are proximal to the HTT CAG repeat expansion. To use Htt CAG knock-in mice, precise genetic replicas of the HTT mutation in patients, as models to study proximal disease events. Using cohorts of B6J.HttQ111/+ mice from 2 to 18 months of age, we analyzed pathological markers, including immunohistochemistry, brain regional volumes and cortical thickness, CAG instability, electron microscopy of striatal synapses, and acute slice electrophysiology to record glutamatergic transmission at striatal synapses. We also incorporated a diet perturbation paradigm for some of these analyses. B6J.HttQ111/+ mice did not exhibit significant neurodegeneration or gliosis but revealed decreased striatal DARPP-32 as well as subtle but regional-specific changes in brain volumes and cortical thickness that parallel those in HD patients. Ultrastructural analyses of the striatum showed reduced synapse density, increased postsynaptic density thickness and increased synaptic cleft width. Acute slice electrophysiology showed alterations in spontaneous AMPA receptor-mediated postsynaptic currents, evoked NMDA receptor-mediated excitatory postsynaptic currents, and elevated extrasynaptic NMDA currents. Diet influenced cortical thickness, but did not impact somatic CAG expansion, nor did it show any significant interaction with genotype on immunohistochemical, brain volume or cortical thickness measures. These data show that a single HttQ111 allele is sufficient to elicit brain region-specific morphological changes and early neuronal dysfunction, highlighting an insidious disease process already apparent in the first few months of life.

Developmental neurotoxicity targeting hepatic and cardiac sympathetic innervation: effects of organophosphates are distinct from those of glucocorticoids.

PubMed

Seidler, Frederic J; Slotkin, Theodore A

2011-05-30

Early-life exposure to organophosphate pesticides leads to subsequent hyperresponsiveness of β-adrenergic receptor-mediated cell signaling that regulates hepatic gluconeogenesis, culminating in metabolic abnormalities resembling prediabetes. In the current study, we evaluated the effects of chlorpyrifos or parathion on presynaptic sympathetic innervation to determine whether the postsynaptic signaling effects are accompanied by defects in neuronal input. We administered either chlorpyrifos or parathion to newborn rats using exposure paradigms known to elicit the later metabolic changes but found no alterations in either hepatic or cardiac norepinephrine levels in adolescence or adulthood. However, shifting chlorpyrifos exposure to the prenatal period did evoke changes: exposure early in gestation produced subsequent elevations in norepinephrine, whereas later gestational exposure produced significant deficits. We also distinguished the organophosphate effects from those of the glucocorticoid, dexamethasone, a known endocrine disruptor that leads to later-life metabolic and cardiovascular disruption. Postnatal exposure to dexamethasone elicited deficits in peripheral norepinephrine levels but prenatal exposure did not. Our results indicate that early-life exposure to organophosphates leads to subsequent abnormalities of peripheral sympathetic innervation through mechanisms entirely distinct from those of glucocorticoids, ruling out the possibility that the organophosphate effects are secondary to stress or disruption of the HPA axis. Further, the effects on innervation were separable from those on postsynaptic signaling, differing in critical period as well as tissue- and sex-selectivity. Organophosphate targeting of both presynaptic and postsynaptic β-adrenergic sites, each with different critical periods of vulnerability, thus sets the stage for compounding of hepatic and cardiac functional abnormalities. Copyright © 2011 Elsevier Inc. All rights reserved.

Kainate receptor-mediated depression of glutamatergic transmission involving protein kinase A in the lateral amygdala.

PubMed

Negrete-Díaz, José Vicente; Duque-Feria, Paloma; Andrade-Talavera, Yuniesky; Carrión, Miriam; Flores, Gonzalo; Rodríguez-Moreno, Antonio

2012-04-01

Kainate receptors (KARs) have been described as modulators of synaptic transmission at different synapses. However, this role of KARs has not been well characterized in the amygdala. We have explored the effect of kainate receptor activation at the synapse established between fibers originating at medial geniculate nucleus and the principal cells in the lateral amygdala. We have observed an inhibition of evoked excitatory postsynaptic currents (eEPSCs) amplitude after a brief application of KARs agonists KA and ATPA. Paired-pulse recordings showed a clear pair pulse facilitation that was enhanced after KA or ATPA application. When postsynaptic cells were loaded with BAPTA, the depression of eEPSC amplitude observed after the perfusion of KAR agonists was not prevented. We have also observed that the inhibition of the eEPSCs by KARs agonists was prevented by protein kinase A but not by protein kinase C inhibitors. Taken together our results indicate that KARs present at this synapse are pre-synaptic and their activation mediate the inhibition of glutamate release through a mechanism that involves the activation of protein kinase A. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

GABAergic miniature postsynaptic currents in septal neurons show differential allosteric sensitivity after binge-like ethanol exposure.

PubMed

DuBois, Dustin W; Trzeciakowski, Jerome P; Parrish, Alan R; Frye, Gerald D

2006-05-17

Binge-like ethanol treatment of septal neurons blunts GABAAR-mediated miniature postsynaptic currents (mPSCs), suggesting it arrests synaptic development. Ethanol may disrupt postsynaptic maturation by blunting feedback signaling through immature GABAARs. Here, the impact of ethanol on the sensitivity of mPSCs to zolpidem, zinc and 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) was tested. The decay phase of mPSCs showed concentration-dependent potentiation by zolpidem (0.03-100 microM), which was substantially blunted after ethanol exposure. Since zolpidem potentiation exhibited a substantial age-dependent increase in untreated neurons, this finding supported the idea that ethanol arrests synaptic development. GABAAR alpha1 subunit protein also increased with age in untreated neurons, paralleling enhanced sensitivity to zolpidem. Surprisingly, alpha1 levels were not reduced by binge ethanol even though mPSCs were relatively zolpidem-insensitive. Zinc (3-30 microM) decreased mPSC parameters in a concentration- and age-related manner with older untreated cells showing less inhibition. However, there was no increase in mPSC zinc sensitivity after binge ethanol as would be expected if a general arrest of synaptic maturation had occurred. 3alpha-OH-DHP (3-1000 nM) induced concentration-dependent potentiation of mPSC decay. Although potentiation was age-independent, binge ethanol treatment exaggerated sensitivity to this neurosteroid. Finally, chronic picrotoxin pretreatment (100 microM) intended to mimic GABAAR inhibition from ethanol pretreatment did not significantly change mPSC modulation by zolpidem, zinc or 3alpha-OH-DHP. These results suggest that binge ethanol treatment selectively arrests a subset of processes important for maturation of postsynaptic GABAA Rs. However, it is unlikely that ethanol causes a broad arrest of postsynaptic development through a direct inhibition of GABAAR signaling.

Heterotypic gap junctions at glutamatergic mixed synapses are abundant in goldfish brain

PubMed Central

Rash, John E.; Kamasawa, Naomi; Vanderpool, Kimberly G.; Yasumura, Thomas; O'Brien, John; Nannapaneni, Srikant; Pereda, Alberto E.; Nagy, James I.

2014-01-01

Gap junctions provide for direct intercellular electrical and metabolic coupling. The abundance of gap junctions at “large myelinated club ending” synapses on Mauthner cells of the teleost brain provided a convenient model to correlate anatomical and physiological properties of electrical synapses. There, presynaptic action potentials were found to evoke short-latency electrical “pre-potentials” immediately preceding their accompanying glutamate-induced depolarizations, making these the first unambiguously identified “mixed” (i.e., chemical plus electrical) synapses in the vertebrate CNS. We recently showed that gap junctions at these synapses exhibit asymmetric electrical resistance (i.e., electrical rectification), which we correlated with total molecular asymmetry of connexin composition in their apposing gap junction hemiplaques, with Cx35 restricted to axon terminal hemiplaques and Cx34.7 restricted to apposing Mauthner cell plasma membranes. We now show that similarly heterotypic neuronal gap junctions are abundant throughout goldfish brain, with labeling exclusively for Cx35 in presynaptic hemiplaques and exclusively for Cx34.7 in postsynaptic hemiplaques. Moreover, the vast majority of these asymmetric gap junctions occur at glutamatergic axon terminals. The widespread distribution of heterotypic gap junctions at glutamatergic mixed synapses throughout goldfish brain and spinal cord implies that pre- vs. postsynaptic asymmetry at electrical synapses evolved early in the chordate lineage. We propose that the advantages of the molecular and functional asymmetry of connexins at electrical synapses that are so prominently expressed in the teleost CNS are unlikely to have been abandoned in higher vertebrates. However, to create asymmetric coupling in mammals, where most gap junctions are composed of Cx36 on both sides, would require some other mechanism, such as differential phosphorylation of connexins on opposite sides of the same gap junction or on asymmetric differences in the complement of their scaffolding and regulatory proteins. PMID:25451276

Low-frequency electrical stimulation enhances the effectiveness of phenobarbital on GABAergic currents in hippocampal slices of kindled rats.

PubMed

Asgari, Azam; Semnanian, Saeed; Atapour, Nafiseh; Shojaei, Amir; Moradi-Chameh, Homeira; Ghafouri, Samireh; Sheibani, Vahid; Mirnajafi-Zadeh, Javad

2016-08-25

Low frequency stimulation (LFS) has been proposed as a new approach in the treatment of epilepsy. The anticonvulsant mechanism of LFS may be through its effect on GABAA receptors, which are the main target of phenobarbital anticonvulsant action. We supposed that co-application of LFS and phenobarbital may increase the efficacy of phenobarbital. Therefore, the interaction of LFS and phenobarbital on GABAergic inhibitory post-synaptic currents (IPSCs) in kindled and control rats was investigated. Animals were kindled by electrical stimulation of basolateral amygdala in a semi rapid manner (12 stimulations/day). The effect of phenobarbital, LFS and phenobarbital+LFS was investigated on GABAA-mediated evoked and miniature IPSCs in the hippocampal brain slices in control and fully kindled animals. Phenobarbital and LFS had positive interaction on GABAergic currents. In vitro co-application of an ineffective pattern of LFS (100 pulses at afterdischarge threshold intensity) and a sub-threshold dose of phenobarbital (100μM) which had no significant effect on GABAergic currents alone, increased the amplitude and area under curve of GABAergic currents in CA1 pyramidal neurons of hippocampal slices significantly. Interestingly, the sub-threshold dose of phenobarbital potentiated the GABAergic currents when applied on the hippocampal slices of kindled animals which received LFS in vivo. Post-synaptic mechanisms may be involved in observed interactions. Obtained results implied a positive interaction between LFS and phenobarbital through GABAA currents. It may be suggested that a combined therapy of phenobarbital and LFS may be a useful manner for reinforcing the anticonvulsant action of phenobarbital. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

A role for N-methyl-D-aspartate receptors in norepinephrine-induced long-lasting potentiation in the dentate gyrus.

PubMed

Stanton, P K; Mody, I; Heinemann, U

1989-01-01

Mechanisms of action of norepinephrine (NE) on dentate gyrus granule cells were studied in rat hippocampal slices using extra- and intracellular recordings and measurements of stimulus and amino acid-induced changes in extracellular Ca2+ and K+ concentration. Bath application of NE (10-50 microM) induced long-lasting potentiation of perforant path evoked potentials, and markedly enhanced high-frequency stimulus-induced Ca2+ influx and K+ efflux, actions blocked by beta-receptor antagonists and mimicked by beta agonists. Enhanced Ca2+ influx was primarily postsynaptic, since presynaptic delta [Ca2+]o in the stratum moleculare synaptic field was not altered by NE. Interestingly, the potentiation of both ionic fluxes and evoked population potentials were antagonized by the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (APV). Furthermore, NE selectively enhanced the delta [Ca2+]o delta [K+]o and extracellular slow negative field potentials elicited by iontophoretically applied NMDA, but not those induced by the excitatory amino acid quisqualate. These results suggest that granule cell influx of Ca2+ through NMDA ionophores is enhanced by NE via beta-receptor activation. In intracellular recordings, NE depolarized granule cells (4.8 +/- 1.1 mV), and increased input resistance (RN) by 34 +/- 6.5%. These actions were also blocked by either the beta-antagonist propranolol or specific beta 1-blocker metoprolol. Moreover, the depolarization and RN increase persisted for long periods (93 +/- 12 min) after NE washout. In contrast, while NE, in the presence of APV, still depolarized granule cells and increased RN, APV made these actions quickly reversible upon NE washout (16 +/- 9 min). This suggested that NE induction of long-term, but not short-term, plasticity in the dentate gyrus requires NMDA receptor activation. NE may be enhancing granule cell firing by some combination of blockade on the late Ca2+-activated K+ conductance and depolarization of granule cells, both actions that can bring granule cells into a voltage range where NMDA receptors are more easily activated. Furthermore, NE also elicited activity-independent long-lasting depolarization and RN increases, which required functional NMDA receptors to persist.

Group II and III metabotropic glutamate receptors and the control of the nucleus reticularis thalami input to rat thalamocortical neurones in vitro.

PubMed

Turner, J P; Salt, T E

2003-01-01

Intracellular recordings were made from neurones in the thalamic reticular nucleus (TRN) and ventro-basal (VB) thalamus in slices of rat midbrain in vitro. Electrical stimulation of the medial lemniscus or TRN resulted in the generation of complex synaptic potentials containing disynaptic inhibitory post-synaptic potentials (IPSPs) in VB thalamocortical neurones. Analysis of the excitatory synaptic responses in TRN neurones indicates they can produce burst output response irrespective of the level of sub-threshold membrane potential. This suggests that network-evoked IPSPs in VB thalamocortical neurones occur following a burst of TRN action potentials. Using ionotropic glutamate receptor antagonists, the activation of these disynaptic events was blocked, and the monosynaptic IPSPs that resulted from the direct activation of the TRN could be isolated. The selective Group II agonists LY354740 (1-10 microM) and N-acetyl-aspartyl-glutamate (NAAG; 100-500 microM) both caused a reversible depression of these monosynaptic TRN IPSPs without any effect on membrane potential or input resistance. Likewise, the specific Group III agonist L-2-amino-4-phosphonobutanoate (10-500 microM), but not (RS)-4-phosphonophenylglycine (1 and 30 microM) also caused a reversible depression of these IPSPs, again without any effect on membrane potential or input resistance.Thus, the IPSPs recorded in VB thalamocortical neurones, evoked by TRN activation, can be depressed by the activation of either Group II or III metabotropic glutamate receptors. This is consistent with the location of these receptor types on the presynaptic terminals of TRN axons in the VB thalamus. This raises the possibility that, during periods of intense excitatory activity, glutamate release could influence the release of GABA from TRN axon terminals in the thalamus. In addition, as NAAG is located in the axons and terminals arising from the TRN, there is the possibility that this dipeptide is also released by these terminals to control the release of GABA during periods of high activity in the TRN.

Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus.

PubMed

Bellinger, F P; Madamba, S; Siggins, G R

1993-11-19

Cytokines such as interleukin-1 beta (IL-1 beta) are released in the nervous system following inflammation or infection. Recently, IL-1 beta was shown to enhance synaptic inhibitory mechanisms. We therefore investigated the effect of IL-1 beta superfusion on long-term potentiation (LTP), the cellular model of memory and learning, evoked in the CA1 region by tetanic stimulation of the stratum radiatum in the rat hippocampal slice. IL-1 beta (150 pM-1.5 nM) superfused 10 min before tetanic stimulation significantly reduced LTP of the slope of the population excitatory postsynaptic potential (pEPSP) and the population spike (PS) amplitude in CA1 in a concentration-dependent manner. IL-1 beta (1.5 nM) applied for 10 min 1 h before tetanus significantly inhibited LTP of the PS amplitude and pEPSP slope and reduced pEPSP and PS values before tetanus as well, although the PS returned to control values before tetanus. Heat-inactivated IL-1 beta had no effect on pre-tetanus pEPSP or PS values or the induction of LTP. These data demonstrate that IL-1 beta modulates synaptic potentials and reduces LTP. These findings have important implications for the role of IL-1 beta in neuronal disorders following infection, perhaps best exemplified by HIV-1-associated dementia.

Genetic dissection of ion currents underlying all-or-none action potentials in C. elegans body-wall muscle cells

PubMed Central

Liu, Ping; Ge, Qian; Chen, Bojun; Salkoff, Lawrence; Kotlikoff, Michael I; Wang, Zhao-Wen

2011-01-01

Although the neuromuscular system of C. elegans has been studied intensively, little is known about the properties of muscle action potentials (APs). By combining mutant analyses with in vivo electrophysiological recording techniques and Ca2+ imaging, we have established the fundamental properties and molecular determinants of body-wall muscle APs. We show that, unlike mammalian skeletal muscle APs, C. elegans muscle APs occur in spontaneous trains, do not require the function of postsynaptic receptors, and are all-or-none overshooting events, rather than graded potentials as has been previously reported. Furthermore, we show that muscle APs depend on Ca2+ entry through the L-type Ca2+ channel EGL-19 with a contribution from the T-type Ca2+ channel CCA-1. Both the Shaker K+ channel SHK-1 and the Ca2+/Cl−-gated K+ channel SLO-2 play important roles in controlling the speed of membrane repolarization, the amplitude of afterhyperpolarization (AHP) and the pattern of AP firing; SLO-2 is also important in setting the resting membrane potential. Finally, AP-elicited elevations of [Ca2+]i require both EGL-19 and the ryanodine receptor UNC-68. Thus, like mammalian skeletal muscle, C. elegans body-wall myocytes generate all-or-none APs, which evoke Ca2+ release from the sarcoplasmic reticulum (SR), although the specific ion channels used for AP upstroke and repolarization differ. PMID:21059759

The effects of L-glutamate, AMPA, quisqualate, and kainate on retinal horizontal cells depend on adaptational state: implications for rod-cone interactions.

PubMed

Krizaj, D; Akopian, A; Witkovsky, P

1994-09-01

We studied the responses of isolated and intact luminosity-type horizontal cells (L-HC) in the Xenopus retina to L-glutamate (L-glu) and its analogs. Isolated L-HCs studied with whole-cell patch clamp responded to L-glu, kainate (KA), AMPA, or quisqualate (quis) with inward currents from a holding potential of -60 mV, associated with a conductance increase. The current elicited by KA was relatively large and sustained, whereas AMPA or quis evoked a desensitizing current. Coapplication of quis and KA resulted in a smaller current and conductance change than that evoked by a pulse of either alone at the same concentration. This finding suggests that the L-HC has a single subtype of glutamate receptor that responds to both quis and KA. Prior exposure to dopamine enhanced the KA-evoked current about twofold. In the superfused eyecup we found that L-HC responses to quinoxalinediones (CNQX or DNQX) and to L-glu, KA, AMPA, and quis varied as a function of adaptational state. When driven exclusively by either cones or by rods, CNQX/DNQX hyperpolarized the L-HC and reduced its light response, without altering response kinetics, indicating that both rods and cones communicate with L-HCs at ionotropic glutamatergic synapses. Under mesopic conditions, however, as CNQX or DNQX reduced cone input, the rod input to the L-HC increased up to fivefold in magnitude and had slowed kinetics. The depolarizing response of the L-HC to L-glu, AMPA, or quis was relatively small and transient under photopic conditions, but was much larger and sustained when the eyecup was dark adapted. The D1 dopamine antagonist SCH 23390 potentiated the response to quis. In contrast, responses to KA were largest in light-adapted eyecups, were potentiated by a D1 dopamine agonist, SKF 38393, and were reduced by SCH 23390. We hypothesize that the segregated populations of glutamate receptors in the L-HC opposite cone and rod synaptic endings can be separately modulated to respond differentially to the native transmitter, glutamate. In photopic and mesopic states the dominant cone input tonically inhibits rod to L-HC communication. This inhibition appears to occur at the postsynaptic membrane and may be mediated by second messengers.

Heterosynaptic changes accompany long-term but not short-term potentiation of the perforant path in the anaesthetized rat.

PubMed

Abraham, W C; Bliss, T V; Goddard, G V

1985-06-01

Brief high-frequency trains of electrical stimulation delivered to the perforant path result in long-term potentiation (l.t.p.) of field potentials recorded extracellularly from granule cells of the dentate gyrus. L.t.p. of the population spike is often disproportionately greater than l.t.p. of the population excitatory post-synaptic potential (e.p.s.p.). We have investigated the basis of this effect in rats anaesthetized with sodium pentobarbitone. A series of graded stimuli were given before and after tetanization of the perforant path. From data obtained in this way, we plotted stimulus-response curves, and the relation (E-S curve) between the slope of the population e.p.s.p. (E) and the amplitude of the population spike (S). Curves relating spike onset latency to the slope of the e.p.s.p. were also constructed. Tetanization of the combined medial and lateral components of the perforant path led to long-term changes in the relation between the e.p.s.p. and the population spike. For a given e.p.s.p., the corresponding population spike was of greater amplitude and earlier onset. This E-S potentiation was marked by a shift to the left of the E-S amplitude curve and a downward displacement of the E-S latency curve. Tetanization of the lateral component of the perforant path had two long-term effects on responses evoked by test stimuli to the untetanized medial component: (1) long-term depression of the medial e.p.s.p. and (2) long-term E-S potentiation. The net result of these two heterosynaptically induced effects was to leave unaltered information transfer across medial perforant path-granule cell synapses; for a given test volley the e.p.s.p. was smaller, but because of E-S potentiation the population spike remained relatively unaffected. Short-term potentiation, which has a time course of only a few minutes and is presumed to be mediated by presynaptic mechanisms, was not accompanied by E-S potentiation or by corresponding changes in spike latency. Possible mechanisms of long-term heterosynaptic depression of the e.p.s.p. and of homo- and heterosynaptic E-S potentiation, are discussed. We conclude that although these effects probably reflect a generalized post-synaptic change, this change is unlikely to be a prolonged reduction in the membrane potential of granule cells.

Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity.

PubMed

Orlando, Marta; Ravasenga, Tiziana; Petrini, Enrica Maria; Falqui, Andrea; Marotta, Roberto; Barberis, Andrea

2017-10-23

Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABA A Receptors (GABA A Rs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABA A R clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABA A R clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.

Spinal N-methyl-D-aspartate receptors and nociception-evoked release of primary afferent substance P.

PubMed

Nazarian, A; Gu, G; Gracias, N G; Wilkinson, K; Hua, X Y; Vasko, M R; Yaksh, T L

2008-03-03

Dorsal horn N-methyl-D-aspartate (NMDA) receptors contribute significantly to spinal nociceptive processing through an effect postsynaptic to non-primary glutamatergic axons, and perhaps presynaptic to the primary afferent terminals. The present study sought to examine the regulatory effects of NMDA receptors on primary afferent release of substance P (SP), as measured by neurokinin 1 receptor (NK1r) internalization in the spinal dorsal horn of rats. The effects of intrathecal NMDA alone or in combination with D-serine (a glycine site agonist) were initially examined on basal levels of NK1r internalization. NMDA alone or when co-administered with D-serine failed to induce NK1r internalization, whereas activation of spinal TRPV1 receptors by capsaicin resulted in a notable NK1r internalization. To determine whether NMDA receptor activation could potentiate NK1r internalization or pain behavior induced by a peripheral noxious stimulus, intrathecal NMDA was given prior to an intraplantar injection of formalin. NMDA did not alter the formalin-induced NK1r internalization nor did it enhance the formalin paw flinching behavior. To further characterize the effects of presynaptic NMDA receptors, the NMDA antagonists DL-2-amino-5-phosphonopentanoic acid (AP-5) and MK-801 were intrathecally administered to assess their regulatory effects on formalin-induced NK1r internalization and pain behavior. AP-5 had no effect on formalin-induced NK1r internalization, whereas MK-801 produced only a modest reduction. Both antagonists, however, reduced the formalin paw flinching behavior. In subsequent in vitro experiments, perfusion of NMDA in spinal cord slice preparations did not evoke basal release of SP or calcitonin gene-related peptide (CGRP). Likewise, perfusion of NMDA did not enhance capsaicin-evoked release of the two peptides. These results suggest that presynaptic NMDA receptors in the spinal cord play little if any role on the primary afferent release of SP.

Synaptically activated Ca2+ waves and NMDA spikes locally suppress voltage-dependent Ca2+ signalling in rat pyramidal cell dendrites

PubMed Central

Manita, Satoshi; Miyazaki, Kenichi; Ross, William N

2011-01-01

Abstract Postsynaptic [Ca2+]i changes contribute to several kinds of plasticity in pyramidal neurons. We examined the effects of synaptically activated Ca2+ waves and NMDA spikes on subsequent Ca2+ signalling in CA1 pyramidal cell dendrites in hippocampal slices. Tetanic synaptic stimulation evoked a localized Ca2+ wave in the primary apical dendrites. The [Ca2+]i increase from a backpropagating action potential (bAP) or subthreshold depolarization was reduced if it was generated immediately after the wave. The suppression had a recovery time of 30–60 s. The suppression only occurred where the wave was generated and was not due to a change in bAP amplitude or shape. The suppression also could be generated by Ca2+ waves evoked by uncaging IP3, showing that other signalling pathways activated by the synaptic tetanus were not required. The suppression was proportional to the amplitude of the [Ca2+]i change of the Ca2+ wave and was not blocked by a spectrum of kinase or phosphatase inhibitors, consistent with suppression due to Ca2+-dependent inactivation of Ca2+ channels. The waves also reduced the frequency and amplitude of spontaneous, localized Ca2+ release events in the dendrites by a different mechanism, probably by depleting the stores at the site of wave generation. The same synaptic tetanus often evoked NMDA spike-mediated [Ca2+]i increases in the oblique dendrites where Ca2+ waves do not propagate. These NMDA spikes suppressed the [Ca2+]i increase caused by bAPs in those regions. [Ca2+]i increases by Ca2+ entry through voltage-gated Ca2+ channels also suppressed the [Ca2+]i increases from subsequent bAPs in regions where the voltage-gated [Ca2+]i increases were largest, showing that all ways of raising [Ca2+]i could cause suppression. PMID:21844002

Importance of stimulation paradigm in determining facilitation and effects of neuromodulation.

PubMed

Crider, M E; Cooper, R L

1999-09-25

Evoked synaptic activity within the CNS and at the neuromuscular junction in most in vivo preparations studied occurs not with single isolated stimuli, but with trains, or bursts, of stimuli. Although for ease in studying the mechanisms of vesicular synaptic transmission one often uses single discrete stimuli, the true mechanisms in the animal may be far more complex. When repetitive stimuli are present at a nerve terminal, often a heightened (i.e., facilitated) postsynaptic potential can be as a result. Facilitation is commonly used as an index of synaptic function and plasticity induced by chronic stimulation or by neuromodulation. The mechanisms that give rise to facilitation are thought to be the same that may underlie short-term learning and memory [C.H. Bailey, E.R. Kandel, Structural changes accompanying memory storage. Annu. Rev. Physiol. 55 (1993) 397-426.]. Differences in short term facilitation (STF) are seen depending on the conventional stimulation paradigm (twin pulse, train, or continuous) used to induce facilitation. Thus, a battery of paradigms should be used to characterize synaptic function to obtain a closer understanding of the possible in vivo conditions.

Muscarinic Long-Term Enhancement of Tonic and Phasic GABAA Inhibition in Rat CA1 Pyramidal Neurons

PubMed Central

Domínguez, Soledad; Fernández de Sevilla, David; Buño, Washington

2016-01-01

Acetylcholine (ACh) regulates network operation in the hippocampus by controlling excitation and inhibition in rat CA1 pyramidal neurons (PCs), the latter through gamma-aminobutyric acid type-A receptors (GABAARs). Although, the enhancing effects of ACh on GABAARs have been reported (Dominguez et al., 2014, 2015), its role in regulating tonic GABAA inhibition has not been explored in depth. Therefore, we aimed at determining the effects of the activation of ACh receptors on responses mediated by synaptic and extrasynaptic GABAARs. Here, we show that under blockade of ionotropic glutamate receptors ACh, acting through muscarinic type 1 receptors, paired with post-synaptic depolarization induced a long-term enhancement of tonic GABAA currents (tGABAA) and puff-evoked GABAA currents (pGABAA). ACh combined with depolarization also potentiated IPSCs (i.e., phasic inhibition) in the same PCs, without signs of interactions of synaptic responses with pGABAA and tGABAA, suggesting the contribution of two different GABAA receptor pools. The long-term enhancement of GABAA currents and IPSCs reduced the excitability of PCs, possibly regulating plasticity and learning in behaving animals. PMID:27833531

[Effect of trimebutine on cholinergic transmission in neurons of the inferior mesenteric ganglion of the rabbit].

PubMed

Julé, Y

1987-01-01

We analyzed the effects of trimebutine on the synaptic activity of neurons of the rabbit inferior mesenteric ganglion, using intracellular recording techniques. The synaptic activity was produced by subthreshold stimuli (0.5 Hz) applied individually, on lumbar splanchnic and lumbar colonic nerves. These stimuli triggered cholinergic responses corresponding to fast excitatory postsynaptic potentials. In 8 of 20 neurones tested trimebutine (10(-6) g/ml) produced an inhibition of excitatory postsynaptic potentials, without any change in the resting membrane potential. In 6 of 20 neurons tested, trimebutine produced, successively, an early facilitation followed by a late inhibition of excitatory postsynaptic potentials. Both effects occurred without change in the resting membrane potential. The inhibitory and facilitatory effects of trimebutine were accompanied, by an increase and a decrease in the number of failures of nerve stimulation respectively. These results indicate that inhibitory and facilitatory effects of trimebutine correspond respectively to a decrease and an increase in the amount of acetylcholine released from presynaptic nerve terminals originating from the spinal cord and the distal colon.

Olfactory Nerve–Evoked, Metabotropic Glutamate Receptor–Mediated Synaptic Responses in Rat Olfactory Bulb Mitral Cells

PubMed Central

Ennis, Matthew; Zhu, Mingyan; Heinbockel, Thomas; Hayar, Abdallah

2008-01-01

The group I metabotropic glutamate receptor (mGluR) subtype, mGluR1, is highly expressed on the apical dendrites of olfactory bulb mitral cells and thus may be activated by glutamate released from olfactory nerve (ON) terminals. Previous studies have shown that mGluR1 agonists directly excite mitral cells. In the present study, we investigated the involvement of mGluR1 in ON-evoked responses in mitral cells in rat olfactory bulb slices using patch-clamp electrophysiology. In voltage-clamp recordings, the average EPSC evoked by single ON shocks or brief trains of ON stimulation (six pulses at 50 Hz) in normal physiological conditions were not significantly affected by the nonselective mGluR antagonist LY341495 (50–100 μM) or the mGluR1-specific antagonist LY367385 (100 μM); ON-evoked responses were attenuated, however, in a subset (36%) of cells. In the presence of blockers of ionotropic glutamate and GABA receptors, application of the glutamate uptake inhibitors THA (300 μM) and TBOA (100 μM) revealed large-amplitude, long-duration responses to ON stimulation, whereas responses elicited by antidromic activation of mitral/tufted cells were unaffected. Magnitudes of the ON-evoked responses elicited in the presence of THA–TBOA were dependent on stimulation intensity and frequency, and were maximal during high-frequency (50-Hz) bursts of ON spikes, which occur during odor stimulation. ON-evoked responses elicited in the presence of THA–TBOA were significantly reduced or completely blocked by LY341495 or LY367385 (100 μM). These results demonstrate that glutamate transporters tightly regulate access of synaptically evoked glutamate from ON terminals to postsynaptic mGluR1s on mitral cell apical dendrites. Taken together with other findings, the present results suggest that mGluR1s may not play a major role in phasic responses to ON input, but instead may play an important role in shaping slow oscillatory activity in mitral cells and/or activity-dependent regulation of plasticity at ON–mitral cell synapses. PMID:16394070

Evidence that GABA ρ subunits contribute to functional ionotropic GABA receptors in mouse cerebellar Purkinje cells

PubMed Central

Harvey, Victoria L; Duguid, Ian C; Krasel, Cornelius; Stephens, Gary J

2006-01-01

Ionotropic γ-amino butyric acid (GABA) receptors composed of heterogeneous molecular subunits are major mediators of inhibitory responses in the adult CNS. Here, we describe a novel ionotropic GABA receptor in mouse cerebellar Purkinje cells (PCs) using agents reported to have increased affinity for ρ subunit-containing GABAC over other GABA receptors. Exogenous application of the GABAC-preferring agonist cis-4-aminocrotonic acid (CACA) evoked whole-cell currents in PCs, whilst equimolar concentrations of GABA evoked larger currents. CACA-evoked currents had a greater sensitivity to the selective GABAC antagonist (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) than GABA-evoked currents. Focal application of agonists produced a differential response profile; CACA-evoked currents displayed a much more pronounced attenuation with increasing distance from the PC soma, displayed a slower time-to-peak and exhibited less desensitization than GABA-evoked currents. However, CACA-evoked currents were also completely blocked by bicuculline, a selective agent for GABAA receptors. Thus, we describe a population of ionotropic GABA receptors with a mixed GABAA/GABAC pharmacology. TPMPA reduced inhibitory synaptic transmission at interneurone–Purkinje cell (IN–PC) synapses, causing clear reductions in miniature inhibitory postsynaptic current (mIPSC) amplitude and frequency. Combined application of NO-711 (a selective GABA transporter subtype 1 (GAT-1) antagonist) and SNAP-5114 (a GAT-(2)/3/4 antagonist) induced a tonic GABA conductance in PCs; however, TPMPA had no effect on this current. Immunohistochemical studies suggest that ρ subunits are expressed predominantly in PC soma and proximal dendritic compartments with a lower level of expression in more distal dendrites; this selective immunoreactivity contrasted with a more uniform distribution of GABAA α1 subunits in PCs. Finally, co-immunoprecipitation studies suggest that ρ subunits can form complexes with GABAA receptor α1 subunits in the cerebellar cortex. Overall, these data suggest that ρ subunits contribute to functional ionotropic receptors that mediate a component of phasic inhibitory GABAergic transmission at IN–PC synapses in the cerebellum. PMID:16945976

An optimized fluorescent probe for visualizing glutamate neurotransmission.

PubMed

Marvin, Jonathan S; Borghuis, Bart G; Tian, Lin; Cichon, Joseph; Harnett, Mark T; Akerboom, Jasper; Gordus, Andrew; Renninger, Sabine L; Chen, Tsai-Wen; Bargmann, Cornelia I; Orger, Michael B; Schreiter, Eric R; Demb, Jonathan B; Gan, Wen-Biao; Hires, S Andrew; Looger, Loren L

2013-02-01

We describe an intensity-based glutamate-sensing fluorescent reporter (iGluSnFR) with signal-to-noise ratio and kinetics appropriate for in vivo imaging. We engineered iGluSnFR in vitro to maximize its fluorescence change, and we validated its utility for visualizing glutamate release by neurons and astrocytes in increasingly intact neurological systems. In hippocampal culture, iGluSnFR detected single field stimulus-evoked glutamate release events. In pyramidal neurons in acute brain slices, glutamate uncaging at single spines showed that iGluSnFR responds robustly and specifically to glutamate in situ, and responses correlate with voltage changes. In mouse retina, iGluSnFR-expressing neurons showed intact light-evoked excitatory currents, and the sensor revealed tonic glutamate signaling in response to light stimuli. In worms, glutamate signals preceded and predicted postsynaptic calcium transients. In zebrafish, iGluSnFR revealed spatial organization of direction-selective synaptic activity in the optic tectum. Finally, in mouse forelimb motor cortex, iGluSnFR expression in layer V pyramidal neurons revealed task-dependent single-spine activity during running.

[Effect of non-selective alpha-adrenergic receptor antagonist nicergoline on the activity of neurons in the ventral lateral thalamic nucleus].

PubMed

Lukhanina, O P; Pil'kevych, N A

2005-01-01

In experiments on rats microionophoretic administration of nicergoline mainly showed the dual effect on the background activity of the ventrolateral thalamic nucleus (VL) neurons and their reactions evoked by the superior cerebellum peduncle stimulation: inhibitory under weak (2-10 nA) and excitatory under stronger (20-40 nA) currents. Microionophoresis (25 nA) of nicergoline led to decrease of the postexcitatory inhibitory processes during paired stimulation of the cerebellum fibers. Paired-pulse ratio (number of spikes in the short-latency neuronal responses elicited by the second pulse/number of spikes by the first pulse) increased, which support a presynaptic mode of drug action. Hence excitatory effect of nicergoline may be related to the blockade of the presynaptic alpha2-receptors, while inhibitory effect by the blockade of the postsynaptic alphal-receptors. Present data reveal the essential participation of the alpha-adrenoreceptor system in the modulation of background and evoked neuronal activity of the motor thalamus. The possible role of noradrenergic denervation in the development of movement disorders accompanying Parkinson's disease is discussed.

The membrane effects, and sensitivity to strychnine, of neural inhibition of the Mauthner cell, and its inhibition by glycine and GABA

PubMed Central

Diamond, J.; Roper, S.; Yasargil, G. M.

1973-01-01

1. Anionic conductance changes in Mauthner neurones of goldfish were measured during synaptically evoked inhibition and inhibition caused by iontophoretic application of the putative inhibitory transmitters glycine and γ-aminobutyric acid (GABA). 2. The effects of either amino acid were indistinguishable from those of the neural inhibitory transmitter(s). The membrane permeability during the neural or drug response was increased to Br-, Cl-, I-, SCN-, NO3-, ClO3-, and formate (HCOO-), but not to HCO3-, BrO3-, IO3-, SO4-, HPO4-, H2PO4-, acetate and citrate. 3. Strychnine was injected intramuscularly, iontophoretically, or applied topically to the exposed brain in order to compare quantitatively its ability to prevent inhibition evoked by synaptic activation and by pharmacological means. Inhibitions were measured by the increase in membrane conductance. 4. Strychnine, at concentrations just adequate to block completely the late collateral inhibition (LCI) and crossed VIII nerve inhibition, had little effect on the pharmacological inhibition caused by glycine, and sometimes there was no detectable effect at all. In one experiment even a local iontophoretic application of strychnine in a sufficient dose to diffuse over the cell and block the LCI almost completely, merely halved the effect of a small dose of glycine applied to the same localized region of the membrane. 5. Higher concentrations of strychnine than those necessary to block synaptically evoked inhibition would reduce the effect of glycine but not that of GABA. The evidence indicated that any apparent effect of strychnine upon GABA could be explained by displacement of the GABA-containing iontophoretic pipette. 6. The glycine-blocking action of iontophoretic pulses of strychnine was of relatively very slow onset and long duration compared to the effects of pulses of glycine and GABA. 7. These findings can be interpreted as either (1) strychnine has a presynaptic action, preventing the release of inhibitory neurotransmitter, in addition to its less potent post-synaptic one in blocking pharmacological inhibition, or (2) strychnine acts entirely post-synaptically, but the physiological transmitter action differs from that of glycine and GABA in being considerably more sensitive to strychnine antagonism. In either case, the use of strychnine as evidence for the claim that glycine is an inhibitory neurotransmitter at the Mauthner cell is questionable. PMID:4354770

Differential control of central cardiorespiratory interactions by hypercapnia and the effect of prenatal nicotine.

PubMed

Huang, Zheng-Gui; Griffioen, Kathleen J S; Wang, Xin; Dergacheva, Olga; Kamendi, Harriet; Gorini, Christopher; Bouairi, Euguenia; Mendelowitz, David

2006-01-04

Hypercapnia evokes a strong cardiorespiratory response including gasping and a pronounced bradycardia; however, the mechanism responsible for these survival responses initiated in the brainstem is unknown. To examine the effects of hypercapnia on the central cardiorespiratory network, we used an in vitro medullary slice that allows simultaneous examination of rhythmic respiratory-related activity and inhibitory synaptic neurotransmission to cardioinhibitory vagal neurons (CVNs). Hypercapnia differentially modulated inhibitory neurotransmission to CVNs; whereas hypercapnia selectively depressed spontaneous glycinergic IPSCs in CVNs without altering respiratory-related increases in glycinergic neurotransmission, it decreased both spontaneous and inspiratory-associated GABAergic IPSCs. Because maternal smoking is the highest risk factor for sudden infant death syndrome (SIDS) and prenatal nicotine exposure is proposed to be the link between maternal smoking and SIDS, we examined the cardiorespiratory responses to hypercapnia in animals exposed to nicotine in the prenatal and perinatal period. In animals exposed to prenatal nicotine, hypercapnia evoked an exaggerated depression of GABAergic IPSCs in CVNs with no significant change in glycinergic neurotransmission. Hypercapnia altered inhibitory neurotransmission to CVNs at both presynaptic and postsynaptic sites. Although the results obtained in this study in vitro cannot be extrapolated with certainty to in vivo responses, the results of this study provide a likely neurochemical mechanism for hypercapnia-evoked bradycardia and the dysregulation of this response with exposure to prenatal nicotine, creating a higher risk for SIDS.

The expression of long-term potentiation: reconciling the preists and the postivists

PubMed Central

MacDougall, Matthew J.; Fine, Alan

2014-01-01

Long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus has been investigated in great detail over the past 40 years. Where and how LTP is actually expressed, however, remain controversial issues. Considerable evidence has been offered to support both pre- and postsynaptic contributions to LTP expression. Though it is widely held that postsynaptic expression mechanisms are the primary contributors to LTP expression, evidence for that conclusion is amenable to alternative explanations. Here, we briefly review some key contributions to the ‘locus’ debate and describe data that support a dominant role for presynaptic mechanisms. Recognition of the state-dependency of expression mechanisms, and consideration of the consequences of the spatial relationship between postsynaptic glutamate receptors and presynaptic vesicular release sites, lead to a model that may reconcile views from both sides of the synapse. PMID:24298138

Acute fasting increases somatodendritic dopamine release in the ventral tegmental area

PubMed Central

2015-01-01

Fasting and food restriction alter the activity of the mesolimbic dopamine system to affect multiple reward-related behaviors. Food restriction decreases baseline dopamine levels in efferent target sites and enhances dopamine release in response to rewards such as food and drugs. In addition to releasing dopamine from axon terminals, dopamine neurons in the ventral tegmental area (VTA) also release dopamine from their soma and dendrites, and this somatodendritic dopamine release acts as an autoinhibitory signal to inhibit neighboring VTA dopamine neurons. It is unknown whether acute fasting also affects dopamine release, including the local inhibitory somatodendritic dopamine release in the VTA. In these studies, I have tested whether fasting affects the inhibitory somatodendritic dopamine release within the VTA by examining whether an acute 24-h fast affects the inhibitory postsynaptic current mediated by evoked somatodendritic dopamine release (D2R IPSC). Fasting increased the contribution of the first action potential to the overall D2R IPSC and increased the ratio of repeated D2R IPSCs evoked at short intervals. Fasting also reduced the effect of forskolin on the D2R IPSC and led to a significantly bigger decrease in the D2R IPSC in low extracellular calcium. Finally, fasting resulted in an increase in the D2R IPSCs when a more physiologically relevant train of D2R IPSCs was used. Taken together, these results indicate that fasting caused a change in the properties of somatodendritic dopamine release, possibly by increasing dopamine release, and that this increased release can be sustained under conditions where dopamine neurons are highly active. PMID:26084913

Prolactin-releasing peptide affects gastric motor function in rat by modulating synaptic transmission in the dorsal vagal complex.

PubMed

Grabauskas, Gintautas; Zhou, Shi-Yi; Das, Sudipto; Lu, Yuanxu; Owyang, Chung; Moises, Hylan C

2004-12-15

Prolactin-releasing peptide (PrRP) is a recently discovered neuropeptide implicated in the central control of feeding behaviour and autonomic homeostasis. PrRP-containing neurones and PrRP receptor mRNA are found in abundance in the caudal portion of the nucleus tractus solitarius (NTS), an area which together with the dorsal motor nucleus of the vagus (DMV) comprises an integrated structure, the dorsal vagal complex (DVC) that processes visceral afferent signals from and provides parasympathetic motor innervation to the gastrointestinal tract. In this study, microinjection experiments were conducted in vivo in combination with whole-cell recording from neurones in rat medullary slices to test the hypothesis that PrRP plays a role in the central control of gastric motor function, acting within the DVC to modulate the activity of preganglionic vagal motor neurones that supply the stomach. Microinjection of PrRP (0.2 pmol (20 nl)(-1)) into the DMV at the level of the area postrema (+0.2 to +0.6 mm from the calamus scriptorius, CS) markedly stimulated gastric contractions and increased intragastric pressure (IGP). Conversely, administration of peptide into the DMV at sites caudal to the obex (0.0 to -0.3 mm from the CS) decreased IGP and reduced phasic contractions. These effects occurred without change in mean arterial pressure and were abolished by ipsilateral vagotomy, indicating mediation via a vagal-dependent mechanism(s). The pattern of gastric motor responses evoked by PrRP mimicked that produced by administration of L-glutamate at the same sites, and both the effects of L-glutamate and PrRP were abolished following local administration of NMDA and non-NMDA-type glutamate receptor antagonists. On the other hand, microinjection of PrRP into the medial or comissural nucleus of the solitary tract (mNTS and comNTS, respectively) resulted in less robust changes in IGP in a smaller percentage of animals, accompanied by marked alterations in arterial pressure. Superfusion of brain slices with PrRP (100-300 nm) produced a small depolarization and increased spontaneous firing in 10 of 30 retrogradely labelled gastric-projecting DMV neurones. The excitatory effects were blocked by administration of TTX (2 mum) or specific glutamate receptor antagonists, indicating that they resulted from interactions of PrRP at a presynaptic site. Congruent with this, PrRP increased the amplitude of excitatory postsynaptic currents (EPSCs, 154 +/- 33%, 12 of 25 neurones) evoked by electrical stimulation in mNTS or comNTS. In addition, administration of PrRP decreased the paired-pulse ratio of EPSCs evoked by two identical stimuli delivered 100 ms apart (from 0.95 +/- 0.08 to 0.71 +/- 0.11, P < 0.05), whereas it did not affect the amplitude of inward currents evoked by exogenous application of L-glutamate to the slice. The frequency, but not amplitude of spontaneous EPSCs and action potential-independent miniature EPSCs was also increased by administration of PrRP, suggesting that the peptide was acting at least in part at receptors on presynaptic nerve terminals to enhance glutamatergic transmission. In recordings obtained from a separate group of slices, we did not observe any direct effects of PrRP on spontaneous discharge or postsynaptic excitability in either mNTS or comNTS neurones (n = 31). These data indicate that PrRP may act within the DVC to regulate gastric motor function by modulating the efficacy of conventional excitatory synaptic inputs from the NTS onto gastric-projecting vagal motor neurones.

Prolactin-releasing peptide affects gastric motor function in rat by modulating synaptic transmission in the dorsal vagal complex

PubMed Central

Grabauskas, Gintautas; Zhou, Shi-Yi; Das, Sudipto; Lu, Yuanxu; Owyang, Chung; Moises, Hylan C

2004-01-01

Prolactin-releasing peptide (PrRP) is a recently discovered neuropeptide implicated in the central control of feeding behaviour and autonomic homeostasis. PrRP-containing neurones and PrRP receptor mRNA are found in abundance in the caudal portion of the nucleus tractus solitarius (NTS), an area which together with the dorsal motor nucleus of the vagus (DMV) comprises an integrated structure, the dorsal vagal complex (DVC) that processes visceral afferent signals from and provides parasympathetic motor innervation to the gastrointestinal tract. In this study, microinjection experiments were conducted in vivo in combination with whole-cell recording from neurones in rat medullary slices to test the hypothesis that PrRP plays a role in the central control of gastric motor function, acting within the DVC to modulate the activity of preganglionic vagal motor neurones that supply the stomach. Microinjection of PrRP (0.2 pmol (20 nl)−1) into the DMV at the level of the area postrema (+0.2 to +0.6 mm from the calamus scriptorius, CS) markedly stimulated gastric contractions and increased intragastric pressure (IGP). Conversely, administration of peptide into the DMV at sites caudal to the obex (0.0 to −0.3 mm from the CS) decreased IGP and reduced phasic contractions. These effects occurred without change in mean arterial pressure and were abolished by ipsilateral vagotomy, indicating mediation via a vagal-dependent mechanism(s). The pattern of gastric motor responses evoked by PrRP mimicked that produced by administration of l-glutamate at the same sites, and both the effects of l-glutamate and PrRP were abolished following local administration of NMDA and non-NMDA-type glutamate receptor antagonists. On the other hand, microinjection of PrRP into the medial or comissural nucleus of the solitary tract (mNTS and comNTS, respectively) resulted in less robust changes in IGP in a smaller percentage of animals, accompanied by marked alterations in arterial pressure. Superfusion of brain slices with PrRP (100–300 nm) produced a small depolarization and increased spontaneous firing in 10 of 30 retrogradely labelled gastric-projecting DMV neurones. The excitatory effects were blocked by administration of TTX (2 μm) or specific glutamate receptor antagonists, indicating that they resulted from interactions of PrRP at a presynaptic site. Congruent with this, PrRP increased the amplitude of excitatory postsynaptic currents (EPSCs, 154 ± 33%, 12 of 25 neurones) evoked by electrical stimulation in mNTS or comNTS. In addition, administration of PrRP decreased the paired-pulse ratio of EPSCs evoked by two identical stimuli delivered 100 ms apart (from 0.95 ± 0.08 to 0.71 ± 0.11, P < 0.05), whereas it did not affect the amplitude of inward currents evoked by exogenous application of l-glutamate to the slice. The frequency, but not amplitude of spontaneous EPSCs and action potential-independent miniature EPSCs was also increased by administration of PrRP, suggesting that the peptide was acting at least in part at receptors on presynaptic nerve terminals to enhance glutamatergic transmission. In recordings obtained from a separate group of slices, we did not observe any direct effects of PrRP on spontaneous discharge or postsynaptic excitability in either mNTS or comNTS neurones (n = 31). These data indicate that PrRP may act within the DVC to regulate gastric motor function by modulating the efficacy of conventional excitatory synaptic inputs from the NTS onto gastric-projecting vagal motor neurones. PMID:15486017

Calcium currents and graded synaptic transmission between heart interneurons of the leech.

PubMed

Angstadt, J D; Calabrese, R L

1991-03-01

Synaptic transmission between reciprocally inhibitory heart interneurons (HN cells) of the medicinal leech was examined in the absence of Na-mediated action potentials. Under voltage clamp, depolarizing steps from a holding potential of -60 mV elicited 2 kinetically distinct components of inward current in the presynaptic HN cell: an early transient current that inactivates within 200 msec and a persistent current that only partially decays over several seconds. Both currents begin to activate near -60 mV. Steady-state inactivation occurs over the voltage range between -70 and -45 mV and is completely removed by 1-2-sec hyperpolarizing voltage steps to -80 mV. The inward currents are carried by Ca2+, Ba2+, or Sr2+ ions, but not by Co2+, Mn2+, or Ni2+. These same inward currents underlie the burst-generating plateau potentials previously described in HN cells (Arbas and Calabrese, 1987a,b). With a presynaptic holding potential of -60 mV, the threshold for transmitter release is near -45 mV. Postsynaptic currents in the contralateral HN cell have a reversal potential near -60 mV. The largest postsynaptic currents (300-400 pA) exhibit an initial peak response that is followed by a more slowly decaying component. The persistent component of Ca2+ current in the presynaptic neuron is strongly correlated with the prolonged component of the postsynaptic current, while the transient presynaptic Ca2+ current appears to correspond to the early peak of postsynaptic current. These data are consistent with the hypothesis that voltage-dependent calcium currents contribute to the oscillatory capability of reciprocally inhibitory HN cells by (1) generating the plateau potential that drives the burst of action potentials and (2) underlying the release of inhibitory transmitter onto the contralateral cell.

Involvement of pre- and postsynaptic NMDA receptors at local circuit interneuron connections in rat neocortex

PubMed Central

De-May, C.L.; Ali, A.B.

2013-01-01

To investigate the involvement of N-Methyl-D-aspartate (NMDA) receptors in local neocortical synaptic transmission, dual whole-cell recordings – combined with biocytin labelling – were obtained from bitufted adapting, multipolar adapting or multipolar non-adapting interneurons and pyramidal cells in layers II–V of rat (postnatal days 17–22) sensorimotor cortex. The voltage dependency of the amplitude of Excitatory postsynaptic potentials (EPSPs) received by the three types of interneuron appeared to coincide with the interneuron subclass; upon depolarisation, EPSPs received by multipolar non-adapting interneurons either decreased in amplitude or appeared insensitive, multipolar adapting interneuron EPSP amplitudes increased or appeared insensitive, whereas bitufted interneuron EPSP amplitudes increased or decreased. Connections were challenged with the NMDA receptor antagonist d-(−)-2-amino-5-phosphonopentanoic acid (d-AP5) (50 μM) revealing NMDA receptors to contribute to EPSPs received by all cell types, this also abolished the non-conventional voltage dependency. Reciprocal connections were frequent between pyramidal cells and multipolar interneurons, and inhibitory postsynaptic potentials (IPSPs) elicited in pyramidal cells by both multipolar adapting and multipolar non-adapting interneurons were sensitive to a significant reduction in amplitude by d-AP5. The involvement of presynaptic NMDA receptors was indicated by coefficient of variation analysis and an increase in the failures of transmission. Furthermore, by loading MK-801 into the pre- or postsynaptic neurons, we observed that a reduction in inhibition requires presynaptic and not postsynaptic NMDA receptors. These results suggest that NMDA receptors possess pre- and postsynaptic roles at selective neocortical synapses that are probably important in governing spike-timing and information flow. PMID:23079623

HttQ111/+ Huntington’s Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic Dysfunction

PubMed Central

Kovalenko, Marina; Milnerwood, Austen; Giordano, James; St. Claire, Jason; Guide, Jolene R.; Stromberg, Mary; Gillis, Tammy; Sapp, Ellen; DiFiglia, Marian; MacDonald, Marcy E.; Carroll, Jeffrey B.; Lee, Jong-Min; Tappan, Susan; Raymond, Lynn; Wheeler, Vanessa C.

2018-01-01

Background: Successful disease-modifying therapy for Huntington’s disease (HD) will require therapeutic intervention early in the pathogenic process. Achieving this goal requires identifying phenotypes that are proximal to the HTT CAG repeat expansion. Objective: To use Htt CAG knock-in mice, precise genetic replicas of the HTT mutation in patients, as models to study proximal disease events. Methods: Using cohorts of B6J.HttQ111/+ mice from 2 to 18 months of age, we analyzed pathological markers, including immunohistochemistry, brain regional volumes and cortical thickness, CAG instability, electron microscopy of striatal synapses, and acute slice electrophysiology to record glutamatergic transmission at striatal synapses. We also incorporated a diet perturbation paradigm for some of these analyses. Results: B6J.HttQ111/+ mice did not exhibit significant neurodegeneration or gliosis but revealed decreased striatal DARPP-32 as well as subtle but regional-specific changes in brain volumes and cortical thickness that parallel those in HD patients. Ultrastructural analyses of the striatum showed reduced synapse density, increased postsynaptic density thickness and increased synaptic cleft width. Acute slice electrophysiology showed alterations in spontaneous AMPA receptor-mediated postsynaptic currents, evoked NMDA receptor-mediated excitatory postsynaptic currents, and elevated extrasynaptic NMDA currents. Diet influenced cortical thickness, but did not impact somatic CAG expansion, nor did it show any significant interaction with genotype on immunohistochemical, brain volume or cortical thickness measures. Conclusions: These data show that a single HttQ111 allele is sufficient to elicit brain region-specific morphological changes and early neuronal dysfunction, highlighting an insidious disease process already apparent in the first few months of life. PMID:29480209

Increased efficiency of the GABAA and GABAB receptor–mediated neurotransmission in the Ts65Dn mouse model of Down syndrome

PubMed Central

Kleschevnikov, Alexander M.; Belichenko, Pavel V.; Gall, Jessica; George, Lizzy; Nosheny, Rachel; Maloney, Michael T.; Salehi, Ahmad; Mobley, William C.

2011-01-01

Cognitive impairment in Down syndrome (DS) involves the hippocampus. In the Ts65Dn mouse model of DS, deficits in hippocampus-dependent learning and synaptic plasticity were linked to enhanced inhibition. However, the mechanistic basis of changes in inhibitory efficiency remains largely unexplored, and efficiency of the GABAergic synaptic neurotransmission has not yet been investigated in direct electrophysiological experiments. To investigate this important feature of neurobiology of DS, we examined synaptic and molecular properties of the GABAergic system in the dentate gyrus (DG) of adult Ts65Dn mice. Both GABAA and GABAB receptor-mediated components of evoked inhibitory postsynaptic currents (IPSCs) were significantly increased in Ts65Dn vs. control (2N) DG granule cells. These changes were unaccompanied by alterations in hippocampal levels of GABAA (α1, α2, α3, α5 and γ2) or GABAB (Gbr1a and Gbr1b) receptor subunits. Immunoreactivity for GAD65, a marker for GABAergic terminals, was also unchanged. In contrast, there was a marked change in functional parameters of GABAergic synapses. Paired stimulations showed reduced paired-pulse ratios of both GABAA and GABAB receptor-mediated IPSC components (IPSC2/IPSC1), suggesting an increase in presynaptic release of GABA. Consistent with increased gene dose, the level of the Kir3.2 subunit of potassium channels, effectors for postsynaptic GABAB receptors, was increased. This change was associated with enhanced postsynaptic GABAB/Kir3.2 signaling following application of the GABAB receptor agonist baclofen. Thus, both GABAA and GABAB receptor-mediated synaptic efficiency is increased in the Ts65Dn DG, thus likely contributing to deficient synaptic plasticity and poor learning in DS. PMID:22062771

Impact of single-site axonal GABAergic synaptic events on cerebellar interneuron activity.

PubMed

de San Martin, Javier Zorrilla; Jalil, Abdelali; Trigo, Federico F

2015-12-01

Axonal ionotropic receptors are present in a variety of neuronal types, and their function has largely been associated with the modulation of axonal activity and synaptic release. It is usually assumed that activation of axonal GABA(A)Rs comes from spillover, but in cerebellar molecular layer interneurons (MLIs) the GABA source is different: in these cells, GABA release activates presynaptic GABA(A) autoreceptors (autoRs) together with postsynaptic targets, producing an autoR-mediated synaptic event. The frequency of presynaptic, autoR-mediated miniature currents is twice that of their somatodendritic counterparts, suggesting that autoR-mediated responses have an important effect on interneuron activity. Here, we used local Ca(2+) photolysis in MLI axons of juvenile rats to evoke GABA release from individual varicosities to study the activation of axonal autoRs in single release sites. Our data show that single-site autoR conductances are similar to postsynaptic dendritic conductances. In conditions of high [Cl(-)](i), autoR-mediated conductances range from 1 to 5 nS; this corresponds to ∼30-150 GABA(A) channels per presynaptic varicosity, a value close to the number of channels in postsynaptic densities. Voltage responses produced by the activation of autoRs in single varicosities are amplified by a Na(v)-dependent mechanism and propagate along the axon with a length constant of 91 µm. Immunolabeling determination of synapse location shows that on average, one third of the synapses produce autoR-mediated signals that are large enough to reach the axon initial segment. Finally, we show that single-site activation of presynaptic GABA(A) autoRs leads to an increase in MLI excitability and thus conveys a strong feedback signal that contributes to spiking activity. © 2015 Zorrilla de San Martin et al.

Impact of single-site axonal GABAergic synaptic events on cerebellar interneuron activity

PubMed Central

Zorrilla de San Martin, Javier; Jalil, Abdelali

2015-01-01

Axonal ionotropic receptors are present in a variety of neuronal types, and their function has largely been associated with the modulation of axonal activity and synaptic release. It is usually assumed that activation of axonal GABAARs comes from spillover, but in cerebellar molecular layer interneurons (MLIs) the GABA source is different: in these cells, GABA release activates presynaptic GABAA autoreceptors (autoRs) together with postsynaptic targets, producing an autoR-mediated synaptic event. The frequency of presynaptic, autoR-mediated miniature currents is twice that of their somatodendritic counterparts, suggesting that autoR-mediated responses have an important effect on interneuron activity. Here, we used local Ca2+ photolysis in MLI axons of juvenile rats to evoke GABA release from individual varicosities to study the activation of axonal autoRs in single release sites. Our data show that single-site autoR conductances are similar to postsynaptic dendritic conductances. In conditions of high [Cl−]i, autoR-mediated conductances range from 1 to 5 nS; this corresponds to ∼30–150 GABAA channels per presynaptic varicosity, a value close to the number of channels in postsynaptic densities. Voltage responses produced by the activation of autoRs in single varicosities are amplified by a Nav-dependent mechanism and propagate along the axon with a length constant of 91 µm. Immunolabeling determination of synapse location shows that on average, one third of the synapses produce autoR-mediated signals that are large enough to reach the axon initial segment. Finally, we show that single-site activation of presynaptic GABAA autoRs leads to an increase in MLI excitability and thus conveys a strong feedback signal that contributes to spiking activity. PMID:26621773

Acid-Sensing Ion Channels Activated by Evoked Released Protons Modulate Synaptic Transmission at the Mouse Calyx of Held Synapse.

PubMed

González-Inchauspe, Carlota; Urbano, Francisco J; Di Guilmi, Mariano N; Uchitel, Osvaldo D

2017-03-08

Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in neurodegenerative diseases. We found that these channels can be activated in neurons of the medial nucleus of the trapezoid body (MNTB) of the auditory system in the CNS. A drop in extracellular pH induces transient inward ASIC currents (I ASIC s) in postsynaptic MNTB neurons from wild-type mice. The inhibition of I ASIC s by psalmotoxin-1 (PcTx1) and the absence of these currents in knock-out mice for ASIC-1a subunit (ASIC1a -/- ) suggest that homomeric ASIC-1as are mediating these currents in MNTB neurons. Furthermore, we detect ASIC1a-dependent currents during synaptic transmission, suggesting an acidification of the synaptic cleft due to the corelease of neurotransmitter and H + from synaptic vesicles. These currents are capable of eliciting action potentials in the absence of glutamatergic currents. A significant characteristic of these homomeric ASIC-1as is their permeability to Ca 2+ Activation of ASIC-1a in MNTB neurons by exogenous H + induces an increase in intracellular Ca 2+ Furthermore, the activation of postsynaptic ASIC-1as during high-frequency stimulation (HFS) of the presynaptic nerve terminal leads to a PcTx1-sensitive increase in intracellular Ca 2+ in MNTB neurons, which is independent of glutamate receptors and is absent in neurons from ASIC1a -/- mice. During HFS, the lack of functional ASICs in synaptic transmission results in an enhanced short-term depression of glutamatergic EPSCs. These results strongly support the hypothesis of protons as neurotransmitters and demonstrate that presynaptic released protons modulate synaptic transmission by activating ASIC-1as at the calyx of Held-MNTB synapse. SIGNIFICANCE STATEMENT The manuscript demonstrates that postsynaptic neurons of the medial nucleus of the trapezoid body at the mouse calyx of Held synapse express functional homomeric Acid-sensing ion channel-1a (ASIC-1as) that can be activated by protons (coreleased with neurotransmitter from acidified synaptic vesicles). These ASIC-1as contribute to the generation of postsynaptic currents and, more relevant, to calcium influx, which could be involved in the modulation of presynaptic transmitter release. Inhibition or deletion of ASIC-1a leads to enhanced short-term depression, demonstrating that they are concerned with short-term plasticity of the synapse. ASICs represent a widespread communication system with unique properties. We expect that our experiments will have an impact in the neurobiology field and will spread in areas related to neuronal plasticity. Copyright © 2017 the authors 0270-6474/17/372589-11$15.00/0.

Decreased Na+ influx lowers hippocampal neuronal excitability in a mouse model of neonatal influenza infection

PubMed Central

Park, Hoyong; Eun Yu, Ji; Kim, Sungmin; Nahm, Sang-Soep; Chung, ChiHye

2015-01-01

Influenza virus infection is one of common infectious diseases occurring worldwide. The human influenza virus can infect the central nervous system and cause brain dysfunctions affecting cognition and spatial memory. It has been previously shown that infection with the influenza viral protein within the hippocampus decreases Ca2+ influx and reduces excitatory postsynaptic currents. However, the neuronal properties of animals surviving neonatal infection have not been investigated. Using a mouse model of neonatal influenza infection, we performed thorough electrophysiological analyses of hippocampal neurotransmission. We found that animals surviving the infection exhibited reduced spontaneous transmission with no significant defects in evoked neurotransmission. Interestingly, the hippocampus of the infected group conducted synaptic transmission with less fidelity upon repeated stimulations and failed to generate action potentials faithfully upon step current injections primarily due to reduced Na+ influx. The reversal potential for the Na+ current was hyperpolarized and the activation of Na+ channels was slower in the infected group while the inactivation process was minimally disturbed. Taken together, our observations suggest that neonatally infected offsprings exhibit noticeable deficits at rest and severe failures when higher activity is required. This study provides insight into understanding the cellular mechanisms of influenza infection-associated functional changes in the brain. PMID:26310542

Balanced ionotropic receptor dynamics support signal estimation via voltage-dependent membrane noise.

PubMed

Marcoux, Curtis M; Clarke, Stephen E; Nesse, William H; Longtin, Andre; Maler, Leonard

2016-01-01

Encoding behaviorally relevant stimuli in a noisy background is critical for animals to survive in their natural environment. We identify core biophysical and synaptic mechanisms that permit the encoding of low-frequency signals in pyramidal neurons of the weakly electric fish Apteronotus leptorhynchus, an animal that can accurately encode even miniscule amplitude modulations of its self-generated electric field. We demonstrate that slow NMDA receptor (NMDA-R)-mediated excitatory postsynaptic potentials (EPSPs) are able to summate over many interspike intervals (ISIs) of the primary electrosensory afferents (EAs), effectively eliminating the baseline EA ISI correlations from the pyramidal cell input. Together with a dynamic balance of NMDA-R and GABA-A-R currents, this permits stimulus-evoked changes in EA spiking to be transmitted efficiently to target electrosensory lobe (ELL) pyramidal cells, for encoding low-frequency signals. Interestingly, AMPA-R activity is depressed and appears to play a negligible role in the generation of action potentials. Instead, we hypothesize that cell-intrinsic voltage-dependent membrane noise supports the encoding of perithreshold sensory input; this noise drives a significant proportion of pyramidal cell spikes. Together, these mechanisms may be sufficient for the ELL to encode signals near the threshold of behavioral detection. Copyright © 2016 the American Physiological Society.

Vasopressin facilitates excitatory transmission in slices of the rat dorso-lateral septum.

PubMed

Van den Hooff, P; Urban, I J

1990-01-01

The effect of vasopressin on neurons of the rat dorso-lateral septum (DLS) was studied in brain slices with intracellular microelectrodes. Two out of 13 neurons showed a small depolarization, spontaneous activity, and increased input resistances following a 15 min exposure to 10(-6) to 10(-8) M vasopressin (VP). These membrane effects disappeared completely within 3-5 min after the application. The remaining DLS neurons treated with these vasopressin concentrations showed an increase in glutamate-mediated excitatory postsynaptic potentials (EPSPs), evoked by stimulation of the fimbria fibers. As little as 10(-12) MVP increased these EPSPs markedly in nearly 80% of the cells studied. This increase in most of the cells disappeared within 15 min after the application period, whereas the increase in EPSPs induced by 10(-10) M VP outlasted the peptide application period for more than 30 min. Neither the blockade of GABA-ergic synaptic inhibition nor the pre-treatment of the neurons with d(CH2)5-Tyr(Me)-arginine vasopressin or 2-amino-5-phosphonovaleric acid (2-APV), antagonists for the V1 type of vasopressin receptor and NMDA receptors, respectively, interfered with the EPSPs potentiating effect of the peptide. It is concluded that a type of vasopressin receptor other then the V1 type is involved in the long-lasting potentiation of the primarily non-NMDA receptor mediated transmission in DLS neurons.

ELECTROPHYSIOLOGY OF ELECTRIC ORGAN IN GYMNOTUS CARAPO

PubMed Central

Bennett, Michael V. L.; Grundfest, Harry

1959-01-01

The electric organ of G. carapo is formed by linearly arrayed electroplaques which lie in four tubes on each side of the fish. In one tube the electroplaques are innervated on their rostral surfaces, in the others on the caudal. Both surfaces of each electroplaque produce spikes, and either can be excited alone by a suitably oriented externally applied stimulating current. The innervated surface, however, has a lower threshold, and in the normal organ activity, which is a continuous discharge at 35 to 60/sec., it is always fired first by the large neurally evoked postsynaptic potential. The spike of the innervated face then fires the opposite face. The potential recorded external to the innervated face is initially negative and becomes positive when the other face fires. The potential outside the other face is inverted. The p.s.p.'s are electrically inexcitable, have short duration, and are augmented by hyperpolarization. A single electroplaque is innervated by several nerve fibers, which produce summative p.s.p.'s. Homosynaptic facilitation of p.s.p.'s is common. The synapses are cholinoceptive. The organ discharge begins with synchronized activity in the rostrally innervated electroplaques. After a brief interval, the electroplaques in the other three tubes fire. The organ discharge therefore is triphasic, resulting from the summation of the two diphasic components that are oppositely directed and asynchronous. Observations on the sensory role of the organ are included. PMID:13654750

Neural 17β-estradiol facilitates long-term potentiation in the hippocampal CA1 region.

PubMed

Grassi, S; Tozzi, A; Costa, C; Tantucci, M; Colcelli, E; Scarduzio, M; Calabresi, P; Pettorossi, V E

2011-09-29

In the hippocampal formation many neuromodulators are possibly implied in the synaptic plasticity such as the long-term potentiation (LTP) induced by high-frequency stimulation (HFS) of afferent fibers. We investigated the involvement of locally synthesized neural 17β-estradiol (nE(2)) in the induction of HFS-LTP in hippocampal slices from male rats by stimulating the Schaffer collateral fibers and recording the evoked field excitatory postsynaptic potential (fEPSP) in the CA1 region. We demonstrated that either the blockade of nE(2) synthesis by the aromatase inhibitor letrozole, or the antagonism of E(2) receptors (ERs) by ICI 182,780 did not prevent the induction of HFS-LTP, but reduced its amplitude by ∼60%, without influencing its maintenance. Moreover, letrozole and ICI 182,780 did not affect the first short-term post-tetanic component of LTP and the paired-pulse facilitation (PPF). These findings demonstrate that nE(2) plays an important role in the induction phase of HFS-dependent LTP. Since the basal responses were not affected by the blocking agents, we suggest that the synthesis of nE(2) is induced or enhanced by HFS through aromatase activation. In this context, the local production of nE(2) seems to be a very effective mechanism to modulate the amplitude of LTP. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

A joint sparse representation-based method for double-trial evoked potentials estimation.

PubMed

Yu, Nannan; Liu, Haikuan; Wang, Xiaoyan; Lu, Hanbing

2013-12-01

In this paper, we present a novel approach to solving an evoked potentials estimating problem. Generally, the evoked potentials in two consecutive trials obtained by repeated identical stimuli of the nerves are extremely similar. In order to trace evoked potentials, we propose a joint sparse representation-based double-trial evoked potentials estimation method, taking full advantage of this similarity. The estimation process is performed in three stages: first, according to the similarity of evoked potentials and the randomness of a spontaneous electroencephalogram, the two consecutive observations of evoked potentials are considered as superpositions of the common component and the unique components; second, making use of their characteristics, the two sparse dictionaries are constructed; and finally, we apply the joint sparse representation method in order to extract the common component of double-trial observations, instead of the evoked potential in each trial. A series of experiments carried out on simulated and human test responses confirmed the superior performance of our method. © 2013 Elsevier Ltd. Published by Elsevier Ltd. All rights reserved.

Postsynaptic density levels of the NMDA receptor NR1 subunit and PSD-95 protein in prefrontal cortex from people with schizophrenia

PubMed Central

Catts, Vibeke Sørensen; Derminio, Dominique Suzanne; Hahn, Chang-Gyu; Weickert, Cynthia Shannon

2015-01-01

Background: There is converging evidence of involvement of N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Our group recently identified a decrease in total NR1 mRNA and protein expression in the dorsolateral prefrontal cortex in a case-control study of individuals with schizophrenia (n=37/group). The NR1 subunit is critical to NMDA receptor function at the postsynaptic density, a cellular structure rich in the scaffolding protein, PSD-95. The extent to which the NMDA receptor NR1 subunit is altered at the site of action, in the postsynaptic density, is not clear. Aims: To extend our previous results by measuring levels of NR1 and PSD-95 protein in postsynaptic density-enriched fractions of prefrontal cortex from the same individuals in the case-control study noted above. Methods: Postsynaptic density-enriched fractions were isolated from fresh-frozen prefrontal cortex (BA10) and subjected to western blot analysis for NR1 and PSD-95. Results: We found a 20% decrease in NR1 protein (t(66)=−2.874, P=0.006) and a 30% decrease in PSD-95 protein (t(63)=−2.668, P=0.010) in postsynaptic density-enriched fractions from individuals with schizophrenia relative to unaffected controls. Conclusions: Individuals with schizophrenia have less NR1 protein, and therefore potentially fewer functional NMDA receptors, at the postsynaptic density. The associated decrease in PSD-95 protein at the postsynaptic density suggests that not only are glutamate receptors compromised in individuals with schizophrenia, but the overall spine architecture and downstream signaling supported by PSD-95 may also be deficient. PMID:27336043

Postsynaptic density levels of the NMDA receptor NR1 subunit and PSD-95 protein in prefrontal cortex from people with schizophrenia.

PubMed

Catts, Vibeke Sørensen; Derminio, Dominique Suzanne; Hahn, Chang-Gyu; Weickert, Cynthia Shannon

2015-01-01

There is converging evidence of involvement of N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Our group recently identified a decrease in total NR1 mRNA and protein expression in the dorsolateral prefrontal cortex in a case-control study of individuals with schizophrenia (n=37/group). The NR1 subunit is critical to NMDA receptor function at the postsynaptic density, a cellular structure rich in the scaffolding protein, PSD-95. The extent to which the NMDA receptor NR1 subunit is altered at the site of action, in the postsynaptic density, is not clear. To extend our previous results by measuring levels of NR1 and PSD-95 protein in postsynaptic density-enriched fractions of prefrontal cortex from the same individuals in the case-control study noted above. Postsynaptic density-enriched fractions were isolated from fresh-frozen prefrontal cortex (BA10) and subjected to western blot analysis for NR1 and PSD-95. We found a 20% decrease in NR1 protein (t(66)=-2.874, P=0.006) and a 30% decrease in PSD-95 protein (t(63)=-2.668, P=0.010) in postsynaptic density-enriched fractions from individuals with schizophrenia relative to unaffected controls. Individuals with schizophrenia have less NR1 protein, and therefore potentially fewer functional NMDA receptors, at the postsynaptic density. The associated decrease in PSD-95 protein at the postsynaptic density suggests that not only are glutamate receptors compromised in individuals with schizophrenia, but the overall spine architecture and downstream signaling supported by PSD-95 may also be deficient.

A simple model for the generation of the vestibular evoked myogenic potential (VEMP).

PubMed

Wit, Hero P; Kingma, Charlotte M

2006-06-01

To describe the mechanism by which the vestibular evoked myogenic potential is generated. Vestibular evoked myogenic potential generation is modeled by adding a large number of muscle motor unit action potentials. These action potentials occur randomly in time along a 100 ms long time axis. But because between approximately 15 and 20 ms after a loud short sound stimulus (almost) no action potentials are generated during VEMP measurements in human subjects, no action potentials are present in the model during this time. The evoked potential is the result of the lack of amplitude cancellation in the averaged surface electromyogram at the edges of this 5 ms long time interval. The relatively simple model describes generation and some properties of the vestibular evoked myogenic potential very well. It is shown that, in contrast with other evoked potentials (BAEPs, VERs), the vestibular evoked myogenic potential is the result of an interruption of activity and not that of summed synchronized neural action potentials.

Synapse-specific and compartmentalized expression of presynaptic homeostatic potentiation

PubMed Central

Li, Xiling; Goel, Pragya; Chen, Catherine; Angajala, Varun; Chen, Xun

2018-01-01

Postsynaptic compartments can be specifically modulated during various forms of synaptic plasticity, but it is unclear whether this precision is shared at presynaptic terminals. Presynaptic homeostatic plasticity (PHP) stabilizes neurotransmission at the Drosophila neuromuscular junction, where a retrograde enhancement of presynaptic neurotransmitter release compensates for diminished postsynaptic receptor functionality. To test the specificity of PHP induction and expression, we have developed a genetic manipulation to reduce postsynaptic receptor expression at one of the two muscles innervated by a single motor neuron. We find that PHP can be induced and expressed at a subset of synapses, over both acute and chronic time scales, without influencing transmission at adjacent release sites. Further, homeostatic modulations to CaMKII, vesicle pools, and functional release sites are compartmentalized and do not spread to neighboring pre- or post-synaptic structures. Thus, both PHP induction and expression mechanisms are locally transmitted and restricted to specific synaptic compartments. PMID:29620520

Are evoked potentials in patients with adult-onset pompe disease indicative of clinically relevant central nervous system involvement?

PubMed

Wirsching, Andreas; Müller-Felber, Wolfgang; Schoser, Benedikt

2014-08-01

Pompe disease is a multisystem autosomal recessive glycogen storage disease. Autoptic findings in patients with classic infantile and late-onset Pompe disease have proven that accumulation of glycogen can also be found in the peripheral and central nervous system. To assess the functional role of these pathologic findings, multimodal sensory evoked potentials were analyzed. Serial recordings for brainstem auditory, visual, and somatosensory evoked potentials of 11 late-onset Pompe patients were reviewed. Data at the onset of the enzyme replacement therapy with alglucosidase alfa were compared with follow-up recordings at 12 and 24 months. Brainstem auditory evoked potentials showed a delayed peak I in 1/10 patients and an increased I-III and I-V interpeak latency in 1/10 patients, respectively. The III-V interpeak latencies were in the normal range. Visual evoked potentials were completely normal. Median somatosensory evoked potentials showed an extended interpeak latency in 3/9 patients. Wilcoxon tests comparing age-matched subgroups found significant differences in brainstem auditory evoked potentials and visual evoked potentials. We found that the majority of recordings for evoked potentials were within the ranges for standard values, therefore reflecting the lack of clinically relevant central nervous system involvement. Regular surveillance by means of evoked potentials does not seem to be appropriate in late-onset Pompe patients.

SNT-1 functions as the Ca2+ sensor for tonic and evoked neurotransmitter release in C. elegans.

PubMed

Li, Lei; Liu, Haowen; Wang, Wei; Chandra, Mintu; Collins, Brett M; Hu, Zhitao

2018-05-14

Synaptotagmin-1 (Syt1) binds Ca 2+ through its tandem C2 domains (C2A and C2B) and triggers Ca 2+ -dependent neurotransmitter release. Here we show that snt-1 , the homolog of mammalian Syt1, functions as the Ca 2+ sensor for both tonic and evoked neurotransmitter release at the C. elegans neuromuscular junction. Mutations that disrupt Ca 2+ binding in double C2 domains of SNT-1 significantly impaired tonic release, whereas disrupting Ca 2+ binding in a single C2 domain had no effect, indicating that the Ca 2+ binding of the two C2 domains is functionally redundant for tonic release. Stimulus-evoked release was significantly reduced in snt-1 mutants, with prolonged release latency as well as faster rise and decay kinetics. Unlike tonic release, evoked release was triggered by Ca 2+ binding solely to the C2B domain. Moreover, we showed that SNT-1 plays an essential role in the priming process in different subpopulations of synaptic vesicles with tight or loose coupling to Ca 2+ entry. SIGNIFICANCE STATEMENT We showed that SNT-1 in C. elegans regulates evoked neurotransmitter release through Ca 2+ binding to its C2B domain, a similar way to Syt1 in the mouse CNS and the fly NMJ. However, the largely decreased tonic release in snt-1 mutants argues SNT-1 has a clamping function. Indeed, Ca 2+ -binding mutations in the C2 domains in SNT-1 significantly reduced the frequency of the miniature excitatory postsynaptic current (mEPSC), indicating that SNT-1 also acts as a Ca 2+ sensor for tonic release. Therefore, revealing the differential mechanisms between invertebrates and vertebrates will provide significant insights into our understanding how synaptic vesicle fusion is regulated. Copyright © 2018 the authors.

Cross-Modulation of Homeostatic Responses to Temperature, Oxygen and Carbon Dioxide in C. elegans

PubMed Central

Kodama-Namba, Eiji; Fenk, Lorenz A.; Bretscher, Andrew J.; Gross, Einav; Busch, K. Emanuel; de Bono, Mario

2013-01-01

Different interoceptive systems must be integrated to ensure that multiple homeostatic insults evoke appropriate behavioral and physiological responses. Little is known about how this is achieved. Using C. elegans, we dissect cross-modulation between systems that monitor temperature, O2 and CO2. CO2 is less aversive to animals acclimated to 15°C than those grown at 22°C. This difference requires the AFD neurons, which respond to both temperature and CO2 changes. CO2 evokes distinct AFD Ca2+ responses in animals acclimated at 15°C or 22°C. Mutants defective in synaptic transmission can reprogram AFD CO2 responses according to temperature experience, suggesting reprogramming occurs cell autonomously. AFD is exquisitely sensitive to CO2. Surprisingly, gradients of 0.01% CO2/second evoke very different Ca2+ responses from gradients of 0.04% CO2/second. Ambient O2 provides further contextual modulation of CO2 avoidance. At 21% O2 tonic signalling from the O2-sensing neuron URX inhibits CO2 avoidance. This inhibition can be graded according to O2 levels. In a natural wild isolate, a switch from 21% to 19% O2 is sufficient to convert CO2 from a neutral to an aversive cue. This sharp tuning is conferred partly by the neuroglobin GLB-5. The modulatory effects of O2 on CO2 avoidance involve the RIA interneurons, which are post-synaptic to URX and exhibit CO2-evoked Ca2+ responses. Ambient O2 and acclimation temperature act combinatorially to modulate CO2 responsiveness. Our work highlights the integrated architecture of homeostatic responses in C. elegans. PMID:24385919

Optogenetic approaches to characterize the long-range synaptic pathways from the hypothalamus to brain stem autonomic nuclei

PubMed Central

Piñol, Ramón A.; Bateman, Ryan; Mendelowitz, David

2012-01-01

Recent advances in optogenetic methods demonstrate the feasibility of selective photoactivation at the soma of neurons that express channelrhodopsin-2 (ChR2), but a comprehensive evaluation of different methods to selectively evoke transmitter release from distant synapses using optogenetic approaches is needed. Here we compared different lentiviral vectors, with sub-population-specific and strong promoters, and transgenic methods to express and photostimulate ChR2 in the long-range projections of paraventricular nucleus of the hypothalamus (PVN) neurons to brain stem cardiac vagal neurons (CVNs). Using PVN subpopulation-specific promoters for vasopressin and oxytocin, we were able to depolarize the soma of these neurons upon photostimulation, but these promoters were not strong enough to drive sufficient expression for optogenetic stimulation and synaptic release from the distal axons. However, utilizing the synapsin promoter photostimulation of distal PVN axons successfully evoked glutamatergic excitatory post-synaptic currents in CVNs. Employing the Cre/loxP system, using the Sim-1 Cre-driver mouse line, we found that the Rosa-CAG-LSL-ChR2-EYFP Cre-responder mice expressed higher levels of ChR2 than the Rosa-CAG-LSL-ChR2-tdTomato line in the PVN, judged by photo-evoked currents at the soma. However, neither was able to drive sufficient expression to observe and photostimulate the long-range projections to brainstem autonomic regions. We conclude that a viral vector approach with a strong promoter is required for successful optogenetic stimulation of distal axons to evoke transmitter release in pre-autonomic PVN neurons. This approach can be very useful to study important hypothalamus-brainstem connections, and can be easily modified to selectively activate other long-range projections within the brain. PMID:22890236

Dexmedetomidine attenuates persistent postsurgical pain by upregulating K+-Cl- cotransporter-2 in the spinal dorsal horn in rats.

PubMed

Dai, Shuhong; Qi, Yu; Fu, Jie; Li, Na; Zhang, Xu; Zhang, Juan; Zhang, Wei; Xu, Haijun; Zhou, Hai; Ma, Zhengliang

2018-01-01

Dexmedetomidine (DEX) could have an analgesic effect on pain transmission through the modulation of brain-derived neurotrophic factor (BDNF). In addition, KCC2-induced shift in neuronal Cl- homeostasis is crucial for postsynaptic inhibition mediated by GABAA receptors. Accumulating evidence shows that nerve injury, peripheral inflammation and stress activate the spinal BDNF/TrkB signal, which results in the downregulation of KCC2 transport and expression, eventually leads to GAGAergic disinhibition and hyperalgesia. The aim of this experiment was to explore the interaction between DEX and KCC2 at a molecular level in rats in the persistent postsurgical pain (PPSP). PPSP in rats was evoked by the skin/muscle incision and retraction (SMIR). Mechanical hypersensitivity was assessed with the Dynamic Plantar Aesthesiometer. Western blot and immunofluorescence assay were used to assess the expressions of related proteins. In the first part of our experiment, the results revealed that the BDNF/TrkB-KCC2 signal plays a critical role in the development of SMIR-evoked PPSP; the second part showed that intraperitoneal administrations of 40 µg/kg DEX at 15 min presurgery and 1 to 3 days post-surgery significantly attenuated SMIR-evoked PPSP. Simultaneously, SMIR-induced KCC2 downregulation was partly reversed, which coincided with the inhibition of the BDNF/TrkB signal in the spinal dorsal horn. Moreover, intrathecal administrations of KCC2 inhibitor VU0240551 significantly reduced the analgesic effect of DEX on SMIR-evoked PPSP. The results of our study indicated that DEX attenuated PPSP by restoring KCC2 function through reducing BDNF/TrkB signal in the spinal dorsal horn in rats, which provides a new insight into the treatment of chronic pain in clinical postsurgical pain management.

Electroretinography and Visual Evoked Potentials in Childhood Brain Tumor Survivors.

PubMed

Pietilä, Sari; Lenko, Hanna L; Oja, Sakari; Koivisto, Anna-Maija; Pietilä, Timo; Mäkipernaa, Anne

2016-07-01

This population-based cross-sectional study evaluates the clinical value of electroretinography and visual evoked potentials in childhood brain tumor survivors. A flash electroretinography and a checkerboard reversal pattern visual evoked potential (or alternatively a flash visual evoked potential) were done for 51 survivors (age 3.8-28.7 years) after a mean follow-up time of 7.6 (1.5-15.1) years. Abnormal electroretinography was obtained in 1 case, bilaterally delayed abnormal visual evoked potentials in 22/51 (43%) cases. Nine of 25 patients with infratentorial tumor location, and altogether 12 out of 31 (39%) patients who did not have tumors involving the visual pathways, had abnormal visual evoked potentials. Abnormal electroretinographies are rarely observed, but abnormal visual evoked potentials are common even without evident anatomic lesions in the visual pathway. Bilateral changes suggest a general and possibly multifactorial toxic/adverse effect on the visual pathway. Electroretinography and visual evoked potential may have clinical and scientific value while evaluating long-term effects of childhood brain tumors and tumor treatment. © The Author(s) 2016.

Two-photon microscope for multisite microphotolysis of caged neurotransmitters in acute brain slices

PubMed Central

Losavio, Bradley E.; Iyer, Vijay; Saggau, Peter

2009-01-01

We developed a two-photon microscope optimized for physiologically manipulating single neurons through their postsynaptic receptors. The optical layout fulfills the stringent design criteria required for high-speed, high-resolution imaging in scattering brain tissue with minimal photodamage. We detail the practical compensation of spectral and temporal dispersion inherent in fast laser beam scanning with acousto-optic deflectors, as well as a set of biological protocols for visualizing nearly diffraction-limited structures and delivering physiological synaptic stimuli. The microscope clearly resolves dendritic spines and evokes electrophysiological transients in single neurons that are similar to endogenous responses. This system enables the study of multisynaptic integration and will assist our understanding of single neuron function and dendritic computation. PMID:20059271

Loss of lower limb motor evoked potentials and spinal cord injury during the initial exposure in scoliosis surgery.

PubMed

Legatt, Alan D; Fried, Stephen J; Amaral, Terry D; Sarwahi, Vishal; Moguilevitch, Marina

2014-04-01

To report a case of motor evoked potential changes and spinal cord injury during the initial dissection in scoliosis surgery. Motor evoked potentials to transcranial electrical stimulation were recorded from multiple muscles. Somatosensory evoked potentials to limb nerve stimulation were recorded from the scalp. Clear motor evoked potentials were initially present in all monitored muscles. The patient was then pharmacologically paralyzed for the initial dissection. More than usual bleeding was encountered during that dissection, prompting transfusion. As the neuromuscular blockade subsided, motor evoked potentials persisted in the hand muscles but disappeared and remained absent in all monitored leg muscles. The spine had not been instrumented. A wake-up test demonstrated paraplegia; the surgery was aborted. There were no adverse somatosensory evoked potential changes. MRI showed an anterior spinal cord infarct. Copious soft tissue bleeding during the initial dissection might have lowered pressures in critical segmental arteries enough to cause spinal cord infarction through a steal phenomenon. The lack of somatosensory evoked potential changes reflected sparing of the dorsal columns. When neuromuscular blockade is used during the initial soft tissue dissection, motor evoked potentials should be assessed after this, but before spinal instrumentation, to determine whether there had been any spinal cord compromise during the initial dissection.

Glutamate spillover modulates GABAergic synaptic transmission in the rat midbrain periaqueductal grey via metabotropic glutamate receptors and endocannabinoid signaling.

PubMed

Drew, Geoffrey M; Mitchell, Vanessa A; Vaughan, Christopher W

2008-01-23

Glutamate spillover regulates GABAergic synaptic transmission at several CNS synapses via presynaptic ionotropic and metabotropic glutamate receptors (mGluRs). We have previously demonstrated that activation of group I-III mGluRs inhibits GABAergic transmission in the midbrain periaqueductal gray (PAG), a region involved in organizing behavioral responses to threat, stress, and pain. Here, we examined the role of glutamate spillover in the modulation of GABAergic transmission in the PAG. Using whole-cell recordings from rat PAG slices, we found that evoked IPSCs were reduced by the nonspecific glutamate transport blockers DL-threo-beta-benzyloxyaspartic acid (TBOA) and L-trans-pyrrolidine-2,4-dicarboxylic acid, but not by the glial GLT1-specific blocker dihydrokainate. In contrast, TBOA had no effect on evoked IPSCs when glutamate uptake into the postsynaptic neuron was selectively impaired. TBOA increased the paired-pulse ratio of evoked IPSCs and reduced the rate but not the amplitude of spontaneous miniature IPSCs. The effect of TBOA on evoked IPSCs was abolished by the broad-spectrum mGluR antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (100 microM), reduced by the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and mimicked by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Furthermore, the effects of both TBOA and DHPG were reduced by the cannabinoid CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251). Finally, although MPEP and AM251 had no effect on single evoked IPSCs, they increased evoked IPSCs during repetitive stimulation. These results indicate that neuronal glutamate transporters limit mGluR5 activation and endocannabinoid signaling, but may be overwhelmed during conditions of elevated glutamate release. Thus, neuronal glutamate transporters play a key role in regulating endocannabinoid-mediated cross talk between glutamatergic and GABAergic synapses within the PAG.

Analysis and prediction of presynaptic and postsynaptic neurotoxins by Chou's general pseudo amino acid composition and motif features.

PubMed

Mei, Juan; Zhao, Ji

2018-06-14

Presynaptic neurotoxins and postsynaptic neurotoxins are two important neurotoxins isolated from venoms of venomous animals and have been proven to be potential effective in neurosciences and pharmacology. With the number of toxin sequences appeared in the public databases, there was a need for developing a computational method for fast and accurate identification and classification of the novel presynaptic neurotoxins and postsynaptic neurotoxins in the large databases. In this study, the Multinomial Naive Bayes Classifier (MNBC) had been developed to discriminate the presynaptic neurotoxins and postsynaptic neurotoxins based on the different kinds of features. The Minimum Redundancy Maximum Relevance (MRMR) feature selection method was used for ranking 400 pseudo amino acid (PseAA) compositions and 50 top ranked PseAA compositions were selected for improving the prediction results. The motif features, 400 PseAA compositions and 50 PseAA compositions were combined together, and selected as the input parameters of MNBC. The best correlation coefficient (CC) value of 0.8213 was obtained when the prediction quality was evaluated by the jackknife test. It was anticipated that the algorithm presented in this study may become a useful tool for identification of presynaptic neurotoxin and postsynaptic neurotoxin sequences and may provide some useful help for in-depth investigation into the biological mechanism of presynaptic neurotoxins and postsynaptic neurotoxins. Copyright © 2018 Elsevier Ltd. All rights reserved.

Postsynaptic Synaptotagmins Mediate AMPA Receptor Exocytosis During LTP

PubMed Central

Wu, Dick; Bacaj, Taulant; Morishita, Wade; Goswami, Debanjan; Arendt, Kristin L.; Xu, Wei; Chen, Lu; Malenka, Robert C.; Südhof, Thomas C.

2017-01-01

Strengthening of synaptic connections by NMDA-receptor-dependent long-term potentiation (LTP) shapes neural circuits and mediates learning and memory. During NMDA-receptor-dependent LTP induction, Ca2+-influx stimulates recruitment of synaptic AMPA-receptors, thereby strengthening synapses. How Ca2+ induces AMPA-receptor recruitment, however, remains unclear. Here we show that, in pyramidal neurons of the hippocampal CA1-region, blocking postsynaptic expression of both synaptotagmin-1 and synaptotagmin-7, but not of synaptotagmin-1 or synaptotagmin-7 alone, abolished LTP. LTP was rescued by wild-type but not by Ca2+-binding-deficient mutant synaptotagmin-7. Blocking postsynaptic synaptotagmin-1/7 expression did not impair basal synaptic transmission, synaptic or extrasynaptic AMPA-receptor levels, or other AMPA-receptor trafficking events. Moreover, expression of dominant-negative mutant synaptotagmin-1 that inhibited Ca2+-dependent presynaptic vesicle exocytosis also blocked Ca2+-dependent postsynaptic AMPA-receptor exocytosis, thereby abolishing LTP. Our results suggest that postsynaptic synaptotagmin-1 and synaptotagmin-7 act as redundant Ca2+-sensors for Ca2+-dependent exocytosis of AMPA-receptors during LTP, thus delineating a simple mechanism for the recruitment of AMPA-receptors that mediates LTP. PMID:28355182

Evidence for postsynaptic modulation of muscle contraction by a Drosophila neuropeptide.

PubMed

Clark, Julie; Milakovic, Maja; Cull, Amanda; Klose, Markus K; Mercier, A Joffre

2008-07-01

DPKQDFMRFamide, the most abundant FMRFamide-like peptide in Drosophila melanogaster, has been shown previously to enhance contractions of larval body wall muscles elicited by nerve stimulation and to increase excitatory junction potentials (EJPs). The present work investigated the possibility that this peptide can also stimulate muscle contraction by a direct action on muscle fibers. DPKQDFMRFamide induced slow contractions and increased tonus in body wall muscles of Drosophila larvae from which the central nervous system had been removed. The threshold for this effect was approximately 10(-8)M. The increase in tonus persisted in the presence of 7x10(-3)M glutamate, which desensitized postsynaptic glutamate receptors. Thus, the effect on tonus could not be explained by enhanced release of glutamate from synaptic terminals and, thus, may represent a postsynaptic effect. The effect on tonus was abolished in calcium-free saline and by treatment with L-type calcium channel blockers, nifedipine and nicardipine, but not by T-type blockers, amiloride and flunarizine. The present results provide evidence that this Drosophila peptide can act postsynaptically in addition to its apparent presynaptic effects, and that the postsynaptic effect requires influx through L-type calcium channels.

Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sekizawa, Shin-ichi, E-mail: ssekizawa@ucdavis.ed; Joad, Jesse P.; Pinkerton, Kent E.

Exposing children to secondhand tobacco smoke (SHS) is associated with increased risk for asthma, bronchiolitis and SIDS. The role for changes in the developing CNS contributing to these problems has not been fully explored. We used rhesus macaques to test the hypothesis that SHS exposure during development triggers neuroplastic changes in the nucleus tractus solitarius (NTS), where lung sensory information related to changes in airway and lung function is first integrated. Pregnant monkeys were exposed to filtered air (FA) or SHS for 6 h/day, 5 days/week starting at 50-day gestational age. Mother/infant pairs continued the exposures postnatally to age 3more » or 13 months, which may be equivalent to approximately 1 or 4 years of human age, respectively. Whole-cell recordings were made of second-order NTS neurons in transverse brainstem slices. To target the consequences of SHS exposure based on neuronal subgroups, we classified NTS neurons into two phenotypes, rapid-onset spiking (RS) and delayed-onset spiking (DS), and then evaluated intrinsic and synaptic excitabilities in FA-exposed animals. RS neurons showed greater cell excitability especially at age of 3 months while DS neurons received greater amplitudes of excitatory postsynaptic currents (EPSCs). Developmental neuroplasticity such as increases in intrinsic and synaptic excitabilities were detected especially in DS neurons. In 3 month olds, SHS exposure effects were limited to excitatory changes in RS neurons, specifically increases in evoked EPSC amplitudes and increased spiking responses accompanied by shortened action potential width. By 13 months, the continued SHS exposure inhibited DS neuronal activity; decreases in evoked EPSC amplitudes and blunted spiking responses accompanied by prolonged action potential width. The influence of SHS exposure on age-related and phenotype specific changes may be associated with age-specific respiratory problems, for which SHS exposure can increase the risk, such as SIDS and bronchiolitis in infants and asthma in older children.« less

Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates.

PubMed

Sekizawa, Shin-Ichi; Joad, Jesse P; Pinkerton, Kent E; Bonham, Ann C

2010-01-15

Exposing children to secondhand tobacco smoke (SHS) is associated with increased risk for asthma, bronchiolitis and SIDS. The role for changes in the developing CNS contributing to these problems has not been fully explored. We used rhesus macaques to test the hypothesis that SHS exposure during development triggers neuroplastic changes in the nucleus tractus solitarius (NTS), where lung sensory information related to changes in airway and lung function is first integrated. Pregnant monkeys were exposed to filtered air (FA) or SHS for 6 h/day, 5 days/week starting at 50-day gestational age. Mother/infant pairs continued the exposures postnatally to age 3 or 13 months, which may be equivalent to approximately 1 or 4 years of human age, respectively. Whole-cell recordings were made of second-order NTS neurons in transverse brainstem slices. To target the consequences of SHS exposure based on neuronal subgroups, we classified NTS neurons into two phenotypes, rapid-onset spiking (RS) and delayed-onset spiking (DS), and then evaluated intrinsic and synaptic excitabilities in FA-exposed animals. RS neurons showed greater cell excitability especially at age of 3 months while DS neurons received greater amplitudes of excitatory postsynaptic currents (EPSCs). Developmental neuroplasticity such as increases in intrinsic and synaptic excitabilities were detected especially in DS neurons. In 3 month olds, SHS exposure effects were limited to excitatory changes in RS neurons, specifically increases in evoked EPSC amplitudes and increased spiking responses accompanied by shortened action potential width. By 13 months, the continued SHS exposure inhibited DS neuronal activity; decreases in evoked EPSC amplitudes and blunted spiking responses accompanied by prolonged action potential width. The influence of SHS exposure on age-related and phenotype specific changes may be associated with age-specific respiratory problems, for which SHS exposure can increase the risk, such as SIDS and bronchiolitis in infants and asthma in older children.

Differential regulation of primary afferent input to spinal cord by muscarinic receptor subtypes delineated using knockout mice.

PubMed

Chen, Shao-Rui; Chen, Hong; Yuan, Wei-Xiu; Wess, Jürgen; Pan, Hui-Lin

2014-05-16

Stimulation of muscarinic acetylcholine receptors (mAChRs) inhibits nociceptive transmission at the spinal level. However, it is unclear how each mAChR subtype regulates excitatory synaptic input from primary afferents. Here we examined excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation in spinal cord slices from wild-type and mAChR subtype knock-out (KO) mice. In wild-type mice, mAChR activation with oxotremorine-M decreased the amplitude of monosynaptic EPSCs in ∼67% of neurons but increased it in ∼10% of neurons. The inhibitory effect of oxotremorine-M was attenuated by the M2/M4 antagonist himbacine in the majority of neurons, and the remaining inhibition was abolished by group II/III metabotropic glutamate receptor (mGluR) antagonists in wild-type mice. In M2/M4 double-KO mice, oxotremorine-M inhibited monosynaptic EPSCs in significantly fewer neurons (∼26%) and increased EPSCs in significantly more neurons (33%) compared with wild-type mice. Blocking group II/III mGluRs eliminated the inhibitory effect of oxotremorine-M in M2/M4 double-KO mice. In M2 single-KO and M4 single-KO mice, himbacine still significantly reduced the inhibitory effect of oxotremorine-M. However, the inhibitory and potentiating effects of oxotremorine-M on EPSCs in M3 single-KO and M1/M3 double-KO mice were similar to those in wild-type mice. In M5 single-KO mice, oxotremorine-M failed to potentiate evoked EPSCs, and its inhibitory effect was abolished by himbacine. These findings indicate that activation of presynaptic M2 and M4 subtypes reduces glutamate release from primary afferents. Activation of the M5 subtype either directly increases primary afferent input or inhibits it through indirectly stimulating group II/III mGluRs. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Differential Regulation of Primary Afferent Input to Spinal Cord by Muscarinic Receptor Subtypes Delineated Using Knockout Mice*

PubMed Central

Chen, Shao-Rui; Chen, Hong; Yuan, Wei-Xiu; Wess, Jürgen; Pan, Hui-Lin

2014-01-01

Stimulation of muscarinic acetylcholine receptors (mAChRs) inhibits nociceptive transmission at the spinal level. However, it is unclear how each mAChR subtype regulates excitatory synaptic input from primary afferents. Here we examined excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation in spinal cord slices from wild-type and mAChR subtype knock-out (KO) mice. In wild-type mice, mAChR activation with oxotremorine-M decreased the amplitude of monosynaptic EPSCs in ∼67% of neurons but increased it in ∼10% of neurons. The inhibitory effect of oxotremorine-M was attenuated by the M2/M4 antagonist himbacine in the majority of neurons, and the remaining inhibition was abolished by group II/III metabotropic glutamate receptor (mGluR) antagonists in wild-type mice. In M2/M4 double-KO mice, oxotremorine-M inhibited monosynaptic EPSCs in significantly fewer neurons (∼26%) and increased EPSCs in significantly more neurons (33%) compared with wild-type mice. Blocking group II/III mGluRs eliminated the inhibitory effect of oxotremorine-M in M2/M4 double-KO mice. In M2 single-KO and M4 single-KO mice, himbacine still significantly reduced the inhibitory effect of oxotremorine-M. However, the inhibitory and potentiating effects of oxotremorine-M on EPSCs in M3 single-KO and M1/M3 double-KO mice were similar to those in wild-type mice. In M5 single-KO mice, oxotremorine-M failed to potentiate evoked EPSCs, and its inhibitory effect was abolished by himbacine. These findings indicate that activation of presynaptic M2 and M4 subtypes reduces glutamate release from primary afferents. Activation of the M5 subtype either directly increases primary afferent input or inhibits it through indirectly stimulating group II/III mGluRs. PMID:24695732

Vestibular evoked potentials (VsEPs) of cortical origin produced by impulsive acceleration applied at the nasion.

PubMed

Todd, Neil P M; McLean, Aisha; Paillard, Aurore; Kluk, Karolina; Colebatch, James G

2014-12-01

We report the results of a study to record vestibular evoked potentials (VsEPs) of cortical origin produced by impulsive acceleration (IA). In a sample of 12 healthy participants, evoked potentials recorded by 70 channel electroencephalography were obtained by IA stimulation at the nasion and compared with evoked potentials from the same stimulus applied to the forefingers. The nasion stimulation gave rise to a series of positive and negative deflections in the latency range of 26-72 ms, which were dependent on the polarity of the applied IA. In contrast, evoked potentials from the fingers were characterised by a single N50/P50 deflection at about 50 ms and were polarity invariant. Source analysis confirmed that the finger evoked potentials were somatosensory in origin, i.e. were somatosensory evoked potentials, and suggested that the nasion evoked potentials plausibly included vestibular midline and frontal sources, as well as contributions from the eyes, and thus were likely VsEPs. These results show considerable promise as a new method for assessment of the central vestibular system by means of VsEPs produced by IA applied to the head.

A Co-operative Regulation of Neuronal Excitability by UNC-7 Innexin and NCA/NALCN Leak Channel

PubMed Central

2011-01-01

Gap junctions mediate the electrical coupling and intercellular communication between neighboring cells. Some gap junction proteins, namely connexins and pannexins in vertebrates, and innexins in invertebrates, may also function as hemichannels. A conserved NCA/Dmα1U/NALCN family cation leak channel regulates the excitability and activity of vertebrate and invertebrate neurons. In the present study, we describe a genetic and functional interaction between the innexin UNC-7 and the cation leak channel NCA in Caenorhabditis elegans neurons. While the loss of the neuronal NCA channel function leads to a reduced evoked postsynaptic current at neuromuscular junctions, a simultaneous loss of the UNC-7 function restores the evoked response. The expression of UNC-7 in neurons reverts the effect of the unc-7 mutation; moreover, the expression of UNC-7 mutant proteins that are predicted to be unable to form gap junctions also reverts this effect, suggesting that UNC-7 innexin regulates neuronal activity, in part, through gap junction-independent functions. We propose that, in addition to gap junction-mediated functions, UNC-7 innexin may also form hemichannels to regulate C. elegans' neuronal activity cooperatively with the NCA family leak channels. PMID:21489288

Skin denervation does not alter cortical potentials to surface concentric electrode stimulation: A comparison with laser evoked potentials and contact heat evoked potentials.

PubMed

La Cesa, S; Di Stefano, G; Leone, C; Pepe, A; Galosi, E; Alu, F; Fasolino, A; Cruccu, G; Valeriani, M; Truini, A

2018-01-01

In the neurophysiological assessment of patients with neuropathic pain, laser evoked potentials (LEPs), contact heat evoked potentials (CHEPs) and the evoked potentials by the intraepidermal electrical stimulation via concentric needle electrode are widely agreed as nociceptive specific responses; conversely, the nociceptive specificity of evoked potentials by surface concentric electrode (SE-PREPs) is still debated. In this neurophysiological study we aimed at verifying the nociceptive specificity of SE-PREPs. We recorded LEPs, CHEPs and SE-PREPs in eleven healthy participants, before and after epidermal denervation produced by prolonged capsaicin application. We also used skin biopsy to verify the capsaicin-induced nociceptive nerve fibre loss in the epidermis. We found that whereas LEPs and CHEPs were suppressed after capsaicin-induced epidermal denervation, the surface concentric electrode stimulation of the same denervated skin area yielded unchanged SE-PREPs. The suppression of LEPs and CHEPs after nociceptive nerve fibre loss in the epidermis indicates that these techniques are selectively mediated by nociceptive system. Conversely, the lack of SE-PREP changes suggests that SE-PREPs do not provide selective information on nociceptive system function. Capsaicin-induced epidermal denervation abolishes laser evoked potentials (LEPs) and contact heat evoked potentials (CHEPs), but leaves unaffected pain-related evoked potentials by surface concentric electrode (SE-PREPs). These findings suggest that unlike LEPs and CHEPs, SE-PREPs are not selectively mediated by nociceptive system. © 2017 European Pain Federation - EFIC®.

Event-induced theta responses as a window on the dynamics of memory.

PubMed

Bastiaansen, Marcel; Hagoort, Peter

2003-01-01

An important, but often ignored distinction in the analysis of EEG signals is that between evoked activity and induced activity. Whereas evoked activity reflects the summation of transient post-synaptic potentials triggered by an event, induced activity, which is mainly oscillatory in nature, is thought to reflect changes in parameters controlling dynamic interactions within and between brain structures. We hypothesize that induced activity may yield information about the dynamics of cell assembly formation, activation and subsequent uncoupling, which may play a prominent role in different types of memory operations. We then describe a number of analysis tools that can be used to study the reactivity of induced rhythmic activity, both in terms of amplitude changes and of phase variability. We briefly discuss how alpha, gamma and theta rhythms are thought to be generated, paying special attention to the hypothesis that the theta rhythm reflects dynamic interactions between the hippocampal system and the neocortex. This hypothesis would imply that studying the reactivity of scalp-recorded theta may provide a window on the contribution of the hippocampus to memory functions. We review studies investigating the reactivity of scalp-recorded theta in paradigms engaging episodic memory, spatial memory and working memory. In addition, we review studies that relate theta reactivity to processes at the interface of memory and language. Despite many unknowns, the experimental evidence largely supports the hypothesis that theta activity plays a functional role in cell assembly formation, a process which may constitute the neural basis of memory formation and retrieval. The available data provide only highly indirect support for the hypothesis that scalp-recorded theta yields information about hippocampal functioning. It is concluded that studying induced rhythmic activity holds promise as an additional important way to study brain function.

Quantal amplitude and quantal variance of strontium-induced asynchronous EPSCs in rat dentate granule neurons

PubMed Central

Bekkers, John M; Clements, John D

1999-01-01

Excitatory postsynaptic currents (EPSCs) were recorded from granule cells of the dentate gyrus in acute slices of 17- to 21-day-old rats (22-25 °C) using tissue cuts and minimal extracellular stimulation to selectively activate a small number of synaptic contacts.Adding millimolar Sr2+ to the external solution produced asynchronous EPSCs (aEPSCs) lasting for several hundred milliseconds after the stimulus. Minimally stimulated aEPSCs resembled miniature EPSCs (mEPSCs) recorded in the same cell but differed from them in ways expected from the greater range of dendritic filtering experienced by mEPSCs. aEPSCs had the same stimulus threshold as the synchronous EPSCs (sEPSCs) that followed the stimulus with a brief latency. aEPSCs following stimulation of distal inputs had a slower mean rise time than those following stimulation of proximal inputs. These results suggest that aEPSCs arose from the same synapses that generated sEPSCs.Proximally elicited aEPSCs had a mean amplitude of 6.7 ± 2.2 pA (± s.d., n = 23 cells) at -70 mV and an amplitude coefficient of variation of 0.46 ± 0.08.The amplitude distributions of sEPSCs never exhibited distinct peaks.Monte Carlo modelling of the shapes of aEPSC amplitude distributions indicated that our data were best explained by an intrasite model of quantal variance.It is concluded that Sr2+-evoked aEPSCs are uniquantal events arising at synaptic terminals that were recently invaded by an action potential, and so provide direct information about the quantal amplitude and quantal variance at those terminals. The large quantal variance obscures quantization of the amplitudes of evoked sEPSCs at this class of excitatory synapse. PMID:10066937

Static γ-motoneurones couple group Ia and II afferents of single muscle spindles in anaesthetised and decerebrate cats

PubMed Central

Gladden, M H; Matsuzaki, H

2002-01-01

Ideas about the functions of static γ-motoneurones are based on the responses of primary and secondary endings to electrical stimulation of single static γ-axons, usually at high frequencies. We compared these effects with the actions of spontaneously active γ-motoneurones. In anaesthetised cats, afferents and efferents were recorded in intramuscular nerve branches to single muscle spindles. The occurrence of γ-spikes, identified by a spike shape recognition system, was linked to video-taped contractions of type-identified intrafusal fibres in the dissected muscle spindles. When some static γ-motoneurones were active at low frequency (< 15 Hz) they coupled the firing of group Ia and II afferents. Activity of other static γ-motoneurones which tensed the intrafusal fibres appeared to enhance this effect. Under these conditions the secondary ending responded at shorter latency than the primary ending. In another series of experiments on decerebrate cats, responses of primary and secondary endings of single muscle spindles to activation of γ-motoneurones by natural stimuli were compared with their responses to electrical stimulation of single γ-axons supplying the same spindle. Electrical stimulation mimicked the natural actions of γ-motoneurones on either the primary or the secondary ending, but not on both together. However, γ-activity evoked by natural stimuli coupled the firing of afferents with the muscle at constant length, and also when it was stretched. Analysis showed that the timing and tightness of this coupling determined the degree of summation of excitatory postsynaptic potentials (EPSPs) evoked by each afferent in α-motoneurones and interneurones contacted by terminals of both endings, and thus the degree of facilitation of reflex actions of group II afferents. PMID:12181298

Synaptic Transmission Optimization Predicts Expression Loci of Long-Term Plasticity.

PubMed

Costa, Rui Ponte; Padamsey, Zahid; D'Amour, James A; Emptage, Nigel J; Froemke, Robert C; Vogels, Tim P

2017-09-27

Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression-pre- or postsynaptic-is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Upregulation of transmitter release probability improves a conversion of synaptic analogue signals into neuronal digital spikes

PubMed Central

2012-01-01

Action potentials at the neurons and graded signals at the synapses are primary codes in the brain. In terms of their functional interaction, the studies were focused on the influence of presynaptic spike patterns on synaptic activities. How the synapse dynamics quantitatively regulates the encoding of postsynaptic digital spikes remains unclear. We investigated this question at unitary glutamatergic synapses on cortical GABAergic neurons, especially the quantitative influences of release probability on synapse dynamics and neuronal encoding. Glutamate release probability and synaptic strength are proportionally upregulated by presynaptic sequential spikes. The upregulation of release probability and the efficiency of probability-driven synaptic facilitation are strengthened by elevating presynaptic spike frequency and Ca2+. The upregulation of release probability improves spike capacity and timing precision at postsynaptic neuron. These results suggest that the upregulation of presynaptic glutamate release facilitates a conversion of synaptic analogue signals into digital spikes in postsynaptic neurons, i.e., a functional compatibility between presynaptic and postsynaptic partners. PMID:22852823

Coexistence of glutamatergic spine synapses and shaft synapses in substantia nigra dopamine neurons

PubMed Central

Jang, Miae; Bum Um, Ki; Jang, Jinyoung; Jin Kim, Hyun; Cho, Hana; Chung, Sungkwon; Kyu Park, Myoung

2015-01-01

Dopamine neurons of the substantia nigra have long been believed to have multiple aspiny dendrites which receive many glutamatergic synaptic inputs from several regions of the brain. But, here, using high-resolution two-photon confocal microscopy in the mouse brain slices, we found a substantial number of common dendritic spines in the nigral dopamine neurons including thin, mushroom, and stubby types of spines. However, the number of dendritic spines of the dopamine neurons was approximately five times lower than that of CA1 pyramidal neurons. Immunostaining and morphological analysis revealed that glutamatergic shaft synapses were present two times more than spine synapses. Using local two-photon glutamate uncaging techniques, we confirmed that shaft synapses and spine synapses had both AMPA and NMDA receptors, but the AMPA/NMDA current ratios differed. The evoked postsynaptic potentials of spine synapses showed lower amplitudes but longer half-widths than those of shaft synapses. Therefore, we provide the first evidence that the midbrain dopamine neurons have two morphologically and functionally distinct types of glutamatergic synapses, spine synapses and shaft synapses, on the same dendrite. This peculiar organization could be a new basis for unraveling many physiological and pathological functions of the midbrain dopamine neurons. PMID:26435058

Exogenous ciliary neurotrophic factor (CNTF) reduces synaptic depression during repetitive stimulation.

PubMed

Garcia, Neus; Santafé, Manel M; Tomàs, Marta; Priego, Mercedes; Obis, Teresa; Lanuza, Maria A; Besalduch, Nuria; Tomàs, Josep

2012-09-01

It has been shown that ciliary neurotrophic factor (CNTF) has trophic and maintenance effects on several types of peripheral and central neurons, glia, and cells outside the nervous system. Both CNTF and its receptor, CNTF-Rα, are expressed in the muscle. We use confocal immunocytochemistry to show that the trophic cytokine and its receptor are present in the pre- and post-synaptic sites of the neuromuscular junctions (NMJs). Applied CNTF (7.5-200 ng/ml, 60 min-3 h) does not acutely affect spontaneous potentials (size or frequency) or quantal content of the evoked acetylcholine release from post-natal (in weak or strong axonal inputs on dually innervated end plates or in the most mature singly innervated synapses at P6) or adult (P30) NMJ of Levator auris longus muscle of the mice. However, CNTF reduces roughly 50% the depression produced by repetitive stimulation (40 Hz, 2 min) on the adult NMJs. Our findings indicate that, unlike neurotrophins, exogenous CNTF does not acutely modulate transmitter release locally at the mammalian neuromuscular synapse but can protect mature end plates from activity-induced synaptic depression. © 2012 Peripheral Nerve Society.

Role of voltage-sensitive receptors in nicotinic transmission.

PubMed Central

Lester, H A; Koblin, D D; Sheridan, R E

1978-01-01

This paper compares the conductance induced by bath-applied acetyl-choline (ACh) and by the same transmitter released from nerve terminals at Electrophorus electroplaques. For the former case, dose-response relations are characterized by the maximal agonist-induced conductance, rgamma (130 mmho/cm2), and by the concentration which induces half this conductance; this concentration is termed Kapp and equals 50 micron at -85 mV. For the latter case, neurally evoked postsynaptic currents (PSCs) are characterized by the peak conductance during strongly facilitated release, gPSC, and by the rate constant for decay, alpha. Since gPSC roughly equals rgamma, it is concluded that the PSC activates nearly all available receptor channels. These and other data agree with recent estimates that during the growth phase of the quantal response, (a) the ACh concentration is at least several hundred micromolar; and (b) most nearby channels are activated. However both alpha and Kapp increase during depolarization, at a rate of about e-fold per 86 mV. These observations on voltage sensitivity suggest that a suprathreshold synaptic event is rapidly terminated because the action potential abruptly releases ACh molecules from receptors. PMID:630039

Receptor-mediated presynaptic facilitation of quantal release of acetylcholine induced by pralidoxime in Aplysia.

PubMed

Fossier, P; Baux, G; Poulain, B; Tauc, L

1990-09-01

1. Possible interactions of contrathion (pralidoxime sulfomethylate), a reactivator of phosphorylated acetylcholinesterase (AChE), with the regulation of cholinergic transmission were investigated on an identified synapse in the buccal ganglion of Aplysia californica. 2. Transmitter release was evoked either by a presynaptic action potential or, under voltage clamp, by a long depolarization of the presynaptic cell. At concentrations higher than 10(-5) M, bath-applied contrathion decreased the amplitude of miniature postsynaptic currents and increased their decay time. At the same time, the quantal release of ACh was transiently facilitated. The facilitatory effect of contrathion was prevented by tubocurarine but not by atropine. Because in this preparation, these drugs block, respectively, the presynaptic nicotinic-like and muscarinic-like receptors involved in positive and negative feedback of ACh release, we proposed that contrathion activates presynaptic nicotinic-like receptors. 3. Differential desensitization of the presynaptic receptors is proposed to explain the transience of the facilitatory action of contrathion on ACh release. 4. The complexity of the synaptic action of contrathion raises the possibility that its therapeutic effects in AChE poisonings are not limited to AChE reactivation.

Excitatory Post-Synaptic Potential Mimicked in Indium-Zinc-Oxide Synaptic Transistors Gated by Methyl Cellulose Solid Electrolyte

PubMed Central

Guo, Liqiang; Wen, Juan; Ding, Jianning; Wan, Changjin; Cheng, Guanggui

2016-01-01

The excitatory postsynaptic potential (EPSP) of biological synapses is mimicked in indium-zinc-oxide synaptic transistors gated by methyl cellulose solid electrolyte. These synaptic transistors show excellent electrical performance at an operating voltage of 0.8 V, Ion/off ratio of 2.5 × 106, and mobility of 38.4 cm2/Vs. After this device is connected to a resistance of 4 MΩ in series, it exhibits excellent characteristics as an inverter. A threshold potential of 0.3 V is achieved by changing the gate pulse amplitude, width, or number, which is analogous to biological EPSP. PMID:27924838

Neurotransmitter Release Can Be Stabilized by a Mechanism That Prevents Voltage Changes Near the End of Action Potentials from Affecting Calcium Currents

PubMed Central

Clarke, Stephen G.; Scarnati, Matthew S.

2016-01-01

At chemical synapses, presynaptic action potentials (APs) activate voltage-gated calcium channels, allowing calcium to enter and trigger neurotransmitter release. The duration, peak amplitude, and shape of the AP falling phase alter calcium entry, which can affect neurotransmitter release significantly. In many neurons, APs do not immediately return to the resting potential, but instead exhibit a period of depolarization or hyperpolarization referred to as an afterpotential. We hypothesized that presynaptic afterpotentials should alter neurotransmitter release by affecting the electrical driving force for calcium entry and calcium channel gating. In support of this, presynaptic calcium entry is affected by afterpotentials after standard instant voltage jumps. Here, we used the mouse calyx of Held synapse, which allows simultaneous presynaptic and postsynaptic patch-clamp recording, to show that the postsynaptic response is affected significantly by presynaptic afterpotentials after voltage jumps. We therefore tested the effects of presynaptic afterpotentials using simultaneous presynaptic and postsynaptic recordings and AP waveforms or real APs. Surprisingly, presynaptic afterpotentials after AP stimuli did not alter calcium channel responses or neurotransmitter release appreciably. We show that the AP repolarization time course causes afterpotential-induced changes in calcium driving force and changes in calcium channel gating to effectively cancel each other out. This mechanism, in which electrical driving force is balanced by channel gating, prevents changes in calcium influx from occurring at the end of the AP and therefore acts to stabilize synaptic transmission. In addition, this mechanism can act to stabilize neurotransmitter release when the presynaptic resting potential changes. SIGNIFICANCE STATEMENT The shape of presynaptic action potentials (APs), particularly the falling phase, affects calcium entry and small changes in calcium influx can produce large changes in postsynaptic responses. We hypothesized that afterpotentials, which often follow APs, affect calcium entry and neurotransmitter release. We tested this in calyx of Held nerve terminals, which allow simultaneous recording of presynaptic calcium currents and postsynaptic responses. Surprisingly, presynaptic afterpotentials did not alter calcium current or neurotransmitter release. We show that the AP falling phase causes afterpotential-induced changes in electrical driving force and calcium channel gating to cancel each other out. This mechanism regulates calcium entry at the end of APs and therefore stabilizes synaptic transmission. This also stabilizes responses when the presynaptic resting potential changes. PMID:27911759

Neurotransmitter Release Can Be Stabilized by a Mechanism That Prevents Voltage Changes Near the End of Action Potentials from Affecting Calcium Currents.

PubMed

Clarke, Stephen G; Scarnati, Matthew S; Paradiso, Kenneth G

2016-11-09

At chemical synapses, presynaptic action potentials (APs) activate voltage-gated calcium channels, allowing calcium to enter and trigger neurotransmitter release. The duration, peak amplitude, and shape of the AP falling phase alter calcium entry, which can affect neurotransmitter release significantly. In many neurons, APs do not immediately return to the resting potential, but instead exhibit a period of depolarization or hyperpolarization referred to as an afterpotential. We hypothesized that presynaptic afterpotentials should alter neurotransmitter release by affecting the electrical driving force for calcium entry and calcium channel gating. In support of this, presynaptic calcium entry is affected by afterpotentials after standard instant voltage jumps. Here, we used the mouse calyx of Held synapse, which allows simultaneous presynaptic and postsynaptic patch-clamp recording, to show that the postsynaptic response is affected significantly by presynaptic afterpotentials after voltage jumps. We therefore tested the effects of presynaptic afterpotentials using simultaneous presynaptic and postsynaptic recordings and AP waveforms or real APs. Surprisingly, presynaptic afterpotentials after AP stimuli did not alter calcium channel responses or neurotransmitter release appreciably. We show that the AP repolarization time course causes afterpotential-induced changes in calcium driving force and changes in calcium channel gating to effectively cancel each other out. This mechanism, in which electrical driving force is balanced by channel gating, prevents changes in calcium influx from occurring at the end of the AP and therefore acts to stabilize synaptic transmission. In addition, this mechanism can act to stabilize neurotransmitter release when the presynaptic resting potential changes. The shape of presynaptic action potentials (APs), particularly the falling phase, affects calcium entry and small changes in calcium influx can produce large changes in postsynaptic responses. We hypothesized that afterpotentials, which often follow APs, affect calcium entry and neurotransmitter release. We tested this in calyx of Held nerve terminals, which allow simultaneous recording of presynaptic calcium currents and postsynaptic responses. Surprisingly, presynaptic afterpotentials did not alter calcium current or neurotransmitter release. We show that the AP falling phase causes afterpotential-induced changes in electrical driving force and calcium channel gating to cancel each other out. This mechanism regulates calcium entry at the end of APs and therefore stabilizes synaptic transmission. This also stabilizes responses when the presynaptic resting potential changes. Copyright © 2016 the authors 0270-6474/16/3611559-14$15.00/0.

Exploring the Mechanisms of Exercise-Induced Hypoalgesia Using Somatosensory and Laser Evoked Potentials.

PubMed

Jones, Matthew D; Taylor, Janet L; Booth, John; Barry, Benjamin K

2016-01-01

Exercise-induced hypoalgesia is well described, but the underlying mechanisms are unclear. The aim of this study was to examine the effect of exercise on somatosensory evoked potentials, laser evoked potentials, pressure pain thresholds and heat pain thresholds. These were recorded before and after 3-min of isometric elbow flexion exercise at 40% of the participant's maximal voluntary force, or an equivalent period of rest. Exercise-induced hypoalgesia was confirmed in two experiments (Experiment 1-SEPs; Experiment 2-LEPs) by increased pressure pain thresholds at biceps brachii (24.3 and 20.6% increase in Experiment 1 and 2, respectively; both d > 0.84 and p < 0.001) and first dorsal interosseous (18.8 and 21.5% increase in Experiment 1 and 2, respectively; both d > 0.57 and p < 0.001). In contrast, heat pain thresholds were not significantly different after exercise (forearm: 10.8% increase, d = 0.35, p = 0.10; hand: 3.6% increase, d = 0.06, p = 0.74). Contrasting effects of exercise on the amplitude of laser evoked potentials (14.6% decrease, d = -0.42, p = 0.004) and somatosensory evoked potentials (10.9% increase, d = -0.02, p = 1) were also observed, while an equivalent period of rest showed similar habituation (laser evoked potential: 7.3% decrease, d = -0.25, p = 0.14; somatosensory evoked potential: 20.7% decrease, d = -0.32, p = 0.006). The differential response of pressure pain thresholds and heat pain thresholds to exercise is consistent with relative insensitivity of thermal nociception to the acute hypoalgesic effects of exercise. Conflicting effects of exercise on somatosensory evoked potentials and laser evoked potentials were observed. This may reflect non-nociceptive contributions to the somatosensory evoked potential, but could also indicate that peripheral nociceptors contribute to exercise-induced hypoalgesia.

Relationships between morphology and physiology of pyramid-pyramid single axon connections in rat neocortex in vitro.

PubMed Central

Deuchars, J; West, D C; Thomson, A M

1994-01-01

1. Double intracellular recordings were made from 1163 pairs of pyramidal neurones in layer V-VI of the rat somatomotor cortex in vitro using sharp electrodes filled with biocytin. Monosynaptically connected pairs of cells were identified when an action potential in one could elicit a constant latency excitatory postsynaptic potential (EPSP) in the other and the cells were filled with biocytin. Labelled cells were subsequently identified histologically with avidin-horseradish peroxidase. 2. Thirty-four pairs of cells were found to be monosynaptically connected. Fifteen of these pairs were sufficiently stable for electrophysiological recordings and three of these were recovered sufficiently to permit full morphological reconstruction. 3. The EPSP recorded between the first pair of pyramids varied in amplitude between 0 and 3 mV (mean 1.33 +/- 1.06 mV) and fluctuated considerably (coefficient of variation, 0.796). This was largely due to a high incidence of apparent failures of transmission. On reconstruction two boutons from the presynaptic pyramid axon were in close apposition to the proximal portions of basal dendrites of the postsynaptic cell. 4. In the second pair of pyramids the EPSP had a mean amplitude of 1.06 mV, and displayed a 10-90% rise time of 2.8 ms and a width at half-amplitude of 23 ms. This EPSP did not alter significantly with changes in membrane potential at the soma. The presynaptic axon closely apposed the distal apical dendrite of the postsynaptic cell in eight places. 5. In the third pair of pyramids, the EPSPs, recorded at a relatively depolarized membrane potential, were long lasting and could elicit slow dendritic spikes with long and variable latencies. These slow spikes suggested that the postsynaptic recording site was dendritic and on reconstruction a possible location was identified on the apical dendrite. A total of five presynaptic boutons closely apposed three separate, proximal branches of the postsynaptic apical dendrite. 6. These results provide the first illustration of a morphological basis for variations in functional properties of pyramid-pyramid connections in the neocortex. Images Figure 1 Figure 3 Figure 5 PMID:7965856

Contribution of Ih to the relative facilitation of synaptic responses induced by carbachol in the entorhinal cortex during repetitive stimulation of the parasubiculum.

PubMed

Sparks, D W; Chapman, C A

2014-10-10

Neurons in the superficial layers of the entorhinal cortex provide the hippocampus with the majority of its cortical sensory input, and also receive the major output projection from the parasubiculum. This puts the parasubiculum in a position to modulate the activity of entorhinal neurons that project to the hippocampus. These brain areas receive cholinergic projections that are active during periods of theta- and gamma-frequency electroencephalographic (EEG) activity. The purpose of this study was to investigate how cholinergic receptor activation affects the strength of repetitive synaptic responses at these frequencies in the parasubiculo-entorhinal pathway and the cellular mechanisms involved. Whole-cell patch-clamp recordings of rat layer II medial entorhinal neurons were conducted using an acute slice preparation, and responses to 5-pulse trains of stimulation at theta- and gamma-frequency delivered to the parasubiculum were recorded. The cholinergic agonist carbachol (CCh) suppressed the amplitude of single synaptic responses, but also produced a relative facilitation of synaptic responses evoked during stimulation trains. The N-methyl-d-aspartate (NMDA) glutamate receptor blocker APV did not significantly reduce the relative facilitation effect. However, the hyperpolarization-activated cationic current (Ih) channel blocker ZD7288 mimicked the relative facilitation induced by CCh, suggesting that CCh-induced inhibition of Ih could produce the effect by increasing dendritic input resistance (Rin). Inward-rectifying and leak K(+) currents are known to interact with Ih to affect synaptic excitability. Application of the K(+) channel antagonist Ba(2+) depolarized neurons and enhanced temporal summation, but did not block further facilitation of train-evoked responses by ZD7288. The Ih-dependent facilitation of synaptic responses can therefore occur during reductions in inward-rectifying potassium current (IKir) associated with dendritic depolarization. Thus, in addition to cholinergic reductions in transmitter release that are known to facilitate train-evoked responses, these findings emphasize the role of inhibition of Ih in the integration of synaptic inputs within the entorhinal cortex during cholinergically-induced oscillatory states, likely due to enhanced summation of excitatory postsynaptic potentials (EPSPs) induced by increases in dendritic Rin. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients

PubMed Central

Rutledge, Robb B.; Zaehle, Tino; Schmitt, Friedhelm C.; Kopitzki, Klaus; Kowski, Alexander B.; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J.

2015-01-01

Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods. PMID:26019312

No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients.

PubMed

Stenner, Max-Philipp; Rutledge, Robb B; Zaehle, Tino; Schmitt, Friedhelm C; Kopitzki, Klaus; Kowski, Alexander B; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J

2015-08-01

Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods. Copyright © 2015 the American Physiological Society.

The soluble extracellular fragment of neuroligin-1 targets Aβ oligomers to the postsynaptic region of excitatory synapses.

PubMed

Dinamarca, Margarita C; Di Luca, Monica; Godoy, Juan A; Inestrosa, Nibaldo C

2015-10-09

Amyloid-β oligomers (Aβo) play a major role in the synaptic dysfunction of Alzheimer's disease (AD). Neuroligins are postsynaptic cell-adhesion molecules, that share an extracellular domain with high degree of similarity to acetylcholinesterase (AChE), one of the first putative Aβo receptors. We recently found that Aβo interact with the soluble N-terminal fragment of neuroligin-1 (NL-1). We report here that Aβo associate with NL-1 at excitatory hippocampal synapses, whereas almost no association was observed with neuroligin-2, an isoform present at inhibitory synapses. Studies using purified hippocampal postsynaptic densities indicate that NL-1 interacts with Aβo in a complex with GluN2B-containing NMDA receptors. Additionally, the soluble fragment of NL-1 was used as a scavenger for Aβo. Field excitatory postsynaptic potentials indicate that fragments of NL-1 protect hippocampal neurons from the impairment induced by Aβo. To our knowledge, this is the first report of the interaction between this extracellular fragment of NL-1 and Aβo, strongly suggest that NL-1 facilitates the targeting of Aβo to the postsynaptic regions of excitatory synapses. Copyright © 2015 Elsevier Inc. All rights reserved.

Age- and Sex-Dependent Impact of Repeated Social Stress on Intrinsic and Synaptic Excitability of the Rat Prefrontal Cortex

PubMed Central

Urban, Kimberly R.; Valentino, Rita J.

2017-01-01

Abstract Stress is implicated in psychiatric illnesses that are characterized by impairments in cognitive functions that are mediated by the medial prefrontal cortex (mPFC). Because sex and age determine stress vulnerability, the effects of repeated social stress occurring during early adolescence, mid-adolescence, or adulthood on the cellular properties of male and female rat mPFC Layer V neurons in vitro were examined. Repeated resident–intruder stress produced age- and sex-specific effects on mPFC intrinsic and synaptic excitability. Mid-adolescents were particularly vulnerable to effects on intrinsic excitability. The maximum number of action potentials (APs) evoked by increasing current intensity was robustly decreased in stressed male and female mid-adolescent rats compared with age-matched controls. These effects were associated with stress-induced changes in AP half-width, amplitude, threshold, and input resistance. Social stress at all ages generally decreased synaptic excitability by decreasing the amplitude of spontaneous excitatory postsynaptic potentials. The results suggest that whereas social stress throughout life can diminish the influence of afferents driving the mPFC, social stress during mid-adolescence additionally affects intrinsic characteristics of mPFC neurons that determine excitability. The depressant effects of social stress on intrinsic and synaptic mPFC neurons may underlie its ability to affect executive functions and emotional responses, particularly during adolescence. PMID:28013234

Age- and Sex-Dependent Impact of Repeated Social Stress on Intrinsic and Synaptic Excitability of the Rat Prefrontal Cortex.

PubMed

Urban, Kimberly R; Valentino, Rita J

2017-01-01

Stress is implicated in psychiatric illnesses that are characterized by impairments in cognitive functions that are mediated by the medial prefrontal cortex (mPFC). Because sex and age determine stress vulnerability, the effects of repeated social stress occurring during early adolescence, mid-adolescence, or adulthood on the cellular properties of male and female rat mPFC Layer V neurons in vitro were examined. Repeated resident-intruder stress produced age- and sex-specific effects on mPFC intrinsic and synaptic excitability. Mid-adolescents were particularly vulnerable to effects on intrinsic excitability. The maximum number of action potentials (APs) evoked by increasing current intensity was robustly decreased in stressed male and female mid-adolescent rats compared with age-matched controls. These effects were associated with stress-induced changes in AP half-width, amplitude, threshold, and input resistance. Social stress at all ages generally decreased synaptic excitability by decreasing the amplitude of spontaneous excitatory postsynaptic potentials. The results suggest that whereas social stress throughout life can diminish the influence of afferents driving the mPFC, social stress during mid-adolescence additionally affects intrinsic characteristics of mPFC neurons that determine excitability. The depressant effects of social stress on intrinsic and synaptic mPFC neurons may underlie its ability to affect executive functions and emotional responses, particularly during adolescence. © The Author 2016. Published by Oxford University Press.

Functional states of rat cortical circuits during the unpredictable availability of a reward-related cue

PubMed Central

Fernández-Lamo, Iván; Sánchez-Campusano, Raudel; Gruart, Agnès; Delgado-García M, José M.

2016-01-01

Proper performance of acquired abilities can be disturbed by the unexpected occurrence of external changes. Rats trained with an operant conditioning task (to press a lever in order to obtain a food pellet) using a fixed-ratio (1:1) schedule were subsequently placed in a Skinner box in which the lever could be removed randomly. Field postsynaptic potentials (fPSPs) were chronically evoked in perforant pathway-hippocampal CA1 (PP-CA1), CA1-subiculum (CA1-SUB), CA1-medial prefrontal cortex (CA1-mPFC), mPFC-nucleus accumbens (mPFC-NAc), and mPFC-basolateral amygdala (mPFC-BLA) synapses during lever IN and lever OUT situations. While lever presses were accompanied by a significant increase in fPSP slopes at the five synapses, the unpredictable absence of the lever were accompanied by decreased fPSP slopes in all, except PP-CA1 synapses. Spectral analysis of local field potentials (LFPs) recorded when the animal approached the corresponding area in the lever OUT situation presented lower spectral powers than during lever IN occasions for all recording sites, apart from CA1. Thus, the unpredictable availability of a reward-related cue modified the activity of cortical and subcortical areas related with the acquisition of operant learning tasks, suggesting an immediate functional reorganization of these neural circuits to address the changed situation and to modify ongoing behaviors accordingly. PMID:27869181

Crayfish neuromuscular facilitation activated by constant presynaptic action potentials and depolarizing pulses

PubMed Central

Zucker, Robert S.

1974-01-01

1. Experiments were conducted to test the hypothesis that facilitation of transmitter release in response to repetitive stimulation of the exciter motor axon to the crayfish claw opener muscle is due to an increase in the amplitude or duration of the action potential in presynaptic terminals. No consistent changes were found in the nerve terminal potential (n.t.p.) recorded extracellularly at synaptic sites on the surface of muscle fibres. 2. Apparent changes in n.t.p. are attributed to three causes. (i) Some recordings are shown to be contaminated by non-specific muscle responses which grow during facilitation. (ii) Some averaged n.t.p.s exhibit opposite changes in amplitude and duration which suggest a change in the synchrony of presynaptic nerve impulses at different frequencies. (iii) Some changes in n.t.p. are blocked by γ-methyl glutamate, an antagonist of the post-synaptic receptor, which suggests that these changes are caused by small muscle movements. 3. The only change in n.t.p. believed to represent an actual change in the intracellular signal is a reduction in n.t.p. amplitude to the second of two stimuli separated by a brief interval. 4. Tetra-ethyl ammonium ions increase synaptic transmission about 20% and prolong the n.t.p. about 15%. This result suggests that an increase in n.t.p. large enough to increase transmission by the several hundred per cent occurring during facilitation would be detected. 5. The nerve terminals are electrically excitable, and most synaptic sites have a diphasic or triphasic n.t.p., which suggests that the motor neurone terminals are actively invaded by nerve impulses. 6. When nerve impulses are blocked in tetrodotoxin, depolarization of nerve terminals increases the frequency of miniature excitatory junctional potentials (e.j.p.s), and a phasic e.j.p. can be evoked by large, brief depolarizing pulses. Responses to repetitive or paired depolarizations of constant amplitude and duration exhibit a facilitation similar to that of e.j.p.s evoked by nerve impulses. 7. It is concluded that facilitation in the crayfish claw opener is not due to a change in the presynaptic action potential, but is due to some change at a later step in the depolarization—secretion process. PMID:4153766

Crayfish neuromuscular facilitation activated by constant presynaptic action potentials and depolarizing pulses.

PubMed

Zucker, R S

1974-08-01

1. Experiments were conducted to test the hypothesis that facilitation of transmitter release in response to repetitive stimulation of the exciter motor axon to the crayfish claw opener muscle is due to an increase in the amplitude or duration of the action potential in presynaptic terminals. No consistent changes were found in the nerve terminal potential (n.t.p.) recorded extracellularly at synaptic sites on the surface of muscle fibres.2. Apparent changes in n.t.p. are attributed to three causes.(i) Some recordings are shown to be contaminated by non-specific muscle responses which grow during facilitation.(ii) Some averaged n.t.p.s exhibit opposite changes in amplitude and duration which suggest a change in the synchrony of presynaptic nerve impulses at different frequencies.(iii) Some changes in n.t.p. are blocked by gamma-methyl glutamate, an antagonist of the post-synaptic receptor, which suggests that these changes are caused by small muscle movements.3. The only change in n.t.p. believed to represent an actual change in the intracellular signal is a reduction in n.t.p. amplitude to the second of two stimuli separated by a brief interval.4. Tetra-ethyl ammonium ions increase synaptic transmission about 20% and prolong the n.t.p. about 15%. This result suggests that an increase in n.t.p. large enough to increase transmission by the several hundred per cent occurring during facilitation would be detected.5. The nerve terminals are electrically excitable, and most synaptic sites have a diphasic or triphasic n.t.p., which suggests that the motor neurone terminals are actively invaded by nerve impulses.6. When nerve impulses are blocked in tetrodotoxin, depolarization of nerve terminals increases the frequency of miniature excitatory junctional potentials (e.j.p.s), and a phasic e.j.p. can be evoked by large, brief depolarizing pulses. Responses to repetitive or paired depolarizations of constant amplitude and duration exhibit a facilitation similar to that of e.j.p.s evoked by nerve impulses.7. It is concluded that facilitation in the crayfish claw opener is not due to a change in the presynaptic action potential, but is due to some change at a later step in the depolarization-secretion process.

The PLC/IP3R/PKC Pathway is Required for Ethanol-enhanced GABA Release

PubMed Central

Kelm, M. Katherine; Weinberg, Richard J.; Criswell, Hugh E.; Breese, George R.

2010-01-01

Summary Research on the actions of ethanol at the GABAergic synapse has traditionally focused on postsynaptic mechanisms, but recent data demonstrate that ethanol also increases both evoked and spontaneous GABA release in many brain regions. Using whole-cell voltage-clamp recordings, we previously showed that ethanol increases spontaneous GABA release at the rat interneuron-Purkinje cell synapse. This presynaptic ethanol effect is dependent on calcium release from internal stores, possibly through activation of inositol 1,4,5-trisphosphate receptors (IP3Rs). After confirming that ethanol targets vesicular GABA release, in the present study we used electron microscopic immunohistochemistry to demonstrate that IP3Rs are located in presynaptic terminals of cerebellar interneurons. Activation of IP3Rs requires binding of IP3, generated through activation of phospholipase C (PLC). We find that the PLC antagonist edelfosine prevents ethanol from increasing spontaneous GABA release. Diacylglycerol generated by PLC and calcium released by activation of the IP3R activate protein kinase C (PKC). Ethanol-enhanced GABA release was blocked by two PKC antagonists, chelerythrine and calphostin C. When a membrane impermeable PKC antagonist, PKC (19-36), was delivered intracellularly to the postsynaptic neuron, ethanol continued to increase spontaneous GABA release. Overall, these results suggest that activation of the PLC/IP3R/PKC pathway is necessary for ethanol to increase spontaneous GABA release from presynaptic terminals onto Purkinje cells. PMID:20206640

Postsynaptic P2X3-containing receptors in gustatory nerve fibres mediate responses to all taste qualities in mice

PubMed Central

Vandenbeuch, Aurelie; Larson, Eric D; Anderson, Catherine B; Smith, Steven A; Ford, Anthony P; Finger, Thomas E; Kinnamon, Sue C

2015-01-01

Abstract Taste buds release ATP to activate ionotropic purinoceptors composed of P2X2 and P2X3 subunits, present on the taste nerves. Mice with genetic deletion of P2X2 and P2X3 receptors (double knockout mice) lack responses to all taste stimuli presumably due to the absence of ATP-gated receptors on the afferent nerves. Recent experiments on the double knockout mice showed, however, that their taste buds fail to release ATP, suggesting the possibility of pleiotropic deficits in these global knockouts. To test further the role of postsynaptic P2X receptors in afferent signalling, we used AF-353, a selective antagonist of P2X3-containing receptors to inhibit the receptors acutely during taste nerve recording and behaviour. The specificity of AF-353 for P2X3-containing receptors was tested by recording Ca2+ transients to exogenously applied ATP in fura-2 loaded isolated geniculate ganglion neurons from wild-type and P2X3 knockout mice. ATP responses were completely inhibited by 10 μm or 100 μm AF-353, but neither concentration blocked responses in P2X3 single knockout mice wherein the ganglion cells express only P2X2-containing receptors. Furthermore, AF-353 had no effect on taste-evoked ATP release from taste buds. In wild-type mice, i.p. injection of AF-353 or simple application of the drug directly to the tongue, inhibited taste nerve responses to all taste qualities in a dose-dependent fashion. A brief access behavioural assay confirmed the electrophysiological results and showed that preference for a synthetic sweetener, SC-45647, was abolished following i.p. injection of AF-353. These data indicate that activation of P2X3-containing receptors is required for transmission of all taste qualities. Key points Acute inhibition of purinergic receptors with a selective P2X3 antagonist prevents transmission of information from taste buds to sensory nerves. The P2X3 antagonist has no effect on taste-evoked release of ATP, confirming the effect is postsynaptic. The results confirm previous results with P2X2/3 double knockout mice that ATP is required for transmission of all taste qualities, including sour and salty. Previously, ATP was confirmed to be required for bitter, sweet and umami tastes, but was questioned for salty and sour tastes due to pleomorphic deficits in the double knockout mice. The geniculate ganglion in mouse contains two populations of ganglion cells with different subunit composition of P2X2 and P2X3 receptors making them differently susceptible to pharmacological block and, presumably, desensitization. PMID:25524179

Whole-brain diffusion tensor imaging in correlation to visual-evoked potentials in multiple sclerosis: a tract-based spatial statistics analysis.

PubMed

Lobsien, D; Ettrich, B; Sotiriou, K; Classen, J; Then Bergh, F; Hoffmann, K-T

2014-01-01

Functional correlates of microstructural damage of the brain affected by MS are incompletely understood. The purpose of this study was to evaluate correlations of visual-evoked potentials with microstructural brain changes as determined by DTI in patients with demyelinating central nervous disease. Sixty-one patients with clinically isolated syndrome or MS were prospectively recruited. The mean P100 visual-evoked potential latencies of the right and left eyes of each patient were calculated and used for the analysis. For DTI acquisition, a single-shot echo-planar imaging pulse sequence with 80 diffusion directions was performed at 3T. Fractional anisotropy, radial diffusivity, and axial diffusivity were calculated and correlated with mean P100 visual-evoked potentials by tract-based spatial statistics. Significant negative correlations between mean P100 visual-evoked potentials and fractional anisotropy and significant positive correlations between mean P100 visual-evoked potentials and radial diffusivity were found widespread over the whole brain. The highest significance was found in the optic radiation, frontoparietal white matter, and corpus callosum. Significant positive correlations between mean P100 visual-evoked potentials and axial diffusivity were less widespread, notably sparing the optic radiation. Microstructural changes of the whole brain correlated significantly with mean P100 visual-evoked potentials. The distribution of the correlations showed clear differences among axial diffusivity, fractional anisotropy, and radial diffusivity, notably in the optic radiation. This finding suggests a stronger correlation of mean P100 visual-evoked potentials to demyelination than to axonal damage. © 2014 by American Journal of Neuroradiology.

Electrophysiological studies of the nervous system

NASA Technical Reports Server (NTRS)

Galambos, R.

1972-01-01

The electrophysiology of the nervous system is studied using cats and human subjects. Data cover effects of chlorolose on evoked potential, the evoked resistance shift that accompanies evoked potentials, and the relationship of eye movements to potentials aroused by visual stimulation.

Dissecting the Components of Long-Term Potentiation

PubMed Central

Blundon, Jay A.; Zakharenko, Stanislav S.

2009-01-01

The formation of memories relies on plastic changes at synapses between neurons. Although the mechanisms of synaptic plasticity have been studied extensively over several decades, many aspects of this process remain controversial. The cellular locus of expression of long-term potentiation (LTP), a major form of synaptic plasticity, is one of the most important unresolved phenomena. In this article, we summarize some recent advances in this area made possible by the development of new imaging tools. These studies have demonstrated that LTP is compound in nature and consists of both presynaptic and postsynaptic components. We also review some features of presynaptic and postsynaptic changes during compound LTP. PMID:18940785

A Perturbation Based Decomposition of Compound-Evoked Potentials for Characterization of Nerve Fiber Size Distributions.

PubMed

Szlavik, Robert B

2016-02-01

The characterization of peripheral nerve fiber distributions, in terms of diameter or velocity, is of clinical significance because information associated with these distributions can be utilized in the differential diagnosis of peripheral neuropathies. Electro-diagnostic techniques can be applied to the investigation of peripheral neuropathies and can yield valuable diagnostic information while being minimally invasive. Nerve conduction velocity studies are single parameter tests that yield no detailed information regarding the characteristics of the population of nerve fibers that contribute to the compound-evoked potential. Decomposition of the compound-evoked potential, such that the velocity or diameter distribution of the contributing nerve fibers may be determined, is necessary if information regarding the population of contributing nerve fibers is to be ascertained from the electro-diagnostic study. In this work, a perturbation-based decomposition of compound-evoked potentials is proposed that facilitates determination of the fiber diameter distribution associated with the compound-evoked potential. The decomposition is based on representing the single fiber-evoked potential, associated with each diameter class, as being perturbed by contributions, of varying degree, from all the other diameter class single fiber-evoked potentials. The resultant estimator of the contributing nerve fiber diameter distribution is valid for relatively large separations in diameter classes. It is also useful in situations where the separation between diameter classes is small and the concomitant single fiber-evoked potentials are not orthogonal.

Auditory- and visual-evoked potentials in Mexican infants are not affected by maternal supplementation with 400 mg/d docosahexaenoic acid in the second half of pregnancy.

PubMed

Stein, Aryeh D; Wang, Meng; Rivera, Juan A; Martorell, Reynaldo; Ramakrishnan, Usha

2012-08-01

The evidence relating prenatal supplementation with DHA to offspring neurological development is limited. We investigated the effect of prenatal DHA supplementation on infant brainstem auditory-evoked responses and visual- evoked potentials in a double-blind, randomized controlled trial in Cuernavaca, Mexico. Pregnant women were supplemented daily with 400 mg DHA or placebo from gestation wk 18-22 through delivery. DHA and placebo groups did not differ in maternal characteristics at randomization or infant characteristics at birth. Brainstem auditory-evoked responses were measured at 1 and 3 mo in 749 and 664 infants, respectively, and visual-evoked potentials were measured at 3 and 6 mo in 679 and 817 infants, respectively. Left-right brainstem auditory-evoked potentials were moderately correlated (range, 0.26-0.43; all P < 0.001) and left-right visual-evoked potentials were strongly correlated (range, 0.79-0.94; all P < 0.001) within any assessment. Correlations across visits were modest to moderate (range, 0.09-0.38; all P < 0.01). The offspring of DHA-supplemented women did not differ from those of control women with respect to any outcome measure (all comparisons P > 0.10). We conclude that DHA supplementation during pregnancy did not influence brainstem auditory-evoked responses at 1 and 3 mo or visual-evoked potentials at 3 and 6 mo.

ROLE OF NMDA, NICOTINIC, AND GABA RECEPTORS IN THE STEADY STATE VISUAL EVOKED POTENTIAL IN RATS.

EPA Science Inventory

This manuscript characterizes the receptor pathways involved in pattern-evoked potential generation in rats

" NMDA and nicotinic acetylcholine receptors appear to be involved in the generation of the steady-state pattern evoked response in vivo.

" The pattern evok...

Maturation of neuronal form and function in a mouse thalamo-cortical circuit.

PubMed

Warren, R A; Jones, E G

1997-01-01

Postnatal development of physiological properties underlying slow intrathalamic oscillations was studied by whole-cell recording from synaptically coupled neurons of the reticular nucleus (RTN) and ventral posterior nucleus (VPN) of mouse brain slices in vitro and compared with the morphological development of dye-injected cells. Between postnatal days 3 and 11 (P3-P11), progressive changes in RTN and VPN neurons included shortening of the membrane time constant, decreasing input resistance, and lowering of the resting membrane potential (RMP). Low-threshold Ca2+ spikes (LTS) were present from P3, but their capacity to sustain multispike bursts was limited before P11. Synaptic responses were evoked in RTN and VPN neurons by electrical stimulation of the internal capsule from P3. Younger RTN neurons responded with a single spike, but their capacity to fire bursts gradually improved as the RMP reached levels below the LTS activation potential. Concomitantly, as the reversal potential of the inhibitory postsynaptic potential in VPN neurons became more negative, its capacity to deinactivate the LTS increased, and rebound bursts that could maintain oscillations were produced; sustained oscillations became the typical response to internal capsule stimulation at P12. The functional maturation of the intrathalamic circuitry, particularly between P10 and P14, occurs in parallel with the morphological maturation (size, dendritic growth, and dendritic field structure) of individual RTN and VPN neurons, as studied by confocal microscopy. Maturation of RTN cells led that of VPN cells by 2-3 d. The appearance of intrathalamic oscillations is probably correlated with the appearance of slow-wave sleep in postnatal animals.

Exploring the Mechanisms of Exercise-Induced Hypoalgesia Using Somatosensory and Laser Evoked Potentials

PubMed Central

Jones, Matthew D.; Taylor, Janet L.; Booth, John; Barry, Benjamin K.

2016-01-01

Exercise-induced hypoalgesia is well described, but the underlying mechanisms are unclear. The aim of this study was to examine the effect of exercise on somatosensory evoked potentials, laser evoked potentials, pressure pain thresholds and heat pain thresholds. These were recorded before and after 3-min of isometric elbow flexion exercise at 40% of the participant's maximal voluntary force, or an equivalent period of rest. Exercise-induced hypoalgesia was confirmed in two experiments (Experiment 1–SEPs; Experiment 2–LEPs) by increased pressure pain thresholds at biceps brachii (24.3 and 20.6% increase in Experiment 1 and 2, respectively; both d > 0.84 and p < 0.001) and first dorsal interosseous (18.8 and 21.5% increase in Experiment 1 and 2, respectively; both d > 0.57 and p < 0.001). In contrast, heat pain thresholds were not significantly different after exercise (forearm: 10.8% increase, d = 0.35, p = 0.10; hand: 3.6% increase, d = 0.06, p = 0.74). Contrasting effects of exercise on the amplitude of laser evoked potentials (14.6% decrease, d = −0.42, p = 0.004) and somatosensory evoked potentials (10.9% increase, d = −0.02, p = 1) were also observed, while an equivalent period of rest showed similar habituation (laser evoked potential: 7.3% decrease, d = −0.25, p = 0.14; somatosensory evoked potential: 20.7% decrease, d = −0.32, p = 0.006). The differential response of pressure pain thresholds and heat pain thresholds to exercise is consistent with relative insensitivity of thermal nociception to the acute hypoalgesic effects of exercise. Conflicting effects of exercise on somatosensory evoked potentials and laser evoked potentials were observed. This may reflect non-nociceptive contributions to the somatosensory evoked potential, but could also indicate that peripheral nociceptors contribute to exercise-induced hypoalgesia. PMID:27965587

Properties of visual evoked potentials to onset of movement on a television screen.

PubMed

Kubová, Z; Kuba, M; Hubacek, J; Vít, F

1990-08-01

In 80 subjects the dependence of movement-onset visual evoked potentials on some measures of stimulation was examined, and these responses were compared with pattern-reversal visual evoked potentials to verify the effectiveness of pattern movement application for visual evoked potential acquisition. Horizontally moving vertical gratings were generated on a television screen. The typical movement-onset reactions were characterized by one marked negative peak only, with a peak time between 140 and 200 ms. In all subjects the sufficient stimulus duration for acquisition of movement-onset-related visual evoked potentials was 100 ms; in some cases it was only 20 ms. Higher velocity (5.6 degree/s) produced higher amplitudes of movement-onset visual evoked potentials than did the lower velocity (2.8 degrees/s). In 80% of subjects, the more distinct reactions were found in the leads from lateral occipital areas (in 60% from the right hemisphere), with no correlation to handedness of subjects. Unlike pattern-reversal visual evoked potentials, the movement-onset responses tended to be larger to extramacular stimulation (annular target of 5 degrees-9 degrees) than to macular stimulation (circular target of 5 degrees diameter).

Neurophysiological detection of impending spinal cord injury during scoliosis surgery.

PubMed

Schwartz, Daniel M; Auerbach, Joshua D; Dormans, John P; Flynn, John; Drummond, Denis S; Bowe, J Andrew; Laufer, Samuel; Shah, Suken A; Bowen, J Richard; Pizzutillo, Peter D; Jones, Kristofer J; Drummond, Denis S

2007-11-01

Despite the many reports attesting to the efficacy of intraoperative somatosensory evoked potential monitoring in reducing the prevalence of iatrogenic spinal cord injury during corrective scoliosis surgery, these afferent neurophysiological signals can provide only indirect evidence of injury to the motor tracts since they monitor posterior column function. Early reports on the use of transcranial electric motor evoked potentials to monitor the corticospinal motor tracts directly suggested that the method holds great promise for improving detection of emerging spinal cord injury. We sought to compare the efficacy of these two methods of monitoring to detect impending iatrogenic neural injury during scoliosis surgery. We reviewed the intraoperative neurophysiological monitoring records of 1121 consecutive patients (834 female and 287 male) with adolescent idiopathic scoliosis (mean age, 13.9 years) treated between 2000 and 2004 at four pediatric spine centers. The same group of experienced surgical neurophysiologists monitored spinal cord function in all patients with use of a standardized multimodality technique with the patient under total intravenous anesthesia. A relevant neurophysiological change (an alert) was defined as a reduction in amplitude (unilateral or bilateral) of at least 50% for somatosensory evoked potentials and at least 65% for transcranial electric motor evoked potentials compared with baseline. Thirty-eight (3.4%) of the 1121 patients had recordings that met the criteria for a relevant signal change (i.e., an alert). Of those thirty-eight patients, seventeen showed suppression of the amplitude of transcranial electric motor evoked potentials in excess of 65% without any evidence of changes in somatosensory evoked potentials. In nine of the thirty-eight patients, the signal change was related to hypotension and was corrected with augmentation of the blood pressure. The remaining twenty-nine patients had an alert that was related directly to a surgical maneuver. Three alerts occurred following segmental vessel clamping, and the remaining twenty-six were related to posterior instrumentation and correction. Nine (35%) of these twenty-six patients with an instrumentation-related alert, or 0.8% of the cohort, awoke with a transient motor and/or sensory deficit. Seven of these nine patients presented solely with a motor deficit, which was detected by intraoperative monitoring of transcranial electric motor evoked potentials in all cases, and two patients had only sensory symptoms. Somatosensory evoked potential monitoring failed to identify a motor deficit in four of the seven patients with a confirmed motor deficit. Furthermore, when changes in somatosensory evoked potentials occurred, they lagged behind the changes in transcranial electric motor evoked potentials by an average of approximately five minutes. With an appropriate response to the alert, the motor or sensory deficit resolved in all nine patients within one to ninety days. This study underscores the advantage of monitoring the spinal cord motor tracts directly by recording transcranial electric motor evoked potentials in addition to somatosensory evoked potentials. Transcranial electric motor evoked potentials are exquisitely sensitive to altered spinal cord blood flow due to either hypotension or a vascular insult. Moreover, changes in transcranial electric motor evoked potentials are detected earlier than are changes in somatosensory evoked potentials, thereby facilitating more rapid identification of impending spinal cord injury.

Two Coincidence Detectors for Spike Timing-Dependent Plasticity in Somatosensory Cortex

PubMed Central

Bender, Vanessa A.; Bender, Kevin J.; Brasier, Daniel J.; Feldman, Daniel E.

2011-01-01

Many cortical synapses exhibit spike timing-dependent plasticity (STDP) in which the precise timing of presynaptic and postsynaptic spikes induces synaptic strengthening [long-term potentiation (LTP)] or weakening [long-term depression (LTD)]. Standard models posit a single, postsynaptic, NMDA receptor-based coincidence detector for LTP and LTD components of STDP. We show instead that STDP at layer 4 to layer 2/3 synapses in somatosensory (S1) cortex involves separate calcium sources and coincidence detection mechanisms for LTP and LTD. LTP showed classical NMDA receptor dependence. LTD was independent of postsynaptic NMDA receptors and instead required group I metabotropic glutamate receptors and calcium from voltage-sensitive channels and IP3 receptor-gated stores. Downstream of postsynaptic calcium, LTD required retrograde endocannabinoid signaling, leading to presynaptic LTD expression, and also required activation of apparently presynaptic NMDA receptors. These LTP and LTD mechanisms detected firing coincidence on ~25 and ~125 ms time scales, respectively, and combined to implement the overall STDP rule. These findings indicate that STDP is not a unitary process and suggest that endocannabinoid-dependent LTD may be relevant to cortical map plasticity. PMID:16624937

Pin1 Modulates the Synaptic Content of NMDA Receptors via Prolyl-Isomerization of PSD-95.

PubMed

Antonelli, Roberta; De Filippo, Roberto; Middei, Silvia; Stancheva, Stefka; Pastore, Beatrice; Ammassari-Teule, Martine; Barberis, Andrea; Cherubini, Enrico; Zacchi, Paola

2016-05-18

Phosphorylation of serine/threonine residues preceding a proline regulates the fate of its targets through postphosphorylation conformational changes catalyzed by the peptidyl-prolyl cis-/trans isomerase Pin1. By flipping the substrate between two different functional conformations, this enzyme exerts a fine-tuning of phosphorylation signals. Pin1 has been detected in dendritic spines and shafts where it regulates protein synthesis required to sustain the late phase of long-term potentiation (LTP). Here, we demonstrate that Pin1 residing in postsynaptic structures can interact with postsynaptic density protein-95 (PSD-95), a key scaffold protein that anchors NMDA receptors (NMDARs) in PSD via GluN2-type receptor subunits. Pin1 recruitment by PSD-95 occurs at specific serine-threonine/proline consensus motifs localized in the linker region connecting PDZ2 to PDZ3 domains. Upon binding, Pin1 triggers structural changes in PSD-95, thus negatively affecting its ability to interact with NMDARs. In electrophysiological experiments, larger NMDA-mediated synaptic currents, evoked in CA1 principal cells by Schaffer collateral stimulation, were detected in hippocampal slices obtained from Pin1(-/-) mice compared with controls. Similar results were obtained in cultured hippocampal cells expressing a PSD-95 mutant unable to undergo prolyl-isomerization, thus indicating that the action of Pin1 on PSD-95 is critical for this effect. In addition, an enhancement in spine density and size was detected in CA1 principal cells of Pin1(-/-) or in Thy-1GFP mice treated with the pharmacological inhibitor of Pin1 catalytic activity PiB.Our data indicate that Pin1 controls synaptic content of NMDARs via PSD-95 prolyl-isomerization and the expression of dendritic spines, both required for LTP maintenance. PSD-95, a membrane-associated guanylate kinase, is the major scaffolding protein at excitatory postsynaptic densities and a potent regulator of synaptic strength and plasticity. The activity of PSD-95 is tightly controlled by several post-translational mechanisms including proline-directed phosphorylation. This signaling cascade regulates the fate of its targets through postphosphorylation conformational modifications catalyzed by the peptidyl-prolyl cis-/trans isomerase Pin1. Here, we uncover a new role of Pin1 in glutamatergic signaling. By interacting with PSD-95, Pin1 dampens PSD-95 ability to complex with NMDARs, thus negatively affecting NMDAR signaling and spine morphology. Our findings further emphasize the emerging role of Pin1 as a key modulator of synaptic transmission. Copyright © 2016 the authors 0270-6474/16/365437-11$15.00/0.

[A Case of Left Vertebral Artery Aneurysm Showing Evoked Potentials on Bilateral Electrode by the Left Vagus Nerve Stimulation to Electromyographic Tracheal Tube].

PubMed

Kadoya, Tatsuo; Uehara, Hirofumi; Yamamoto, Toshinori; Shiraishi, Munehiro; Kinoshita, Yuki; Joyashiki, Takeshi; Enokida, Kengo

2016-02-01

Previously, we reported a case of brainstem cavernous hemangioma showing false positive responses to electromyographic tracheal tube (EMG tube). We concluded that the cause was spontaneous respiration accompanied by vocal cord movement. We report a case of left vertebral artery aneurysm showing evoked potentials on bilateral electrodes by the left vagus nerve stimulation to EMG tube. An 82-year-old woman underwent clipping of a left unruptured vertebral artery-posterior inferior cerebellar artery aneurysm. General anesthesia was induced with remifentanil, propofol and suxamethonium, and was maintained with oxygen, air, remifentanil and propofol. We monitored somatosensory evoked potentials, motor evoked potentials, and electromyogram of the vocal cord. When the manipulation reached brainstem and the instrument touched the left vagus nerve, evoked potentials appeared on bilateral electrodes. EMG tube is equipped with two electrodes on both sides. We concluded that the left vagus nerve stimulation generated evoked potentials of the left laryngeal muscles, and they were simultaneously detected as potential difference between two electrodes on both sides. EMG tube is used to identify the vagus nerve. However, it is necessary to bear in mind that each vagus nerve stimulation inevitably generates evoked potentials on bilateral electrodes.

Combined evoked potentials in co-occuring attention deficit hyperactivity disorder and epilepsy.

PubMed

Major, Zoltán Zsigmond

2011-07-30

Evoked potentials, both stimulus related and event related, show disturbances in attention deficit-hyperactivity disorder and epilepsies, too. This study was designed to evaluate if these potentials are characteristically influenced by the presence of the two diseases, individually, and in the case of co-occurrence. Forty children were included, and four groups were formed, control group, ADHD group, epilepsy group and a group with the comorbidity of epilepsy and ADHD. Epilepsy patients were under proper antiepileptic treatment; ADHD patients were free of specific therapy. Brainstem auditory evoked potentials, visual evoked potentials and auditory P300 evaluation were performed. The latency of the P100 and N135 visual evoked potential components was significantly extended by the presence of epilepsy. If ADHD was concomitantly present, this effect was attenuated. Brainstem auditory evoked potential components were prolonged in the presence of the comorbidity, considering the waves elicited in the brainstem. P300 latencies were prolonged by the presence of co-occurring ADHD and epilepsy. Feedback parameters showed overall reduction of the tested cognitive performances in the ADHD group. Disturbances produced by the presence of ADHD-epilepsy comorbidity reveal hypothetically a linked physiopathological path for both diseases, and offers an approach with possible diagnostic importance, combined evoked potential recordings.

Monitoring somatosensory evoked potentials in spinal cord ischemia-reperfusion injury

PubMed Central

Ji, Yiming; Meng, Bin; Yuan, Chenxi; Yang, Huilin; Zou, Jun

2013-01-01

It remains unclear whether spinal cord ischemia-reperfusion injury caused by ischemia and other non-mechanical factors can be monitored by somatosensory evoked potentials. Therefore, we monitored spinal cord ischemia-reperfusion injury in rabbits using somatosensory evoked potential detection technology. The results showed that the somatosensory evoked potential latency was significantly prolonged and the amplitude significantly reduced until it disappeared during the period of spinal cord ischemia. After reperfusion for 30–180 minutes, the amplitude and latency began to gradually recover; at 360 minutes of reperfusion, the latency showed no significant difference compared with the pre-ischemic value, while the somatosensory evoked potential amplitude in-creased, and severe hindlimb motor dysfunctions were detected. Experimental findings suggest that changes in somatosensory evoked potential latency can reflect the degree of spinal cord ischemic injury, while the amplitude variations are indicators of the late spinal cord reperfusion injury, which provide evidence for the assessment of limb motor function and avoid iatrogenic spinal cord injury. PMID:25206629

USP5/Leon deubiquitinase confines postsynaptic growth by maintaining ubiquitin homeostasis through Ubiquilin.

PubMed

Wang, Chien-Hsiang; Huang, Yi-Chun; Chen, Pei-Yi; Cheng, Ying-Ju; Kao, Hsiu-Hua; Pi, Haiwei; Chien, Cheng-Ting

2017-05-10

Synapse formation and growth are tightly controlled processes. How synaptic growth is terminated after reaching proper size remains unclear. Here, we show that Leon, the Drosophila USP5 deubiquitinase, controls postsynaptic growth. In leon mutants, postsynaptic specializations of neuromuscular junctions are dramatically expanded, including the subsynaptic reticulum, the postsynaptic density, and the glutamate receptor cluster. Expansion of these postsynaptic features is caused by a disruption of ubiquitin homeostasis with accumulation of free ubiquitin chains and ubiquitinated substrates in the leon mutant. Accumulation of Ubiquilin (Ubqn), the ubiquitin receptor whose human homolog ubiquilin 2 is associated with familial amyotrophic lateral sclerosis, also contributes to defects in postsynaptic growth and ubiquitin homeostasis. Importantly, accumulations of postsynaptic proteins cause different aspects of postsynaptic overgrowth in leon mutants. Thus, the deubiquitinase Leon maintains ubiquitin homeostasis and proper Ubqn levels, preventing postsynaptic proteins from accumulation to confine postsynaptic growth.

Neural and receptor cochlear potentials obtained by transtympanic electrocochleography in auditory neuropathy.

PubMed

Santarelli, Rosamaria; Starr, Arnold; Michalewski, Henry J; Arslan, Edoardo

2008-05-01

Transtympanic electrocochleography (ECochG) was recorded bilaterally in children and adults with auditory neuropathy (AN) to evaluate receptor and neural generators. Test stimuli were clicks from 60 to 120dB p.e. SPL. Measures obtained from eight AN subjects were compared to 16 normally hearing children. Receptor cochlear microphonics (CMs) in AN were of normal or enhanced amplitude. Neural compound action potentials (CAPs) and receptor summating potentials (SPs) were identified in five AN ears. ECochG potentials in those ears without CAPs were of negative polarity and of normal or prolonged duration. We used adaptation to rapid stimulus rates to distinguish whether the generators of the negative potentials were of neural or receptor origin. Adaptation in controls resulted in amplitude reduction of CAP twice that of SP without affecting the duration of ECochG potentials. In seven AN ears without CAP and with prolonged negative potential, adaptation was accompanied by reduction of both amplitude and duration of the negative potential to control values consistent with neural generation. In four ears without CAP and with normal duration potentials, adaptation was without effect consistent with receptor generation. In five AN ears with CAP, there was reduction in amplitude of CAP and SP as controls but with a significant decrease in response duration. Three patterns of cochlear potentials were identified in AN: (1) presence of receptor SP without CAP consistent with pre-synaptic disorder of inner hair cells; (2) presence of both SP and CAP consistent with post-synaptic disorder of proximal auditory nerve; (3) presence of prolonged neural potentials without a CAP consistent with post-synaptic disorder of nerve terminals. Cochlear potential measures may identify pre- and post-synaptic disorders of inner hair cells and auditory nerves in AN.

Auditory- and Visual-Evoked Potentials in Mexican Infants Are Not Affected by Maternal Supplementation with 400 mg/d Docosahexaenoic Acid in the Second Half of Pregnancy1234

PubMed Central

Stein, Aryeh D.; Wang, Meng; Rivera, Juan A.; Martorell, Reynaldo; Ramakrishnan, Usha

2012-01-01

The evidence relating prenatal supplementation with DHA to offspring neurological development is limited. We investigated the effect of prenatal DHA supplementation on infant brainstem auditory-evoked responses and visual- evoked potentials in a double-blind, randomized controlled trial in Cuernavaca, Mexico. Pregnant women were supplemented daily with 400 mg DHA or placebo from gestation wk 18–22 through delivery. DHA and placebo groups did not differ in maternal characteristics at randomization or infant characteristics at birth. Brainstem auditory-evoked responses were measured at 1 and 3 mo in 749 and 664 infants, respectively, and visual-evoked potentials were measured at 3 and 6 mo in 679 and 817 infants, respectively. Left-right brainstem auditory-evoked potentials were moderately correlated (range, 0.26–0.43; all P < 0.001) and left-right visual-evoked potentials were strongly correlated (range, 0.79–0.94; all P < 0.001) within any assessment. Correlations across visits were modest to moderate (range, 0.09–0.38; all P < 0.01). The offspring of DHA-supplemented women did not differ from those of control women with respect to any outcome measure (all comparisons P > 0.10). We conclude that DHA supplementation during pregnancy did not influence brainstem auditory-evoked responses at 1 and 3 mo or visual-evoked potentials at 3 and 6 mo. PMID:22739364

Evoked potentials in multiple sclerosis.

PubMed

Kraft, George H

2013-11-01

Before the development of magnetic resonance imaging (MRI), evoked potentials (EPs)-visual evoked potentials, somatosensory evoked potentials, and brain stem auditory evoked responses-were commonly used to determine a second site of disease in patients being evaluated for possible multiple sclerosis (MS). The identification of an area of the central nervous system showing abnormal conduction was used to supplement the abnormal signs identified on the physical examination-thus identifying the "multiple" in MS. This article is a brief overview of additional ways in which central nervous system (CNS) physiology-as measured by EPs-can still contribute value in the management of MS in the era of MRIs. Copyright © 2013 Elsevier Inc. All rights reserved.

Enhanced Stress Response in 5-HT1AR Overexpressing Mice: Altered HPA Function and Hippocampal Long-Term Potentiation.

PubMed

Pilar-Cuéllar, Fuencisla; Vidal, Rebeca; Díaz, Álvaro; Garro-Martínez, Emilio; Linge, Raquel; Castro, Elena; Haberzettl, Robert; Fink, Heidrun; Bert, Bettina; Brosda, Jan; Romero, Beatriz; Crespo-Facorro, Benedicto; Pazos, Ángel

2017-11-15

Postsynaptic 5-HT 1A receptors (5-HT 1A R) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT 1A Rs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT 1A Rs in anxiety response after pre-exposure to an acute stressor. Under basal conditions, 5-HT 1A R overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/glucocorticoid receptor ratio. After pre-exposure to a single stressor, they showed a high anxiety-like response, associated with a blunted increase in corticosterone levels and higher c-Fos activation in the prefrontal cortex. Moreover, these mice also presented a lack of downregulation of hippocampal long-term potentiation after stress exposure. Therefore, higher postsynaptic 5-HT 1A R activation might predispose to a high anxious phenotype and an impaired stress coping behavior.

Delayed and Temporally Imprecise Neurotransmission in Reorganizing Cortical Microcircuits

PubMed Central

Barnes, Samuel J.; Cheetham, Claire E.; Liu, Yan; Bennett, Sophie H.; Albieri, Giorgia; Jorstad, Anne A.; Knott, Graham W.

2015-01-01

Synaptic neurotransmission is modified at cortical connections throughout life. Varying the amplitude of the postsynaptic response is one mechanism that generates flexible signaling in neural circuits. The timing of the synaptic response may also play a role. Here, we investigated whether weakening and loss of an entire connection between excitatory cortical neurons was foreshadowed in the timing of the postsynaptic response. We made electrophysiological recordings in rat primary somatosensory cortex that was undergoing experience-dependent loss of complete local excitatory connections. The synaptic latency of pyramid–pyramid connections, which typically comprise multiple synapses, was longer and more variable. Connection strength and latency were not correlated. Instead, prolonged latency was more closely related to progression of connection loss. The action potential waveform and axonal conduction velocity were unaffected, suggesting that the altered timing of neurotransmission was attributable to a synaptic mechanism. Modeling studies indicated that increasing the latency and jitter at a subset of synapses reduced the number of action potentials fired by a postsynaptic neuron. We propose that prolonged synaptic latency and diminished temporal precision of neurotransmission are hallmarks of impending loss of a cortical connection. PMID:26085628

Ionotropic glutamate receptor GluA4 and T-type calcium channel Cav 3.1 subunits control key aspects of synaptic transmission at the mouse L5B-POm giant synapse.

PubMed

Seol, Min; Kuner, Thomas

2015-12-01

The properties and molecular determinants of synaptic transmission at giant synapses connecting layer 5B (L5B) neurons of the somatosensory cortex (S1) with relay neurons of the posteriomedial nucleus (POm) of the thalamus have not been investigated in mice. We addressed this by using direct electrical stimulation of fluorescently labelled single corticothalamic terminals combined with molecular perturbations and whole-cell recordings from POm relay neurons. Consistent with their function as drivers, we found large-amplitude excitatory postsynaptic currents (EPSCs) and multiple postsynaptic action potentials triggered by a single presynaptic action potential. To study the molecular basis of these two features, ionotropic glutamate receptors and low voltage-gated T-type calcium channels were probed by virus-mediated genetic perturbation. Loss of GluA4 almost abolished the EPSC amplitude, strongly delaying the onset of action potential generation, but maintaining the number of action potentials generated per presynaptic action potential. In contrast, knockdown of the Cav 3.1 subunit abrogated the driver function of the synapse at a typical resting membrane potential of -70 mV. However, when depolarizing the membrane potential to -60 mV, the synapse relayed single action potentials. Hence, GluA4 subunits are required to produce an EPSC sufficiently large to trigger postsynaptic action potentials within a defined time window after the presynaptic action potential, while Cav 3.1 expression is essential to establish the driver function of L5B-POm synapses at hyperpolarized membrane potentials. © 2015 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Combined ocular and cervical vestibular evoked myogenic potential in individuals with vestibular hyporeflexia and in patients with Ménière's disease.

PubMed

Silva, Tatiana Rocha; de Resende, Luciana Macedo; Santos, Marco Aurélio Rocha

The vestibular evoked myogenic potential is a potential of mean latency that measures the muscle response to auditory stimulation. This potential can be generated from the contraction of the sternocleidomastoid muscle and also from the contraction of extraocular muscles in response to high-intensity sounds. This study presents a combined or simultaneous technique of cervical and ocular vestibular evoked myogenic potential in individuals with changes in the vestibular system, for use in otoneurologic diagnosis. To characterize the records and analyze the results of combined cervical and ocular VEMP in individuals with vestibular hyporeflexia and in those with Ménière's disease. The study included 120 subjects: 30 subjects with vestibular hyporeflexia, 30 with Ménière's disease, and 60 individuals with normal hearing. Data collection was performed by simultaneously recording the cervical and ocular vestibular evoked myogenic potential. There were differences between the study groups (individuals with vestibular hyporeflexia and individuals with Ménière's disease) and the control group for most of wave parameters in combined cervical and ocular vestibular evoked myogenic potential. For cervical vestibular evoked myogenic potential, it was observed that the prolongation of latency of the P13 and N23 waves was the most frequent finding in the group with vestibular hyporeflexia and in the group with Ménière's disease. For ocular vestibular evoked myogenic potential, prolonged latency of N10 and P15 waves was the most frequent finding in the study groups. Combined cervical and ocular vestibular evoked myogenic potential presented relevant results for individuals with vestibular hyporeflexia and for those with Ménière's disease. There were differences between the study groups and the control group for most of the wave parameters in combined cervical and ocular vestibular evoked myogenic potential. Copyright © 2016 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Brainstem auditory and somatosensory evoked potentials in relation to clinical and neuroimaging findings in Chiari type 1 malformation.

PubMed

Moncho, Dulce; Poca, Maria-Antonia; Minoves, Teresa; Ferré, Alejandro; Rahnama, Kimia; Sahuquillo, Juan

2015-04-01

The aim of this study was to describe the abnormalities found in the recordings of evoked potentials (EPs), in particular those of brainstem auditory evoked potentials and somatosensory evoked potentials, in a homogeneous series of patients with Chiari type 1 malformation (CM-1) and study their relationship with clinical symptoms and malformation severity. CM-1 is characterized by cerebellar tonsils that descend below the foramen magnum and may be associated with EP alterations. However, only a small number of authors have described these tests in CM-1, and the patient groups studied to date have been small and heterogeneous. The clinical findings, neuroimages, and EP findings were retrospectively studied in a cohort of 50 patients with CM-1. Seventy percent of patients had EP abnormalities (brainstem auditory evoked potential: 52%, posterior tibial nerve somatosensory evoked potential: 42%, and median nerve somatosensory evoked potential: 34%). The most frequent alteration was an increased central conduction time. Morphometric measurements differed between the normal and pathological groups, although no statistical significance was found when comparing these groups. A high percentage of patients with CM-1 show EP alterations regardless of their clinical or radiological findings, thus highlighting the necessity of performing these tests, especially in patients with few or no symptoms.

Calmodulin Activation by Calcium Transients in the Postsynaptic Density of Dendritic Spines

PubMed Central

Keller, Daniel X.; Franks, Kevin M.; Bartol, Thomas M.; Sejnowski, Terrence J.

2008-01-01

The entry of calcium into dendritic spines can trigger a sequence of biochemical reactions that begins with the activation of calmodulin (CaM) and ends with long-term changes to synaptic strengths. The degree of activation of CaM can depend on highly local elevations in the concentration of calcium and the duration of transient increases in calcium concentration. Accurate measurement of these local changes in calcium is difficult because the spaces are so small and the numbers of molecules are so low. We have therefore developed a Monte Carlo model of intracellular calcium dynamics within the spine that included calcium binding proteins, calcium transporters and ion channels activated by voltage and glutamate binding. The model reproduced optical recordings using calcium indicator dyes and showed that without the dye the free intracellular calcium concentration transient was much higher than predicted from the fluorescent signal. Excitatory postsynaptic potentials induced large, long-lasting calcium gradients across the postsynaptic density, which activated CaM. When glutamate was released at the synapse 10 ms before an action potential occurred, simulating activity patterns that strengthen hippocampal synapses, the calcium gradient and activation of CaM in the postsynaptic density were much greater than when the order was reversed, a condition that decreases synaptic strengths, suggesting a possible mechanism underlying the induction of long-term changes in synaptic strength. The spatial and temporal mechanisms for selectivity in CaM activation demonstrated here could be used in other signaling pathways. PMID:18446197

Assessment and Development of Oculomotor Flying Skills by the Application of the Channel Theory of Vision.

DTIC Science & Technology

1983-11-04

visual acuity in amblyopia , using steady-state visual evoked potentials. In J. E. Desmedt (Ed.), Visual evoked potentials in man: new developments... amblyopia by the evoked potential method. Ophthalmologica, 1977s 175, 159-164. 61. Regan, D. & Spekreijse, H. Auditory-visual interactions and the

Postoperative neurological deficits may occur despite unchanged intraoperative somatosensory evoked potentials.

PubMed

Lesser, R P; Raudzens, P; Lüders, H; Nuwer, M R; Goldie, W D; Morris, H H; Dinner, D S; Klem, G; Hahn, J F; Shetter, A G

1986-01-01

We describe 6 patients who demonstrated postoperative neurological deficits despite unchanged somatosensory evoked potentials during intraoperative monitoring. Although there is both experimental and clinical evidence that somatosensory evoked potentials are sensitive to some types of intraoperative mishap, the technique should be employed with an awareness of its possible limitations.

Neurotoxic effects of n-hexane on the human central nervous system: evoked potential abnormalities in n-hexane polyneuropathy.

PubMed Central

Chang, Y C

1987-01-01

An outbreak of n-hexane polyneuropathy as a result of industrial exposure occurred in printing factories in Taipei area from December 1983 to February 1985. Multimodality evoked potentials study was performed on 22 of the polyneuropathy cases, five of the subclinical cases, and seven of the unaffected workers. The absolute and interpeak latencies of patterned visual evoked potential (pVEP) in both the polyneuropathy and subclinical groups were longer than in the normal controls. The pVEP interpeak amplitude was also decreased in the polyneuropathy cases. Brainstem auditory evoked potentials (BAEP), showed no difference of wave I latency between factory workers and normal controls, but prolongation of the wave I-V interpeak latencies was noted, corresponding with the severity of the polyneuropathy. In somatosensory evoked potentials (SEPs), both the absolute latencies and central conduction time (CCT) were longer in subclinical and polyneuropathy cases than in the unaffected workers and normal controls. From this evoked potentials study, chronic toxic effects of n-hexane on the central nervous system were shown. PMID:3031221

Brainstem Auditory Evoked Potential in HIV-Positive Adults.

PubMed

Matas, Carla Gentile; Samelli, Alessandra Giannella; Angrisani, Rosanna Giaffredo; Magliaro, Fernanda Cristina Leite; Segurado, Aluísio C

2015-10-20

To characterize the findings of brainstem auditory evoked potential in HIV-positive individuals exposed and not exposed to antiretroviral treatment. This research was a cross-sectional, observational, and descriptive study. Forty-five HIV-positive individuals (18 not exposed and 27 exposed to the antiretroviral treatment - research groups I and II, respectively - and 30 control group individuals) were assessed through brainstem auditory evoked potential. There were no significant between-group differences regarding wave latencies. A higher percentage of altered brainstem auditory evoked potential was observed in the HIV-positive groups when compared to the control group. The most common alteration was in the low brainstem. HIV-positive individuals have a higher percentage of altered brainstem auditory evoked potential that suggests central auditory pathway impairment when compared to HIV-negative individuals. There was no significant difference between individuals exposed and not exposed to antiretroviral treatment.

Cortico-cortical evoked potentials for sites of early versus late seizure spread in stereoelectroencephalography.

PubMed

Lega, Bradley; Dionisio, Sasha; Flanigan, Patrick; Bingaman, William; Najm, Imad; Nair, Dileep; Gonzalez-Martinez, Jorge

2015-09-01

Cortico-cortical evoked potentials offer the possibility of understanding connectivity within seizure networks to improve diagnosis and more accurately identify candidates for seizure surgery. We sought to determine if cortico-cortical evoked potentials and post-stimulation oscillatory changes differ for sites of EARLY versus LATE ictal spread. 37 patients undergoing stereoelectroencephalography were tested using a cortico-cortical evoked potential paradigm. All electrodes were classified according to the speed of ictal spread. EARLY spread sites were matched to a LATE spread site equidistant from the onset zone. Root-mean-square was used to quantify evoked responses and post-stimulation gamma band power and coherence were extracted and compared. Sites of EARLY spread exhibited significantly greater evoked responses after stimulation across all patients (t(36)=2.973, p=0.004). Stimulation elicited enhanced gamma band activity at EARLY spread sites (t(36)=2.61, p=0.03, FDR corrected); this gamma band oscillation was highly coherent with the onset zone. Cortico-cortical evoked potentials and post-stimulation changes in gamma band activity differ between sites of EARLY versus LATE ictal spread. The oscillatory changes can help visualize connectivity within the seizure network. Copyright © 2015 Elsevier B.V. All rights reserved.

Differential distribution of voltage-gated ion channels in cortical neurons: implications for epilepsy.

PubMed

Child, Nicholas D; Benarroch, Eduardo E

2014-03-18

Neurons contain different functional somatodendritic and axonal domains, each with a characteristic distribution of voltage-gated ion channels, synaptic inputs, and function. The dendritic tree of a cortical pyramidal neuron has 2 distinct domains, the basal and the apical dendrites, both containing dendritic spines; the different domains of the axon are the axonal initial segment (AIS), axon proper (which in myelinated axons includes the node of Ranvier, paranodes, juxtaparanodes, and internodes), and the axon terminals. In the cerebral cortex, the dendritic spines of the pyramidal neurons receive most of the excitatory synapses; distinct populations of γ-aminobutyric acid (GABA)ergic interneurons target specific cellular domains and thus exert different influences on pyramidal neurons. The multiple synaptic inputs reaching the somatodendritic region and generating excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) sum and elicit changes in membrane potential at the AIS, the site of initiation of the action potential.

Excitatory amino acid transporters tonically restrain nTS synaptic and neuronal activity to modulate cardiorespiratory function

PubMed Central

2015-01-01

The nucleus tractus solitarii (nTS) is the initial central termination site for visceral afferents and is important for modulation and integration of multiple reflexes including cardiorespiratory reflexes. Glutamate is the primary excitatory neurotransmitter in the nTS and is removed from the extracellular milieu by excitatory amino acid transporters (EAATs). The goal of this study was to elucidate the role of EAATs in the nTS on basal synaptic and neuronal function and cardiorespiratory regulation. The majority of glutamate clearance in the central nervous system is believed to be mediated by astrocytic EAAT 1 and 2. We confirmed the presence of EAAT 1 and 2 within the nTS and their colocalization with astrocytic markers. EAAT blockade with dl-threo-β-benzyloxyaspartic acid (TBOA) produced a concentration-related depolarization, increased spontaneous excitatory postsynaptic current (EPSC) frequency, and enhanced action potential discharge in nTS neurons. Solitary tract-evoked EPSCs were significantly reduced by EAAT blockade. Microinjection of TBOA into the nTS of anesthetized rats induced apneic, sympathoinhibitory, depressor, and bradycardic responses. These effects mimicked the response to microinjection of exogenous glutamate, and glutamate responses were enhanced by EAAT blockade. Together these data indicate that EAATs tonically restrain nTS excitability to modulate cardiorespiratory function. PMID:26719090

Short-term effects of beta-amyloid25-35 peptide aggregates on transmitter release in neuromuscular synapses.

PubMed

Garcia, Neus; Santafé, Manel M; Tomàs, Marta; Lanuza, Maria A; Tomàs, Josep

2008-03-01

The beta-amyloid (AB) peptide25-35 contains the functional domain of the AB precursor protein that is both required for neurotrophic effects in normal neural tissues and is involved in the neurotoxic effects in Alzheimer disease. We demonstrated the presence of the amyloid precursor protein/AB peptide in intramuscular axons, presynaptic motor nerve terminals, terminal and myelinating Schwann cells, and the postsynaptic and subsarcolemmal region in the Levator auris longus muscle of adult rats by immunocytochemistry. Using intracellular recording, we investigated possible short-term functional effects of the AB fragment (0.1-10 micromol/L) on acetylcholine release in adult and newborn motor end plates. We found no change in evoked, spontaneous transmitter release or resting membrane potential of the muscle cells. A previous block of the presynaptic muscarinic receptor subtypes and a previous block or stimulation of protein kinase C revealed no masked effect of the peptide on the regulation of transmitter release. The aggregated form of AB peptide25-35, however, interfered acutely with acetylcholine release (quantal content reduction) when synaptic activity was maintained by electric stimulation. The possible relevance of this inhibition of neurotransmission by AB peptide25-35 to the pathogenesis of Alzheimer remains to be determined.

Modification of GABA-mediated inhibition by various injectable anesthetics.

PubMed

Albertson, T E; Walby, W F; Joy, R M

1992-09-01

Increasing doses of the injectable anesthetics etomidate, Saffan, thiopental, ketamine, and xylazine and the vehicles saline and propylene glycol were administered to urethane-anesthetized rats. Their effects in vivo on perforant pathway-evoked field excitatory post-synaptic potentials and population spikes in the hippocampal dentate gyrus were determined. The primary purpose was to ascertain whether these compounds affect hippocampal excitability in a manner consistent with their proposed mechanisms of action. Compared with their respective vehicles, thiopental, etomidate, and xylazine reduced the amplitude of population spikes to single perforant pathway stimulation by 20-30% at the highest doses tested. Xylazine also increased the latency to onset of the population spike. No other effects were observed. Using paired pulse paradigms, it was determined that etomidate produced a dramatic, prolonged reduction in granule cell excitability at interpulse intervals of 10-100 ms. The magnitude of the effect was dose related and was reversible with the discontinuance of administration of the drug. Similar changes occurred with Saffan (althesin) and thiopental. Ketamine produced a small but significant depression in granule cell excitability during intervals of 10-200 ms. Xylazine had no effect. These data corroborate the importance of a prolongation of gamma-aminobutyric acid A-mediated inhibition to the mechanism of actions of etomidate, thiopental, and Saffan at relevant exposure concentrations in vivo.

Differential Modifications of Synaptic Weights During Odor Rule Learning: Dynamics of Interaction Between the Piriform Cortex with Lower and Higher Brain Areas

PubMed Central

Cohen, Yaniv; Wilson, Donald A.; Barkai, Edi

2015-01-01

Learning of a complex olfactory discrimination (OD) task results in acquisition of rule learning after prolonged training. Previously, we demonstrated enhanced synaptic connectivity between the piriform cortex (PC) and its ascending and descending inputs from the olfactory bulb (OB) and orbitofrontal cortex (OFC) following OD rule learning. Here, using recordings of evoked field postsynaptic potentials in behaving animals, we examined the dynamics by which these synaptic pathways are modified during rule acquisition. We show profound differences in synaptic connectivity modulation between the 2 input sources. During rule acquisition, the ascending synaptic connectivity from the OB to the anterior and posterior PC is simultaneously enhanced. Furthermore, post-training stimulation of the OB enhanced learning rate dramatically. In sharp contrast, the synaptic input in the descending pathway from the OFC was significantly reduced until training completion. Once rule learning was established, the strength of synaptic connectivity in the 2 pathways resumed its pretraining values. We suggest that acquisition of olfactory rule learning requires a transient enhancement of ascending inputs to the PC, synchronized with a parallel decrease in the descending inputs. This combined short-lived modulation enables the PC network to reorganize in a manner that enables it to first acquire and then maintain the rule. PMID:23960200

Cervical sympathetic block prolongs the latency and reduces the amplitude of trigeminal somatosensory evoked potentials on the contralateral side.

PubMed

Kawaguchi, Jun; Matsuura, Nobuyuki; Kasahara, Masataka; Ichinohe, Tatsuya

2015-02-01

The purpose of this study was to investigate the latency and amplitude of trigeminal somatosensory evoked potentials to clarify how nerve function on the contralateral side is affected after cervical sympathetic block (CSB). Subjects comprised 16 volunteers. For CSB, the tip of a needle was contacted with the transverse process of the sixth cervical vertebra on the right side, and lidocaine was injected. Trigeminal somatosensory evoked potentials were recorded bilaterally from C5/C6 scalp positions. Pupil diameters were also measured. Electrical stimulations were applied to the left-side lower lip, and trigeminal somatosensory evoked potentials waveforms derived from both sides of the scalp were recorded. Then, electrical stimulations were applied to the right-side of the lower lip, and recording was again performed. Recordings were performed at 5, 15, and 30 minutes after CSB. On the CSB side, pupil diameter decreased at 5 and 15 minutes after CSB. Trigeminal somatosensory evoked potentials at contralateral stimulation showed a prolongation of the latency in both P20 and N25 components on bilateral recording sites 5 and 15 minutes after CSB. Trigeminal somatosensory evoked potentials' amplitude at contralateral stimulation was smaller than at ipsilateral stimulation 5 minutes after CSB. Cervical sympathetic block prolongs the latency and reduces the amplitude of trigeminal somatosensory evoked potentials on the contralateral side.

Axonal propagation of simple and complex spikes in cerebellar Purkinje neurons.

PubMed

Khaliq, Zayd M; Raman, Indira M

2005-01-12

In cerebellar Purkinje neurons, the reliability of propagation of high-frequency simple spikes and spikelets of complex spikes is likely to regulate inhibition of Purkinje target neurons. To test the extent to which a one-to-one correspondence exists between somatic and axonal spikes, we made dual somatic and axonal recordings from Purkinje neurons in mouse cerebellar slices. Somatic action potentials were recorded with a whole-cell pipette, and the corresponding axonal signals were recorded extracellularly with a loose-patch pipette. Propagation of spontaneous and evoked simple spikes was highly reliable. At somatic firing rates of approximately 200 spikes/sec, <10% of spikes failed to propagate, with failures becoming more frequent only at maximal somatic firing rates (approximately 260 spikes/sec). Complex spikes were elicited by climbing fiber stimulation, and their somatic waveforms were modulated by tonic current injection, as well as by paired stimulation to depress the underlying EPSCs. Across conditions, the mean number of propagating action potentials remained just above two spikes per climbing fiber stimulation, but the instantaneous frequency of the propagating spikes changed, from approximately 375 Hz during somatic hyperpolarizations that silenced spontaneous firing to approximately 150 Hz during spontaneous activity. The probability of propagation of individual spikelets could be described quantitatively as a saturating function of spikelet amplitude, rate of rise, or preceding interspike interval. The results suggest that ion channels of Purkinje axons are adapted to produce extremely short refractory periods and that brief bursts of forward-propagating action potentials generated by complex spikes may contribute transiently to inhibition of postsynaptic neurons.

Peptidergic contribution to posttetanic potentiation at a central synapse of aplysia.

PubMed

Koh, Hae-Young; Weiss, Klaudiusz R

2005-08-01

Posttetanic potentiation (PTP)-like phenomena appear to be mediated by a variety of mechanisms. Although neuropeptides are located in a large number of neurons and many neuropeptides, like PTP, can enhance synaptic transmission, there is a paucity of studies indicating that peptides may actually participate in PTP. Here, we utilize a single central synapse in the feeding circuit of Aplysia to investigate a possible peptidergic contribution to PTP in the CNS. The cholinergic command-like interneuron, cerebral-buccal interneuron 2 (CBI-2), contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that tetanic prestimulation or repeated stimulation of CBI-2, as well as perfusion of FCAP and CP2, increase the size of the cholinergic excitatory postsynaptic potentials (EPSPs) that CBI-2 evokes in the motoneurons B61/62 and shorten the latency to initiate B61/62 firing in response to CBI-2 stimulation. We used temperature-dependent suppression of peptide release and occlusion experiments to examine the possible contribution of FCAP and CP2 to PTP at the CBI-2 to B61/62 synapse. When peptide release was suppressed, perfusion of exogenous peptides increased the size of posttetanic EPSPs. In contrast, when peptide release was not suppressed, exogenous peptides did not enhance the size of posttetanic EPSPs, thus indicating occlusion. Temperature manipulation and occlusion experiments also indicated that peptides extend PTP duration. This peptide-dependent prolongation of PTP has functional consequences in that it extends the duration of time during which the latency to initiate B61/62 firing in response to CBI-2 stimulation is shortened.

Forced cell cycle exit and modulation of GABAA, CREB, and GSK3β signaling promote functional maturation of induced pluripotent stem cell-derived neurons.

PubMed

Telezhkin, Vsevolod; Schnell, Christian; Yarova, Polina; Yung, Sun; Cope, Emma; Hughes, Alis; Thompson, Belinda A; Sanders, Philip; Geater, Charlene; Hancock, Jane M; Joy, Shona; Badder, Luned; Connor-Robson, Natalie; Comella, Andrea; Straccia, Marco; Bombau, Georgina; Brown, Jon T; Canals, Josep M; Randall, Andrew D; Allen, Nicholas D; Kemp, Paul J

2016-04-01

Although numerous protocols have been developed for differentiation of neurons from a variety of pluripotent stem cells, most have concentrated on being able to specify effectively appropriate neuronal subtypes and few have been designed to enhance or accelerate functional maturity. Of those that have, most employ time courses of functional maturation that are rather protracted, and none have fully characterized all aspects of neuronal function, from spontaneous action potential generation through to postsynaptic receptor maturation. Here, we describe a simple protocol that employs the sequential addition of just two supplemented media that have been formulated to separate the two key phases of neural differentiation, the neurogenesis and synaptogenesis, each characterized by different signaling requirements. Employing these media, this new protocol synchronized neurogenesis and enhanced the rate of maturation of pluripotent stem cell-derived neural precursors. Neurons differentiated using this protocol exhibited large cell capacitance with relatively hyperpolarized resting membrane potentials; moreover, they exhibited augmented: 1) spontaneous electrical activity; 2) regenerative induced action potential train activity; 3) Na(+) current availability, and 4) synaptic currents. This was accomplished by rapid and uniform development of a mature, inhibitory GABAAreceptor phenotype that was demonstrated by Ca(2+) imaging and the ability of GABAAreceptor blockers to evoke seizurogenic network activity in multielectrode array recordings. Furthermore, since this protocol can exploit expanded and frozen prepatterned neural progenitors to deliver mature neurons within 21 days, it is both scalable and transferable to high-throughput platforms for the use in functional screens. Copyright © 2016 the American Physiological Society.

Long-term modifications of synaptic efficacy in the human inferior and middle temporal cortex

NASA Technical Reports Server (NTRS)

Chen, W. R.; Lee, S.; Kato, K.; Spencer, D. D.; Shepherd, G. M.; Williamson, A.

1996-01-01

The primate temporal cortex has been demonstrated to play an important role in visual memory and pattern recognition. It is of particular interest to investigate whether activity-dependent modification of synaptic efficacy, a presumptive mechanism for learning and memory, is present in this cortical region. Here we address this issue by examining the induction of synaptic plasticity in surgically resected human inferior and middle temporal cortex. The results show that synaptic strength in the human temporal cortex could undergo bidirectional modifications, depending on the pattern of conditioning stimulation. High frequency stimulation (100 or 40 Hz) in layer IV induced long-term potentiation (LTP) of both intracellular excitatory postsynaptic potentials and evoked field potentials in layers II/III. The LTP induced by 100 Hz tetanus was blocked by 50-100 microM DL-2-amino-5-phosphonovaleric acid, suggesting that N-methyl-D-aspartate receptors were responsible for its induction. Long-term depression (LTD) was elicited by prolonged low frequency stimulation (1 Hz, 15 min). It was reduced, but not completely blocked, by DL-2-amino-5-phosphonovaleric acid, implying that some other mechanisms in addition to N-methyl-DL-aspartate receptors were involved in LTD induction. LTD was input-specific, i.e., low frequency stimulation of one pathway produced LTD of synaptic transmission in that pathway only. Finally, the LTP and LTD could reverse each other, suggesting that they can act cooperatively to modify the functional state of cortical network. These results suggest that LTP and LTD are possible mechanisms for the visual memory and pattern recognition functions performed in the human temporal cortex.

KCNQ/Kv7 channel activator flupirtine protects against acute stress-induced impairments of spatial memory retrieval and hippocampal LTP in rats.

PubMed

Li, C; Huang, P; Lu, Q; Zhou, M; Guo, L; Xu, X

2014-11-07

Spatial memory retrieval and hippocampal long-term potentiation (LTP) are impaired by stress. KCNQ/Kv7 channels are closely associated with memory and the KCNQ/Kv7 channel activator flupirtine represents neuroprotective effects. This study aims to test whether KCNQ/Kv7 channel activation prevents acute stress-induced impairments of spatial memory retrieval and hippocampal LTP. Rats were placed on an elevated platform in the middle of a bright room for 30 min to evoke acute stress. The expression of KCNQ/Kv7 subunits was analyzed at 1, 3 and 12 h after stress by Western blotting. Spatial memory was examined by the Morris water maze (MWM) and the field excitatory postsynaptic potential (fEPSP) in the hippocampal CA1 area was recorded in vivo. Acute stress transiently decreased the expression of KCNQ2 and KCNQ3 in the hippocampus. Acute stress impaired the spatial memory retrieval and hippocampal LTP, the KCNQ/Kv7 channel activator flupirtine prevented the impairments, and the protective effects of flupirtine were blocked by XE-991 (10,10-bis(4-Pyridinylmethyl)-9(10H)-anthracenone), a selective KCNQ channel blocker. Furthermore, acute stress decreased the phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9 in the hippocampus, and flupirtine inhibited the reduction. These results suggest that the KCNQ/Kv7 channels may be a potential target for protecting both hippocampal synaptic plasticity and spatial memory retrieval from acute stress influences. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

G protein betagamma-subunits activated by serotonin mediate presynaptic inhibition by regulating vesicle fusion properties.

PubMed

Photowala, Huzefa; Blackmer, Trillium; Schwartz, Eric; Hamm, Heidi E; Alford, Simon

2006-03-14

Neurotransmitters are thought to be released as quanta, where synaptic vesicles deliver packets of neurotransmitter to the synaptic cleft by fusion with the plasma membrane. However, synaptic vesicles may undergo incomplete fusion. We provide evidence that G protein-coupled receptors inhibit release by causing such incomplete fusion. 5-hydroxytryptamine (5-HT) receptor signaling potently inhibits excitatory postsynaptic currents (EPSCs) between lamprey reticulospinal axons and their postsynaptic targets by a direct action on the vesicle fusion machinery. We show that 5-HT receptor-mediated presynaptic inhibition, at this synapse, involves a reduction in EPSC quantal size. Quantal size was measured directly by comparing unitary quantal amplitudes of paired EPSCs before and during 5-HT application and indirectly by determining the effect of 5-HT on the relationship between mean-evoked EPSC amplitude and variance. Results from FM dye-labeling experiments indicate that 5-HT prevents full fusion of vesicles. 5-HT reduces FM1-43 staining of vesicles with a similar efficacy to its effect on the EPSC. However, destaining of FM1-43-labeled vesicles is abolished by lower concentrations of 5-HT that leave a substantial EPSC. The use of a water-soluble membrane impermeant quenching agent in the extracellular space reduced FM1-43 fluorescence during stimulation in 5-HT. Thus vesicles contact the extracellular space during inhibition of synaptic transmission by 5-HT. We conclude that 5-HT, via free Gbetagamma, prevents the collapse of synaptic vesicles into the presynaptic membrane.

Modulation of nociceptive dural input to the trigeminocervical complex through GluK1 kainate receptors.

PubMed

Andreou, Anna P; Holland, Philip R; Lasalandra, Michele P; Goadsby, Peter J

2015-03-01

Migraine is a common and disabling neurologic disorder, with important psychiatric comorbidities. Its pathophysiology involves activation of neurons in the trigeminocervical complex (TCC). Kainate receptors carrying the glutamate receptor subunit 5 (GluK1) are present in key brain areas involved in migraine pathophysiology. To study the influence of kainate receptors on trigeminovascular neurotransmission, we determined the presence of GluK1 receptors within the trigeminal ganglion and TCC with immunohistochemistry. We performed in vivo electrophysiologic recordings from TCC neurons and investigated whether local or systemic application of GluK1 receptor antagonists modulated trigeminovascular transmission. Microiontophoretic application of a selective GluK1 receptor antagonist, but not of a nonspecific ionotropic glutamate receptor antagonist, markedly attenuated cell firing in a subpopulation of neurons activated in response to dural stimulation, consistent with selective inhibition of postsynaptic GluK1 receptor-evoked firing seen in all recorded neurons. In contrast, trigeminovascular activation was significantly facilitated in a different neuronal population. The clinically active kainate receptor antagonist LY466195 attenuated trigeminovascular activation in all neurons. In addition, LY466195 demonstrated an N-methyl-d-aspartate receptor-mediated effect. This study demonstrates a differential role of GluK1 receptors in the TCC, antagonism of which can inhibit trigeminovascular activation through postsynaptic mechanisms. Furthermore, the data suggest a novel, possibly presynaptic, modulatory role of trigeminocervical kainate receptors in vivo. Differential activation of kainate receptors suggests unique roles for this receptor in pro- and antinociceptive mechanisms in migraine pathophysiology.

Neuroanatomy and neurophysiology related to sexual dysfunction in male neurogenic patients with lesions to the spinal cord or peripheral nerves.

PubMed

Everaert, K; de Waard, W I Q; Van Hoof, T; Kiekens, C; Mulliez, T; D'herde, C

2010-03-01

Review article. The neuroanatomy and physiology of psychogenic erection, cholinergic versus adrenergic innervation of emission and the predictability of outcome of vibration and electroejaculation require a review and synthesis. University Hospital Belgium. We reviewed the literature with PubMed 1973-2008. Erection, emission and ejaculation are separate phenomena and have different innervations. It is important to realize, which are the afferents and efferents and where the motor neuron of the end organ is located. When interpreting a specific lesion it is important to understand if postsynaptic fibres are intact or not. Afferents of erection, emission and ejaculation are the pudendal nerve and descending pathways from the brain. Erection is cholinergic and NO-mediated. Emission starts cholinergically (as a secretion) and ends sympathetically (as a contraction). Ejaculation is mainly adrenergic and somatic. For vibratory-evoked ejaculation, the reflex arch must be complete; for electroejaculation, the postsynaptic neurons (paravertebral ganglia) must be intact. Afferents of erection, emission and ejaculation are the pudendal nerve and descending pathways from the brain. Erection is cholinergic and NO-mediated. Emission starts cholinergically (as a secretion) and ends sympathetically (as a contraction). Ejaculation is mainly adrenergic and somatic. In neurogenic disease, a good knowledge of neuroanatomy and physiology makes understanding of sexual dysfunction possible and predictable. The minimal requirement for the success of penile vibration is a preserved reflex arch and the minimal requirement for the success of electroejaculation is the existence of intact post-ganglionic fibres.

Synaptic plasticity in a cerebellum-like structure depends on temporal order

NASA Astrophysics Data System (ADS)

Bell, Curtis C.; Han, Victor Z.; Sugawara, Yoshiko; Grant, Kirsty

1997-05-01

Cerebellum-like structures in fish appear to act as adaptive sensory processors, in which learned predictions about sensory input are generated and subtracted from actual sensory input, allowing unpredicted inputs to stand out1-3. Pairing sensory input with centrally originating predictive signals, such as corollary discharge signals linked to motor commands, results in neural responses to the predictive signals alone that are Negative images' of the previously paired sensory responses. Adding these 'negative images' to actual sensory inputs minimizes the neural response to predictable sensory features. At the cellular level, sensory input is relayed to the basal region of Purkinje-like cells, whereas predictive signals are relayed by parallel fibres to the apical dendrites of the same cells4. The generation of negative images could be explained by plasticity at parallel fibre synapses5-7. We show here that such plasticity exists in the electrosensory lobe of mormyrid electric fish and that it has the necessary properties for such a model: it is reversible, anti-hebbian (excitatory postsynaptic potentials (EPSPs) are depressed after pairing with a postsynaptic spike) and tightly dependent on the sequence of pre- and postsynaptic events, with depression occurring only if the postsynaptic spike follows EPSP onset within 60 ms.

Postsynaptic activity reverses the sign of the acetylcholine-induced long-term plasticity of GABAA inhibition

PubMed Central

Domínguez, Soledad; Fernández de Sevilla, David; Buño, Washington

2014-01-01

Acetylcholine (ACh) regulates forms of plasticity that control cognitive functions but the underlying mechanisms remain largely unknown. ACh controls the intrinsic excitability, as well as the synaptic excitation and inhibition of CA1 hippocampal pyramidal cells (PCs), cells known to participate in circuits involved in cognition and spatial navigation. However, how ACh regulates inhibition in function of postsynaptic activity has not been well studied. Here we show that in rat PCs, a brief pulse of ACh or a brief stimulation of cholinergic septal fibers combined with repeated depolarization induces strong long-term enhancement of GABAA inhibition (GABAA-LTP). Indeed, this enhanced inhibition is due to the increased activation of α5βγ2 subunit-containing GABAA receptors by the GABA released. GABAA-LTP requires the activation of M1-muscarinic receptors and an increase in cytosolic Ca2+. In the absence of PC depolarization ACh triggered a presynaptic depolarization-induced suppression of inhibition (DSI), revealing that postsynaptic activity gates the effects of ACh from presynaptic DSI to postsynaptic LTP. These results provide key insights into mechanisms potentially linked with cognitive functions, spatial navigation, and the homeostatic control of abnormal hyperexcitable states. PMID:24938789

Click- and chirp-evoked human compound action potentials

PubMed Central

Chertoff, Mark; Lichtenhan, Jeffery; Willis, Marie

2010-01-01

In the experiments reported here, the amplitude and the latency of human compound action potentials (CAPs) evoked from a chirp stimulus are compared to those evoked from a traditional click stimulus. The chirp stimulus was created with a frequency sweep to compensate for basilar membrane traveling wave delay using the O-Chirp equations from Fobel and Dau [(2004). J. Acoust. Soc. Am. 116, 2213–2222] derived from otoacoustic emission data. Human cochlear traveling wave delay estimates were obtained from derived compound band action potentials provided by Eggermont [(1979). J. Acoust. Soc. Am. 65, 463–470]. CAPs were recorded from an electrode placed on the tympanic membrane (TM), and the acoustic signals were monitored with a probe tube microphone attached to the TM electrode. Results showed that the amplitude and latency of chirp-evoked N1 of the CAP differed from click-evoked CAPs in several regards. For the chirp-evoked CAP, the N1 amplitude was significantly larger than the click-evoked N1s. The latency-intensity function was significantly shallower for chirp-evoked CAPs as compared to click-evoked CAPs. This suggests that auditory nerve fibers respond with more unison to a chirp stimulus than to a click stimulus. PMID:21117748

Neuromodulated Spike-Timing-Dependent Plasticity, and Theory of Three-Factor Learning Rules.

PubMed

Frémaux, Nicolas; Gerstner, Wulfram

2015-01-01

Classical Hebbian learning puts the emphasis on joint pre- and postsynaptic activity, but neglects the potential role of neuromodulators. Since neuromodulators convey information about novelty or reward, the influence of neuromodulators on synaptic plasticity is useful not just for action learning in classical conditioning, but also to decide "when" to create new memories in response to a flow of sensory stimuli. In this review, we focus on timing requirements for pre- and postsynaptic activity in conjunction with one or several phasic neuromodulatory signals. While the emphasis of the text is on conceptual models and mathematical theories, we also discuss some experimental evidence for neuromodulation of Spike-Timing-Dependent Plasticity. We highlight the importance of synaptic mechanisms in bridging the temporal gap between sensory stimulation and neuromodulatory signals, and develop a framework for a class of neo-Hebbian three-factor learning rules that depend on presynaptic activity, postsynaptic variables as well as the influence of neuromodulators.

Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission

NASA Astrophysics Data System (ADS)

Accardi, Michael V.; Daniels, Bryan A.; Brown, Patricia M. G. E.; Fritschy, Jean-Marc; Tyagarajan, Shiva K.; Bowie, Derek

2014-01-01

Neuronal communication imposes a heavy metabolic burden in maintaining ionic gradients essential for action potential firing and synaptic signalling. Although cellular metabolism is known to regulate excitatory neurotransmission, it is still unclear whether the brain’s energy supply affects inhibitory signalling. Here we show that mitochondrial-derived reactive oxygen species (mROS) regulate the strength of postsynaptic GABAA receptors at inhibitory synapses of cerebellar stellate cells. Inhibition is strengthened through a mechanism that selectively recruits α3-containing GABAA receptors into synapses with no discernible effect on resident α1-containing receptors. Since mROS promotes the emergence of postsynaptic events with unique kinetic properties, we conclude that newly recruited α3-containing GABAA receptors are activated by neurotransmitter released onto discrete postsynaptic sites. Although traditionally associated with oxidative stress in neurodegenerative disease, our data identify mROS as a putative homeostatic signalling molecule coupling cellular metabolism to the strength of inhibitory transmission.

Melatonin potentiates glycine currents through a PLC/PKC signalling pathway in rat retinal ganglion cells.

PubMed

Zhao, Wen-Jie; Zhang, Min; Miao, Yanying; Yang, Xiong-Li; Wang, Zhongfeng

2010-07-15

In vertebrate retina, melatonin regulates various physiological functions. In this work we investigated the mechanisms underlying melatonin-induced potentiation of glycine currents in rat retinal ganglion cells (RGCs). Immunofluorescence double labelling showed that rat RGCs were solely immunoreactive to melatonin MT(2) receptors. Melatonin potentiated glycine currents of RGCs, which was reversed by the MT(2) receptor antagonist 4-P-PDOT. The melatonin effect was blocked by intracellular dialysis of GDP-beta-S. Either preincubation with pertussis toxin or application of the phosphatidylcholine (PC)-specific phospholipase C (PLC) inhibitor D609, but not the phosphatidylinositol (PI)-PLC inhibitor U73122, blocked the melatonin effect. The protein kinase C (PKC) activator PMA potentiated the glycine currents and in the presence of PMA melatonin failed to cause further potentiation of the currents, whereas application of the PKC inhibitor bisindolylmaleimide IV abolished the melatonin-induced potentiation. The melatonin effect persisted when [Ca(2+)](i) was chelated by BAPTA, and melatonin induced no increase in [Ca(2+)](i). Neither cAMP-PKA nor cGMP-PKG signalling pathways seemed to be involved because 8-Br-cAMP or 8-Br-cGMP failed to cause potentiation of the glycine currents and both the PKA inhibitor H-89 and the PKG inhibitor KT5823 did not block the melatonin-induced potentiation. In consequence, a distinct PC-PLC/PKC signalling pathway, following the activation of G(i/o)-coupled MT(2) receptors, is most likely responsible for the melatonin-induced potentiation of glycine currents of rat RGCs. Furthermore, in rat retinal slices melatonin potentiated light-evoked glycine receptor-mediated inhibitory postsynaptic currents in RGCs. These results suggest that melatonin, being at higher levels at night, may help animals to detect positive or negative contrast in night vision by modulating inhibitory signals largely mediated by glycinergic amacrine cells in the inner retina.

Melatonin potentiates glycine currents through a PLC/PKC signalling pathway in rat retinal ganglion cells

PubMed Central

Zhao, Wen-Jie; Zhang, Min; Miao, Yanying; Yang, Xiong-Li; Wang, Zhongfeng

2010-01-01

In vertebrate retina, melatonin regulates various physiological functions. In this work we investigated the mechanisms underlying melatonin-induced potentiation of glycine currents in rat retinal ganglion cells (RGCs). Immunofluorescence double labelling showed that rat RGCs were solely immunoreactive to melatonin MT2 receptors. Melatonin potentiated glycine currents of RGCs, which was reversed by the MT2 receptor antagonist 4-P-PDOT. The melatonin effect was blocked by intracellular dialysis of GDP-β-S. Either preincubation with pertussis toxin or application of the phosphatidylcholine (PC)-specific phospholipase C (PLC) inhibitor D609, but not the phosphatidylinositol (PI)-PLC inhibitor U73122, blocked the melatonin effect. The protein kinase C (PKC) activator PMA potentiated the glycine currents and in the presence of PMA melatonin failed to cause further potentiation of the currents, whereas application of the PKC inhibitor bisindolylmaleimide IV abolished the melatonin-induced potentiation. The melatonin effect persisted when [Ca2+]i was chelated by BAPTA, and melatonin induced no increase in [Ca2+]i. Neither cAMP-PKA nor cGMP-PKG signalling pathways seemed to be involved because 8-Br-cAMP or 8-Br-cGMP failed to cause potentiation of the glycine currents and both the PKA inhibitor H-89 and the PKG inhibitor KT5823 did not block the melatonin-induced potentiation. In consequence, a distinct PC-PLC/PKC signalling pathway, following the activation of Gi/o-coupled MT2 receptors, is most likely responsible for the melatonin-induced potentiation of glycine currents of rat RGCs. Furthermore, in rat retinal slices melatonin potentiated light-evoked glycine receptor-mediated inhibitory postsynaptic currents in RGCs. These results suggest that melatonin, being at higher levels at night, may help animals to detect positive or negative contrast in night vision by modulating inhibitory signals largely mediated by glycinergic amacrine cells in the inner retina. PMID:20519319

Motor Training Promotes Both Synaptic and Intrinsic Plasticity of Layer II/III Pyramidal Neurons in the Primary Motor Cortex

PubMed Central

Kida, Hiroyuki; Tsuda, Yasumasa; Ito, Nana; Yamamoto, Yui; Owada, Yuji; Kamiya, Yoshinori; Mitsushima, Dai

2016-01-01

Motor skill training induces structural plasticity at dendritic spines in the primary motor cortex (M1). To further analyze both synaptic and intrinsic plasticity in the layer II/III area of M1, we subjected rats to a rotor rod test and then prepared acute brain slices. Motor skill consistently improved within 2 days of training. Voltage clamp analysis showed significantly higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate (AMPA/NMDA) ratios and miniature EPSC amplitudes in 1-day trained rats compared with untrained rats, suggesting increased postsynaptic AMPA receptors in the early phase of motor learning. Compared with untrained controls, 2-days trained rats showed significantly higher miniature EPSC amplitude and frequency. Paired-pulse analysis further demonstrated lower rates in 2-days trained rats, suggesting increased presynaptic glutamate release during the late phase of learning. One-day trained rats showed decreased miniature IPSC frequency and increased paired-pulse analysis of evoked IPSC, suggesting a transient decrease in presynaptic γ-aminobutyric acid (GABA) release. Moreover, current clamp analysis revealed lower resting membrane potential, higher spike threshold, and deeper afterhyperpolarization in 1-day trained rats—while 2-days trained rats showed higher membrane potential, suggesting dynamic changes in intrinsic properties. Our present results indicate dynamic changes in glutamatergic, GABAergic, and intrinsic plasticity in M1 layer II/III neurons after the motor training. PMID:27193420

Motor Training Promotes Both Synaptic and Intrinsic Plasticity of Layer II/III Pyramidal Neurons in the Primary Motor Cortex.

PubMed

Kida, Hiroyuki; Tsuda, Yasumasa; Ito, Nana; Yamamoto, Yui; Owada, Yuji; Kamiya, Yoshinori; Mitsushima, Dai

2016-08-01

Motor skill training induces structural plasticity at dendritic spines in the primary motor cortex (M1). To further analyze both synaptic and intrinsic plasticity in the layer II/III area of M1, we subjected rats to a rotor rod test and then prepared acute brain slices. Motor skill consistently improved within 2 days of training. Voltage clamp analysis showed significantly higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate (AMPA/NMDA) ratios and miniature EPSC amplitudes in 1-day trained rats compared with untrained rats, suggesting increased postsynaptic AMPA receptors in the early phase of motor learning. Compared with untrained controls, 2-days trained rats showed significantly higher miniature EPSC amplitude and frequency. Paired-pulse analysis further demonstrated lower rates in 2-days trained rats, suggesting increased presynaptic glutamate release during the late phase of learning. One-day trained rats showed decreased miniature IPSC frequency and increased paired-pulse analysis of evoked IPSC, suggesting a transient decrease in presynaptic γ-aminobutyric acid (GABA) release. Moreover, current clamp analysis revealed lower resting membrane potential, higher spike threshold, and deeper afterhyperpolarization in 1-day trained rats-while 2-days trained rats showed higher membrane potential, suggesting dynamic changes in intrinsic properties. Our present results indicate dynamic changes in glutamatergic, GABAergic, and intrinsic plasticity in M1 layer II/III neurons after the motor training. © The Author 2016. Published by Oxford University Press.

NMDA-receptor dependent synaptic activation of TRPC channels in olfactory bulb granule cells

PubMed Central

Stroh, Olga; Freichel, Marc; Kretz, Oliver; Birnbaumer, Lutz; Hartmann, Jana; Egger, Veronica

2012-01-01

TRPC channels are widely expressed throughout the nervous system including the olfactory bulb where their function is largely unknown. Here we describe their contribution to central synaptic processing at the reciprocal mitral and tufted cell - granule cell microcircuit, the most abundant synapse of the mammalian olfactory bulb. Suprathreshold activation of the synapse causes sodium action potentials in mouse granule cells and a subsequent long-lasting depolarization (LLD) linked to a global dendritic postsynaptic calcium signal recorded with two-photon laser scanning microscopy. These signals are not observed after action potentials evoked by current injection in the same cells. The LLD persists in the presence of group I metabotropic glutamate receptor antagonists but is entirely absent from granule cells deficient for the NMDA receptor subunit NR1. Moreover, both depolarization and Ca2+ rise are sensitive to the blockade of NMDA receptors. The LLD and the accompanying Ca2+ rise are also absent in granule cells from mice deficient for both TRPC channel subtypes 1 and 4, whereas the deletion of either TRPC1 or TRPC4 results in only a partial reduction of the LLD. Recordings from mitral cells in the absence of both subunits reveal a reduction of asynchronous neurotransmitter release from the granule cells during recurrent inhibition. We conclude that TRPC1 and TRPC4 can be activated downstream of NMDA receptor activation and contribute to slow synaptic transmission in the olfactory bulb, including the calcium dynamics required for asynchronous release from the granule cell spine. PMID:22539836

Chronic intermittent hypoxia-hypercapnia blunts heart rate responses and alters neurotransmission to cardiac vagal neurons.

PubMed

Dyavanapalli, Jhansi; Jameson, Heather; Dergacheva, Olga; Jain, Vivek; Alhusayyen, Mona; Mendelowitz, David

2014-07-01

Patients with obstructive sleep apnoea experience chronic intermittent hypoxia-hypercapnia (CIHH) during sleep that elicit sympathetic overactivity and diminished parasympathetic activity to the heart, leading to hypertension and depressed baroreflex sensitivity. The parasympathetic control of heart rate arises from pre-motor cardiac vagal neurons (CVNs) located in nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMNX). The mechanisms underlying diminished vagal control of heart rate were investigated by studying the changes in blood pressure, heart rate, and neurotransmission to CVNs evoked by acute hypoxia-hypercapnia (H-H) and CIHH. In vivo telemetry recordings of blood pressure and heart rate were obtained in adult rats during 4 weeks of CIHH exposure. Retrogradely labelled CVNs were identified in an in vitro brainstem slice preparation obtained from adult rats exposed either to air or CIHH for 4 weeks. Postsynaptic inhibitory or excitatory currents were recorded using whole cell voltage clamp techniques. Rats exposed to CIHH had increases in blood pressure, leading to hypertension, and blunted heart rate responses to acute H-H. CIHH induced an increase in GABAergic and glycinergic neurotransmission to CVNs in NA and DMNX, respectively; and a reduction in glutamatergic neurotransmission to CVNs in both nuclei. CIHH blunted the bradycardia evoked by acute H-H and abolished the acute H-H evoked inhibition of GABAergic transmission while enhancing glycinergic neurotransmission to CVNs in NA. These changes with CIHH inhibit CVNs and vagal outflow to the heart, both in acute and chronic exposures to H-H, resulting in diminished levels of cardioprotective parasympathetic activity to the heart as seen in OSA patients. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Presynaptic Muscarinic M2 Receptors Modulate Glutamatergic Transmission in the Bed Nucleus of the Stria Terminalis

PubMed Central

Guo, Ji-Dong; Hazra, Rimi; Dabrowska, Joanna; Muly, E. Chris; Wess, Jürgen; Rainnie, Donald G.

2012-01-01

The anterolateral cell group of the bed nucleus of the stria terminalis (BNSTALG) serves as an important relay station in stress circuitry. Limbic inputs to the BNSTALG are primarily glutamatergic and activity-dependent changes in this input have been implicated in abnormal behaviors associated with chronic stress and addiction. Significantly, local infusion of acetylcholine (ACh) receptor agonists into the BNST trigger stress-like cardiovascular responses, however, little is known about the effects of these agents on glutamatergic transmission in the BNSTALG. Here, we show that glutamate- and ACh-containing fibers are found in close association in the BNSTALG. Moreover, in the presence of the acetylcholinesterase inhibitor, eserine, endogenous ACh release evoked a long-lasting reduction of the amplitude of stimulus-evoked EPSCs. This effect was mimicked by exogenous application of the ACh analogue, carbachol, which caused a reversible, dose-dependent, reduction of the evoked EPSC amplitude, and an increase in both the paired pulse ratio and coefficient of variation, suggesting a presynaptic site of action. Uncoupling of postsynaptic G-proteins with intracellular GDP-β-S, or application of the nicotinic receptor antagonist, tubocurarine, failed to block the carbachol effect. In contrast, the carbachol effect was blocked by prior application of atropine or M2 receptor-preferring antagonists, and was absent in M2/M4 receptor knockout mice, suggesting that presynaptic M2 receptors mediate the effect of ACh. Immuno-electron microscopy studies further revealed the presence of M2 receptors on axon terminals that formed asymmetric synapses with BNST neurons. Our findings suggest that presynaptic M2 receptors might be an important modulator of the stress circuit and hence a novel target for drug development. PMID:22166222

[The algorithms and development for the extraction of evoked potentials].

PubMed

Niu, Jie; Qiu, Tianshuang

2004-06-01

The extraction of evoked potentials is a main subject in the area of brain signal processing. In recent years, the single-trial extraction of evoked potentials has been focused on by many studies. In this paper, the approaches based on the wavelet transform, the neural network, the high order acumulants and the independent component analysis are briefly reviewed.

Human cerebral potentials evoked by moving dynamic random dot stereograms.

PubMed

Herpers, M J; Caberg, H B; Mol, J M

1981-07-01

In 11 normal healthy human subjects an evoked potential was elicited by moving dynamic random dot stereograms. The random dots were generated by a minicomputer. An average of each of 8 EEG channels of the subjects tested was made. The maximum of the cerebral evoked potentials thus found was localized in the central and parietal region. No response earlier than 130--150 msec after the stimulus could be proved. The influence of fixation, the number of dots provided, an interocular interstimulus interval in the presentation of the dots, and lense accommodation movements on the evoked stereoptic potentials was investigated and discussed. An interocular interstimulus interval (left eye leading) in the presentation of the dots caused an increase in latency of the response much longer than the imposed interstimulus interval itself. It was shown that no accommodation was needed to perceive the depth impression, and to evoke the cerebral response with random dot stereograms. There are indications of an asymmetry between the two hemispheres in the handling of depth perception after 250 msec. The potential distribution of the evoked potentials strongly suggests that they are not generated in the occipital region.

[Application of evoked potentials monitoring in total thoracoabdominal aorta aneurysm repair].

PubMed

Duan, Y Y; Zheng, J; Pan, X D; Zhu, J M; Liu, Y M; Ge, Y P; Cheng, L J; Sun, L Z

2016-04-05

To evaluate the application value of evoked potentials (EP) monitoring in patients undergoing aorta-iliac bypass for total thoracoabdominal aorta aneurysm repair (tTAAAR). A prospective study, with a total of 31 patients undergoing tTAAAR and intraoperative EP monitoring from June 2014 to April 2015 was carried out. The results of intraoperative evoked potentials, clinical outcomes and follow-up data of patients were collected for further evaluation. The EP wave disappeared [motor evoked potentials for (55.6±18.1) min, somatosensory evoked potentials for (50.3±18.7) min] after proximal descending aorta being clamped, and gradually recovered after the segment arteries of spine cord were reconstructed. The EP wave was restored to normal level at the end of operation in all the cases. The somatosensory evoked potentials remained unchanged in 2 cases (false negative). One case died after operation. No spinal cord injury occurred. The median follow-up after operation was 10 months (5-14 months). There was no delayed neurological deficit. EP provided an on-line monitoring of the condition of spinal cord function, which become an intraoperative protocol to avoid the irreversible injury of spinal cord.

Objective correlate of subjective pain perception by contact heat-evoked potentials.

PubMed

Granovsky, Yelena; Granot, Michal; Nir, Rony-Reuven; Yarnitsky, David

2008-01-01

The method of pain-evoked potentials has gained considerable acceptance over the last 3 decades regarding its objectivity, repeatability, and quantifiability. The present study explored whether the relationship between pain-evoked potentials and pain psychophysics obtained by contact heat stimuli is similar to those observed for the conventionally used laser stimulation. Evoked potentials (EPs) were recorded in response to contact heat stimuli at different body sites in 24 healthy volunteers. Stimuli at various temperatures were applied to the forearm (43 degrees C, 46 degrees C, 49 degrees C, and 52 degrees C) and leg (46 degrees C and 49 degrees C). The amplitudes of both components (N2 and P2) were strongly associated with the intensity of the applied stimuli and with subjective pain perception. Yet, regression analysis revealed pain perception and not stimulus intensity as the major contributing factor. A significant correlation was found between the forearm and the leg for both psychophysics and EPs amplitude. Contact heat can generate readily distinguishable evoked potentials on the scalp, consistent between upper and lower limbs. Although these potentials bear positive correlation with both stimulus intensity and pain magnitude, the latter is the main contributor to the evoked brain response.

Contact Heat Evoked Potentials (CHEPs) in Patients with Mild-Moderate Alzheimer's Disease and Matched Control--A Pilot Study.

PubMed

Jensen-Dahm, Christina; Madsen, Caspar Skau; Waldemar, Gunhild; Ballegaard, Martin; Hejl, Anne-Mette; Johnsen, Birger; Jensen, Troels Staehelin

2016-04-01

Clinical studies have found that patients with Alzheimer's disease report pain of less intensity and with a lower affective response, which has been thought to be due to altered pain processing. The authors wished to examine the cerebral processing of non-painful and painful stimuli using somatosensory evoked potentials and contact heat evoked potentials in patients with Alzheimer's disease and in healthy elderly controls. Case-control study Twenty outpatients with mild-moderate Alzheimer's disease and in 17 age- and gender-matched healthy controls were included Contact heat evoked potentials and somatosensory evoked potentials were recorded in all subjects. Furthermore, warmth detection threshold and heat pain threshold were assessed. Patients and controls also rated quality and intensity of the stimuli. The authors found no difference on contact heat evoked potential amplitude (P = 0.59) or latency of N2 or P2 wave (P = 0.62 and P = 0.75, respectively) between patients and controls. In addition, there was no difference in regard to pain intensity scores or pain quality. The patients and controls had similar warmth detection threshold and heat pain threshold. Somatosensory evoked potentials, amplitude, and latency were within normal range and similar for the two groups. The findings suggest that the processing of non-painful and painful stimuli is preserved in patients with mild to moderate Alzheimer's disease. © 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Sunlight irradiance and habituation of visual evoked potentials in migraine: The environment makes its mark.

PubMed

Lisicki, Marco; D'Ostilio, Kevin; Erpicum, Michel; Schoenen, Jean; Magis, Delphine

2017-01-01

Background Migraine is a complex multifactorial disease that arises from the interaction between a genetic predisposition and an enabling environment. Habituation is considered as a fundamental adaptive behaviour of the nervous system that is often impaired in migraine populations. Given that migraineurs are hypersensitive to light, and that light deprivation is able to induce functional changes in the visual cortex recognizable through visual evoked potentials habituation testing, we hypothesized that regional sunlight irradiance levels could influence the results of visual evoked potentials habituation studies performed in different locations worldwide. Methods We searched the literature for visual evoked potentials habituation studies comparing healthy volunteers and episodic migraine patients and correlated their results with levels of local solar radiation. Results After reviewing the literature, 26 studies involving 1291 participants matched our inclusion criteria. Deficient visual evoked potentials habituation in episodic migraine patients was reported in 19 studies. Mean yearly sunlight irradiance was significantly higher in locations of studies reporting deficient habituation. Correlation analyses suggested that visual evoked potentials habituation decreases with increasing sunlight irradiance in migraine without aura patients. Conclusion Results from this hypothesis generating analysis suggest that variations in sunlight irradiance may induce adaptive modifications in visual processing systems that could be reflected in visual evoked potentials habituation, and thus partially account for the difference in results between studies performed in geographically distant centers. Other causal factors such as genetic differences could also play a role, and therefore well-designed prospective trials are warranted.

Spinal NMDA-receptor dependent amplification of nociceptive transmission to rat primary somatosensory cortex (SI).

PubMed

Kalliomäki, Jarkko; Granmo, Marcus; Schouenborg, Jens

2003-07-01

The role of NMDA mechanisms in spinal pathways mediating acute nociceptive input to the somatosensory cortex is not clear. In this study, the effect of NMDA-antagonists on nociceptive C fibre transmission to the primary somatosensory cortex (SI) was investigated. Cortical field potentials evoked by CO(2)-laser stimulation of the skin were recorded in the halothane/nitrous oxide anaesthetized rat. The SI nociceptive evoked potential (EP) amplitudes were dependent on the frequency of noxious heat stimulation. The amplitudes of SI potentials evoked by CO(2)-laser pulses (duration 15-20 ms, stimulation energy 21-28 mJ/mm(2)) delivered at a frequency of 0.1 Hz were approximately 40% of the amplitudes of potentials evoked by 1.0 Hz stimulation. After intrathecal lumbar application of either of the NMDA-antagonists CPP or MK-801, the amplitudes of nociceptive SI potentials, evoked by 1.0 Hz stimulation of the contralateral hindpaw, were reduced to approximately 40% of controls. By contrast, field potentials evoked by 0.1 Hz stimulation of the hindpaw were unaffected by MK-801. SI potentials evoked by 1.0 Hz stimulation of the contralateral forepaw did not change after lumbar application of CPP or MK-801, indicating that the depression of hindpaw EPs was due to a segmental effect in the spinal cord. It is concluded that spinal NMDA-receptor mechanisms amplify the acute transmission of nociceptive C fiber input to SI in a frequency-dependent way.

Clinical Applications for EPs in the ICU.

PubMed

Koenig, Matthew A; Kaplan, Peter W

2015-12-01

In critically ill patients, evoked potential (EP) testing is an important tool for measuring neurologic function, signal transmission, and secondary processing of sensory information in real time. Evoked potential measures conduction along the peripheral and central sensory pathways with longer-latency potentials representing more complex thalamocortical and intracortical processing. In critically ill patients with limited neurologic exams, EP provides a window into brain function and the potential for recovery of consciousness. The most common EP modalities in clinical use in the intensive care unit include somatosensory evoked potentials, brainstem auditory EPs, and cortical event-related potentials. The primary indications for EP in critically ill patients are prognostication in anoxic-ischemic or traumatic coma, monitoring for neurologic improvement or decline, and confirmation of brain death. Somatosensory evoked potentials had become an important prognostic tool for coma recovery, especially in comatose survivors of cardiac arrest. In this population, the bilateral absence of cortical somatosensory evoked potentials has nearly 100% specificity for death or persistent vegetative state. Historically, EP has been regarded as a negative prognostic test, that is, the absence of cortical potentials is associated with poor outcomes while the presence cortical potentials are prognostically indeterminate. In recent studies, the presence of middle-latency and long-latency potentials as well as the amplitude of cortical potentials is more specific for good outcomes. Event-related potentials, particularly mismatch negativity of complex auditory patterns, is emerging as an important positive prognostic test in patients under comatose. Multimodality predictive algorithms that combine somatosensory evoked potentials, event-related potentials, and clinical and radiographic factors are gaining favor for coma prognostication.

The Relationship of Visual Evoked Potential Asymmetries to the Performance of Sonar Operators

DTIC Science & Technology

1981-08-11

also been related to EP variability. Schizophrenic adults and patients with Korsakoff’s Syndrome have shown higher evoked potential variability than...average evoked response in Korsakoff patients. J. Psychiatry Res. 6: 253-260, 1969. Santoro, T. and D. Fender. Rules for the perception of

β2-Adrenergic Receptor Activation Suppresses the Rat Phenethylamine Hallucinogen-Induced Head Twitch Response: Hallucinogen-Induced Excitatory Post-synaptic Potentials as a Potential Substrate

PubMed Central

Marek, Gerard J.; Ramos, Brian P.

2018-01-01

5-Hydroxytryptamine2A (5-HT2A) receptors are enriched in layers I and Va of the rat prefrontal cortex and neocortex and their activation increases the frequency of glutamatergic excitatory post-synaptic potentials/currents (EPSP/Cs) onto layer V pyramidal cells. A number of other G-protein coupled receptors (GPCRs) are also enriched in cortical layers I and Va and either induce (α1-adrenergic and orexin2) or suppress (metabotropic glutamate2 [mGlu2], adenosine A1, μ-opioid) both 5-HT-induced EPSCs and head twitches or head shakes induced by the phenethylamine hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Another neurotransmitter receptor also localized to apparent thalamocortical afferents to layers I and Va of the rat prefrontal cortex and neocortex is the β2-adrenergic receptor. Therefore, we conducted preliminary electrophysiological experiments with rat brain slices examining the effects of epinephrine on electrically-evoked EPSPs following bath application of DOI (3 μM). Epinephrine (0.3–10 μM) suppressed the late EPSPs produced by electrical stimulation and DOI. The selective β2-adrenergic receptor antagonist ICI-118,551 (300 nM) resulted in a rightward shift of the epinephrine concentration-response relationship. We also tested the selective β2-adrenergic receptor agonist clenbuterol and the antagonist ICI-118,551 on DOI-induced head twitches. Clenbuterol (0.3–3 mg/kg, i.p.) suppressed DOI (1.25 mg/kg, i.p.)-induced head twitches. This clenbuterol effect appeared to be at least partially reversed by the selective β2-adrenergic receptor antagonist ICI-118,553 (0.01–1 mg/kg, i.p.), with significant reversal at doses of 0.1 and 1 mg/kg. Thus, β2-adrenergic receptor activation reverses the effects of phenethylamine hallucinogens in the rat prefrontal cortex. While Gi/Go-coupled GPCRs have previously been shown to suppress both the electrophysiological and behavioral effects of 5-HT2A receptor activation in the mPFC, the present work appears to extend this suppressant action to a Gs-coupled GPCR. Furthermore, the modulation of 5-HT2A receptor activation-induced glutamate release onto mPFC layer V pyramidal neurons apical dendrites by a range GPCRs in rat brain slices appears to results in behaviorally salient effects of relevance when screening for novel CNS therapeutic drugs. PMID:29472863

CaMKII Regulates Synaptic NMDA Receptor Activity of Hypothalamic Presympathetic Neurons and Sympathetic Outflow in Hypertension.

PubMed

Li, De-Pei; Zhou, Jing-Jing; Zhang, Jixiang; Pan, Hui-Lin

2017-11-01

NMDAR activity in the hypothalamic paraventricular nucleus (PVN) is increased and critically involved in heightened sympathetic vasomotor tone in hypertension. Calcium/calmodulin-dependent protein kinase II (CaMKII) binds to and modulates NMDAR activity. In this study, we determined the role of CaMKII in regulating NMDAR activity of PVN presympathetic neurons in male spontaneously hypertensive rats (SHRs). NMDAR-mediated EPSCs and puff NMDA-elicited currents were recorded in spinally projecting PVN neurons in SHRs and male Wistar-Kyoto (WKY) rats. The basal amplitude of evoked NMDAR-EPSCs and puff NMDA currents in retrogradely labeled PVN neurons were significantly higher in SHRs than in WKY rats. The CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP) normalized the increased amplitude of NMDAR-EPSCs and puff NMDA currents in labeled PVN neurons in SHRs but had no effect in WKY rats. Treatment with AIP also normalized the higher frequency of NMDAR-mediated miniature EPSCs of PVN neurons in SHRs. CaMKII-mediated phosphorylation level of GluN2B serine 1303 (S1303) in the PVN, but not in the hippocampus and frontal cortex, was significantly higher in SHRs than in WKY rats. Lowering blood pressure with celiac ganglionectomy in SHRs did not alter the increased level of phosphorylated GluN2B S1303 in the PVN. In addition, microinjection of AIP into the PVN significantly reduced arterial blood pressure and lumbar sympathetic nerve discharges in SHRs. Our findings suggest that CaMKII activity is increased in the PVN and contributes to potentiated presynaptic and postsynaptic NMDAR activity to elevate sympathetic vasomotor tone in hypertension. SIGNIFICANCE STATEMENT Heightened sympathetic vasomotor tone is a major contributor to the development of hypertension. Although glutamate NMDA receptor (NMDAR)-mediated excitatory drive in the hypothalamus plays a critical role in increased sympathetic output in hypertension, the molecular mechanism involved in potentiated NMDAR activity of hypothalamic presympathetic neurons remains unclear. Here we show that the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) is increased and plays a key role in the potentiated presynaptic and postsynaptic NMDAR activity of hypothalamic presympathetic neurons in hypertension. Also, the inhibition of CaMKII in the hypothalamus reduces elevated blood pressure and sympathetic nerve discharges in hypertension. This new knowledge extends our understanding of the mechanism of synaptic plasticity in the hypothalamus and suggests new strategies to treat neurogenic hypertension. Copyright © 2017 the authors 0270-6474/17/3710690-10$15.00/0.

The association between later cortical potentials and later phases of postural reactions evoked by perturbations to upright stance.

PubMed

Quant, Sylvia; Maki, Brian E; McIlroy, William E

2005-06-24

Previous studies have suggested that early cortical potentials (e.g. N1) that are evoked by perturbations to upright stance are associated with sensory processing of the initial perturbation and that later potentials may represent cognitive processing of this perturbation. However, it has also been suggested that later cortical potentials could reflect sensory and motor processing of later phases of the postural reaction. The current study set out to provide additional insight into the association between perturbation-evoked cortical potentials and postural reactions evoked by whole-body perturbations. By altering the deceleration onset of the perturbation, which altered the timing of later postural responses, we determined whether changes in later postural responses were associated with changes in later potentials. Based on previous work, we hypothesized that later potentials would not be associated with changes in later postural responses. During stance, seven healthy young adults were instructed to maintain their balance following two types of perturbations: (1) acceleration phase immediately followed by a deceleration phase (TASK 1), and (2) acceleration phase followed by a delayed deceleration phase (TASK 2). In spite of profound task differences in later postural responses, results revealed no significant differences in later potentials. This work provides additional support for the idea that latter elements of perturbation-evoked cortical responses are likely independent of evoked motor reactions required to maintain stability.

Auditory evoked potentials in two short-finned pilot whales (Globicephala macrorhynchus).

PubMed

Schlundt, Carolyn E; Dear, Randall L; Houser, Dorian S; Bowles, Ann E; Reidarson, Tom; Finneran, James J

2011-02-01

The hearing sensitivities of two short-finned pilot whales (Globicephala macrorhynchus) were investigated by measuring auditory evoked potentials generated in response to clicks and sinusoidal amplitude modulated (SAM) tones. The first whale tested, an adult female, was a long-time resident at SeaWorld San Diego with a known health history. Click-evoked responses in this animal were similar to those measured in other echolocating odontocetes. Auditory thresholds were comparable to dolphins of similar age determined with similar evoked potential methods. The region of best sensitivity was near 40 kHz and the upper limit of functional hearing was between 80 and 100 kHz. The second whale tested, a juvenile male, was recently stranded and deemed non-releasable. Click-evoked potentials were not detected in this animal and testing with SAM tones suggested severe hearing loss above 10 kHz.

Unified pre- and postsynaptic long-term plasticity enables reliable and flexible learning.

PubMed

Costa, Rui Ponte; Froemke, Robert C; Sjöström, P Jesper; van Rossum, Mark Cw

2015-08-26

Although it is well known that long-term synaptic plasticity can be expressed both pre- and postsynaptically, the functional consequences of this arrangement have remained elusive. We show that spike-timing-dependent plasticity with both pre- and postsynaptic expression develops receptive fields with reduced variability and improved discriminability compared to postsynaptic plasticity alone. These long-term modifications in receptive field statistics match recent sensory perception experiments. Moreover, learning with this form of plasticity leaves a hidden postsynaptic memory trace that enables fast relearning of previously stored information, providing a cellular substrate for memory savings. Our results reveal essential roles for presynaptic plasticity that are missed when only postsynaptic expression of long-term plasticity is considered, and suggest an experience-dependent distribution of pre- and postsynaptic strength changes.

Use of the Stockwell Transform in the Detection of P300 Evoked Potentials with Low-Cost Brain Sensors.

PubMed

Pérez-Vidal, Alan F; Garcia-Beltran, Carlos D; Martínez-Sibaja, Albino; Posada-Gómez, Rubén

2018-05-09

The evoked potential is a neuronal activity that originates when a stimulus is presented. To achieve its detection, various techniques of brain signal processing can be used. One of the most studied evoked potentials is the P300 brain wave, which usually appears between 300 and 500 ms after the stimulus. Currently, the detection of P300 evoked potentials is of great importance due to its unique properties that allow the development of applications such as spellers, lie detectors, and diagnosis of psychiatric disorders. The present study was developed to demonstrate the usefulness of the Stockwell transform in the process of identifying P300 evoked potentials using a low-cost electroencephalography (EEG) device with only two brain sensors. The acquisition of signals was carried out using the Emotiv EPOC ® device—a wireless EEG headset. In the feature extraction, the Stockwell transform was used to obtain time-frequency information. The algorithms of linear discriminant analysis and a support vector machine were used in the classification process. The experiments were carried out with 10 participants; men with an average age of 25.3 years in good health. In general, a good performance (75⁻92%) was obtained in identifying P300 evoked potentials.

Visual and brainstem auditory evoked potentials in infants with severe vitamin B12 deficiency.

PubMed

Demir, Nihat; Koç, Ahmet; Abuhandan, Mahmut; Calik, Mustafa; Işcan, Akin

2015-01-01

Vitamin B12 plays an important role in the development of mental, motor, cognitive, and social functions via its role in DNA synthesis and nerve myelination. Its deficiency in infants might cause neuromotor retardation as well as megaloblastic anemia. The objective of this study was to investigate the effects of infantile vitamin B12 deficiency on evoked brain potentials and determine whether improvement could be obtained with vitamin B12 replacement at appropriate dosages. Thirty patients with vitamin B12 deficiency and 30 age-matched healthy controls were included in the study. Hematological parameters, visual evoked potentials, and brainstem auditory evoked potentials tests were performed prior to treatment, 1 week after treatment, and 3 months after treatment. Visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs) were found to be prolonged in 16 (53.3%) and 15 (50%) patients, respectively. Statistically significant improvements in VEP and BAEP examinations were determined 3 months after treatment. Three months after treatment, VEP and BAEP examinations returned to normal in 81.3% and 53.3% of subjects with prolonged VEPs and BAEPs, respectively. These results demonstrate that vitamin B12 deficiency in infants causes significant impairment in the auditory and visual functioning tests of the brain, such as VEP and BAEP.

Carbon nanotube multi-electrode array chips for noninvasive real-time measurement of dopamine, action potentials, and postsynaptic potentials.

PubMed

Suzuki, Ikuro; Fukuda, Mao; Shirakawa, Keiichi; Jiko, Hideyasu; Gotoh, Masao

2013-11-15

Multi-electrode arrays (MEAs) can be used for noninvasive, real-time, and long-term recording of electrophysiological activity and changes in the extracellular chemical microenvironment. Neural network organization, neuronal excitability, synaptic and phenotypic plasticity, and drug responses may be monitored by MEAs, but it is still difficult to measure presynaptic activity, such as neurotransmitter release, from the presynaptic bouton. In this study, we describe the development of planar carbon nanotube (CNT)-MEA chips that can measure both the release of the neurotransmitter dopamine as well as electrophysiological responses such as field postsynaptic potentials (fPSPs) and action potentials (APs). These CNT-MEA chips were fabricated by electroplating the indium-tin oxide (ITO) microelectrode surfaces. The CNT-plated ITO electrode exhibited electrochemical response, having much higher current density compared with the bare ITO electrode. Chronoamperometric measurements using these CNT-MEA chips detected dopamine at nanomolar concentrations. By placing mouse striatal brain slices on the CNT-MEA chip, we successfully measured synaptic dopamine release from spontaneous firings with a high S/N ratio of 62. Furthermore, APs and fPSPs were measured from cultured hippocampal neurons and slices with high temporal resolution and a 100-fold greater S/N ratio. Our CNT-MEA chips made it possible to measure neurotransmitter dopamine (presynaptic activities), postsynaptic potentials, and action potentials, which have a central role in information processing in the neuronal network. CNT-MEA chips could prove useful for in vitro studies of stem cell differentiation, drug screening and toxicity, synaptic plasticity, and pathogenic processes involved in epilepsy, stroke, and neurodegenerative diseases. Copyright © 2013 Elsevier B.V. All rights reserved.

Middle Latency Auditory Evoked Potential (MLAEP) in Workers with and without Tinnitus who are Exposed to Occupational Noise.

PubMed

dos Santos Filha, Valdete Alves Valentins; Samelli, Alessandra Giannella; Matas, Carla Gentile

2015-09-11

Tinnitus is an important occupational health concern, but few studies have focused on the central auditory pathways of workers with a history of occupational noise exposure. Thus, we analyzed the central auditory pathways of workers with a history of occupational noise exposure who had normal hearing threshold, and compared middle latency auditory evoked potential in those with and without noise-induced tinnitus. Sixty individuals (30 with and 30 without tinnitus) underwent the following procedures: anamnesis, immittance measures, pure-tone air conduction thresholds at all frequencies between 0.25-8 kHz, and middle latency auditory evoked potentials. Quantitative analysis of latencies and amplitudes of middle latency auditory evoked potential showed no significant differences between the groups with and without tinnitus. In the qualitative analysis, we found that both groups showed increased middle latency auditory evoked potential latencies. The study group had more alterations of the "both" type regarding the Na-Pa amplitude, while the control group had more "electrode effect" alterations, but these alterations were not significantly different when compared to controls. Individuals with normal hearing with or without tinnitus who are exposed to occupational noise have altered middle latency auditory evoked potential, suggesting impairment of the auditory pathways in cortical and subcortical regions. Although differences did not reach significance, individuals with tinnitus seemed to have more abnormalities in components of the middle latency auditory evoked potential when compared to individuals without tinnitus, suggesting alterations in the generation and transmission of neuroelectrical impulses along the auditory pathway.

Refractory episodic vertigo: role of intratympanic gentamicin and vestibular evoked myogenic potentials.

PubMed

Celis-Aguilar, Erika; Hinojosa-González, Ramon; Vales-Hidalgo, Olivia; Coutinho-Toledo, Heloisa

Even today, the treatment of intractable vertigo remains a challenge. Vestibular ablation with intratympanic gentamicin stands as a good alternative in the management of refractory vertigo patients. To control intractable vertigo through complete saccular and horizontal canal vestibular ablation with intratympanic gentamicin treatment. Patients with refractory episodic vertigo were included. The inclusion criteria were: unilateral ear disease, moderate to profound sensorineural hearing loss, and failure to other treatments. Included patients underwent 0.5-0.8mL of gentamicin intratympanic application at a 30mg/mL concentration. Vestibular ablation was confirmed by the absence of response on cervical vestibular evoked myogenic potentials and no response on caloric tests. Audiometry, electronystagmography with iced water, and vestibular evoked myogenic potentials were performed in all patients. Ten patients were included; nine patients with Meniere's disease and one patient with (late onset) delayed hydrops. Nine patients showed an absent response on vestibular evoked myogenic potentials and no response on caloric tests. The only patient with low amplitude on cervical vestibular evoked myogenic potentials had vertigo recurrence. Vertigo control was achieved in 90% of the patients. One patient developed hearing loss >30dB. Cervical vestibular evoked myogenic potentials confirmed vestibular ablation in patients treated with intratympanic gentamicin. High-grade vertigo control was due to complete saccular and horizontal canal ablation (no response to iced water in electronystagmography and no response on cervical vestibular evoked myogenic potentials). Copyright © 2016 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Muscle-derived collagen XIII regulates maturation of the skeletal neuromuscular junction.

PubMed

Latvanlehto, Anne; Fox, Michael A; Sormunen, Raija; Tu, Hongmin; Oikarainen, Tuomo; Koski, Anu; Naumenko, Nikolay; Shakirzyanova, Anastasia; Kallio, Mika; Ilves, Mika; Giniatullin, Rashid; Sanes, Joshua R; Pihlajaniemi, Taina

2010-09-15

Formation, maturation, stabilization, and functional efficacy of the neuromuscular junction (NMJ) are orchestrated by transsynaptic and autocrine signals embedded within the synaptic cleft. Here, we demonstrate that collagen XIII, a nonfibrillar transmembrane collagen, is another such signal. We show that collagen XIII is expressed by muscle and its ectodomain can be proteolytically shed into the extracellular matrix. The collagen XIII protein was found present in the postsynaptic membrane and synaptic basement membrane. To identify a role for collagen XIII at the NMJ, mice were generated lacking this collagen. Morphological and ultrastructural analysis of the NMJ revealed incomplete adhesion of presynaptic and postsynaptic specializations in collagen XIII-deficient mice of both genders. Strikingly, Schwann cells erroneously enwrapped nerve terminals and invaginated into the synaptic cleft, resulting in a decreased contact surface for neurotransmission. Consistent with morphological findings, electrophysiological studies indicated both postsynaptic and presynaptic defects in Col13a1(-/-) mice, such as decreased amplitude of postsynaptic potentials, diminished probabilities of spontaneous release and reduced readily releasable neurotransmitter pool. To identify the role of collagen XIII at the NMJ, shed ectodomain of collagen XIII was applied to cultured myotubes, and it was found to advance acetylcholine receptor (AChR) cluster maturation. Together with the delay in AChR cluster development observed in collagen XIII-deficient mutants in vivo, these results suggest that collagen XIII plays an autocrine role in postsynaptic maturation of the NMJ. Altogether, the results presented here reveal that collagen XIII is a novel muscle-derived cue necessary for the maturation and function of the vertebrate NMJ.

Modulation of NMDA and AMPA-Mediated Synaptic Transmission by CB1 Receptors in Frontal Cortical Pyramidal Cells

PubMed Central

Li, Qiang; Yan, Haidun; Wilson, Wilkie A.; Swartzwelder, H. Scott

2010-01-01

Although the endogenous cannabinoid system modulates a variety of physiological and pharmacological processes, the specific role of cannabinoid CB1 receptors in the modulation of glutamatergic neurotransmission and neural plasticity is not well understood. Using whole-cell patch clamp recording techniques, evoked or spontaneous excitatory postsynaptic currents (eEPSCs or sEPSCs) were recorded from visualized, layer II/III pyramidal cells in frontal cortical slices from rat brain. Bath application of the CB1 receptor agonist, WIN 55212-2 (WIN), reduced the amplitude of NMDA receptor-mediated EPSCs in a concentration-dependent manner. When co-applied with the specific CB1 antagonists, AM251 or AM281, WIN did not suppress NMDA receptor mediated EPSCs. WIN also reduced the amplitude of evoked AMPA receptor-mediated EPSCs, an effect that was also reversed by AM251. Both the frequency and amplitude of spontaneous AMPA receptor-mediated EPSCs were significantly reduced by WIN. In contrast, WIN reduced the frequency, but not the amplitude of miniature EPSCs, suggesting that the suppression of glutmatergic activity by CB1 receptors in the frontal neocortex is mediated by a pre-synaptic mechanism. Taken together, these data indicate a critical role for endocannabinoid signaling in the regulation of excitatory synaptic transmission in frontal neocortex, and suggest a possible neuronal mechanism whereby THC regulates cortical function. PMID:20420813

Evoked potentials in immobilized cats to a combination of clicks with painful electrocutaneous stimuli

NASA Technical Reports Server (NTRS)

Gilinskiy, M. A.; Korsakov, I. A.

1979-01-01

Averaged evoked potentials in the auditory, somatosensory, and motor cortical zones, as well as in the mesencephalic reticular formation were recorded in acute experiments on nonanesthetized, immobilized cats. Omission of the painful stimulus after a number of pairings resulted in the appearance of a delayed evoked potential, often resembling the late phases of the response to the painful stimulus. The characteristics of this response are discussed in comparison with conditioned changes of the sensory potential amplitudes.

Crucial Role of Postsynaptic Syntaxin 4 in Mediating Basal Neurotransmission and Synaptic Plasticity in Hippocampal CA1 Neurons.

PubMed

Bin, Na-Ryum; Ma, Ke; Harada, Hidekiyo; Tien, Chi-Wei; Bergin, Fiona; Sugita, Kyoko; Luyben, Thomas T; Narimatsu, Masahiro; Jia, Zhengping; Wrana, Jeffrey L; Monnier, Philippe P; Zhang, Liang; Okamoto, Kenichi; Sugita, Shuzo

2018-06-05

Trafficking of neurotransmitter receptors on postsynaptic membranes is critical for basal neurotransmission and synaptic plasticity, yet the underlying mechanisms remain elusive. Here, we investigated the role of syntaxin 4 in postsynaptic hippocampal CA1 neurons by analyzing conditional knockout (syntaxin 4 cKO) mice. We show that syntaxin 4 cKO resulted in reduction of basal neurotransmission without changes in paired-pulse ratios. Both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptor-mediated charge transfers were diminished. Patch-clamp experiments revealed that amplitudes, but not frequencies, of spontaneous excitatory postsynaptic currents are reduced. Syntaxin 4 knockout (KO) caused drastic reduction in expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptors in cultured hippocampal neurons. Furthermore, cKO caused defects in theta-burst stimulation induced long-term potentiation and spatial learning as assessed by a water maze task, indicating that synaptic plasticity was altered. Our data reveal a crucial role of syntaxin 4 in trafficking of ionotropic glutamate receptors that are essential for basal neurotransmission, synaptic plasticity, and spatial memory. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Properties of synaptic transmission from the reticular formation dorsal to the facial nucleus to trigeminal motoneurons during early postnatal development in rats.

PubMed

Gemba-Nishimura, A; Inoue, T; Nakamura, S; Nakayama, K; Mochizuki, A; Shintani, S; Yoshimura, S

2010-03-31

We previously reported that electrical stimulation of the reticular formation dorsal to the facial nucleus (RdVII) elicited excitatory masseter responses at short latencies and that RdVII neurons were antidromically activated by stimulation of the trigeminal motor nucleus (MoV), suggesting that excitatory premotor neurons targeting the MoV are likely located in the RdVII. We thus examined the properties of synaptic transmission from the RdVII to jaw-closing and jaw-opening motoneurons in horizontal brainstem preparations from developing rats using voltage-sensitive dye, patch-clamp recordings and laser photostimulation. Electrical stimulation of the RdVII evoked optical responses in the MoV. Combined bath application of the non-N-methyl-d-aspartate (non-NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (APV) reduced these optical responses, and addition of the glycine receptor antagonist strychnine and the GABA(A) receptor antagonist bicuculline further reduced the remaining responses. Electrical stimulation of the RdVII evoked postsynaptic currents (PSCs) in all 19 masseter motoneurons tested in postnatal day (P)1-4 rats, and application of CNQX and the NMDA receptor antagonist (+/-)-3(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) reduced the PSC amplitudes by more than 50%. In the presence of CNQX and CPP, the GABA(A) receptor antagonist SR95531 further reduced PSC amplitude, and addition of strychnine abolished the remaining PSCs. Photostimulation of the RdVII with caged glutamate also evoked PSCs in masseter motoneurons of P3-4 rats. In P8-11 rats, electrical stimulation of the RdVII also evoked PSCs in all 14 masseter motoneurons tested, and the effects of the antagonists on the PSCs were similar to those in P1-4 rats. On the other hand, RdVII stimulation evoked PSCs in only three of 16 digastric motoneurons tested. These results suggest that both neonatal and juvenile jaw-closing motoneurons receive strong synaptic inputs from the RdVII through activation of glutamate, glycine and GABA(A) receptors, whereas inputs from the RdVII to jaw-opening motoneurons seem to be weak. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Associative, Bidirectional Changes in Neural Signaling Utilizing NMDA Receptor- and Endocannabinoid-Dependent Mechanisms

ERIC Educational Resources Information Center

Li, Qin; Burrell, Brian D.

2011-01-01

Persistent, bidirectional changes in synaptic signaling (that is, potentiation and depression of the synapse) can be induced by the precise timing of individual pre- and postsynaptic action potentials. However, far less attention has been paid to the ability of paired trains of action potentials to elicit persistent potentiation or depression. We…

Chirp-modulated visual evoked potential as a generalization of steady state visual evoked potential

NASA Astrophysics Data System (ADS)

Tu, Tao; Xin, Yi; Gao, Xiaorong; Gao, Shangkai

2012-02-01

Visual evoked potentials (VEPs) are of great concern in cognitive and clinical neuroscience as well as in the recent research field of brain-computer interfaces (BCIs). In this study, a chirp-modulated stimulation was employed to serve as a novel type of visual stimulus. Based on our empirical study, the chirp stimuli visual evoked potential (Chirp-VEP) preserved frequency features of the chirp stimulus analogous to the steady state evoked potential (SSVEP), and therefore it can be regarded as a generalization of SSVEP. Specifically, we first investigated the characteristics of the Chirp-VEP in the time-frequency domain and the fractional domain via fractional Fourier transform. We also proposed a group delay technique to derive the apparent latency from Chirp-VEP. Results on EEG data showed that our approach outperformed the traditional SSVEP-based method in efficiency and ease of apparent latency estimation. For the recruited six subjects, the average apparent latencies ranged from 100 to 130 ms. Finally, we implemented a BCI system with six targets to validate the feasibility of Chirp-VEP as a potential candidate in the field of BCIs.

Comparative Study of Human and Mouse Postsynaptic Proteomes Finds High Compositional Conservation and Abundance Differences for Key Synaptic Proteins

PubMed Central

Bayés, Àlex; Collins, Mark O.; Croning, Mike D. R.; van de Lagemaat, Louie N.; Choudhary, Jyoti S.; Grant, Seth G. N.

2012-01-01

Direct comparison of protein components from human and mouse excitatory synapses is important for determining the suitability of mice as models of human brain disease and to understand the evolution of the mammalian brain. The postsynaptic density is a highly complex set of proteins organized into molecular networks that play a central role in behavior and disease. We report the first direct comparison of the proteome of triplicate isolates of mouse and human cortical postsynaptic densities. The mouse postsynaptic density comprised 1556 proteins and the human one 1461. A large compositional overlap was observed; more than 70% of human postsynaptic density proteins were also observed in the mouse postsynaptic density. Quantitative analysis of postsynaptic density components in both species indicates a broadly similar profile of abundance but also shows that there is higher abundance variation between species than within species. Well known components of this synaptic structure are generally more abundant in the mouse postsynaptic density. Significant inter-species abundance differences exist in some families of key postsynaptic density proteins including glutamatergic neurotransmitter receptors and adaptor proteins. Furthermore, we have identified a closely interacting set of molecules enriched in the human postsynaptic density that could be involved in dendrite and spine structural plasticity. Understanding synapse proteome diversity within and between species will be important to further our understanding of brain complexity and disease. PMID:23071613

Vestibular receptors contribute to cortical auditory evoked potentials.

PubMed

Todd, Neil P M; Paillard, Aurore C; Kluk, Karolina; Whittle, Elizabeth; Colebatch, James G

2014-03-01

Acoustic sensitivity of the vestibular apparatus is well-established, but the contribution of vestibular receptors to the late auditory evoked potentials of cortical origin is unknown. Evoked potentials from 500 Hz tone pips were recorded using 70 channel EEG at several intensities below and above the vestibular acoustic threshold, as determined by vestibular evoked myogenic potentials (VEMPs). In healthy subjects both auditory mid- and long-latency auditory evoked potentials (AEPs), consisting of Na, Pa, N1 and P2 waves, were observed in the sub-threshold conditions. However, in passing through the vestibular threshold, systematic changes were observed in the morphology of the potentials and in the intensity dependence of their amplitude and latency. These changes were absent in a patient without functioning vestibular receptors. In particular, for the healthy subjects there was a fronto-central negativity, which appeared at about 42 ms, referred to as an N42, prior to the AEP N1. Source analysis of both the N42 and N1 indicated involvement of cingulate cortex, as well as bilateral superior temporal cortex. Our findings are best explained by vestibular receptors contributing to what were hitherto considered as purely auditory evoked potentials and in addition tentatively identify a new component that appears to be primarily of vestibular origin. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Differential temperature sensitivity of synaptic and firing processes in a neural mass model of epileptic discharges explains heterogeneous response of experimental epilepsy to focal brain cooling.

PubMed

Soriano, Jaymar; Kubo, Takatomi; Inoue, Takao; Kida, Hiroyuki; Yamakawa, Toshitaka; Suzuki, Michiyasu; Ikeda, Kazushi

2017-10-01

Experiments with drug-induced epilepsy in rat brains and epileptic human brain region reveal that focal cooling can suppress epileptic discharges without affecting the brain's normal neurological function. Findings suggest a viable treatment for intractable epilepsy cases via an implantable cooling device. However, precise mechanisms by which cooling suppresses epileptic discharges are still not clearly understood. Cooling experiments in vitro presented evidence of reduction in neurotransmitter release from presynaptic terminals and loss of dendritic spines at post-synaptic terminals offering a possible synaptic mechanism. We show that termination of epileptic discharges is possible by introducing a homogeneous temperature factor in a neural mass model which attenuates the post-synaptic impulse responses of the neuronal populations. This result however may be expected since such attenuation leads to reduced post-synaptic potential and when the effect on inhibitory interneurons is less than on excitatory interneurons, frequency of firing of pyramidal cells is consequently reduced. While this is observed in cooling experiments in vitro, experiments in vivo exhibit persistent discharges during cooling but suppressed in magnitude. This leads us to conjecture that reduction in the frequency of discharges may be compensated through intrinsic excitability mechanisms. Such compensatory mechanism is modelled using a reciprocal temperature factor in the firing response function in the neural mass model. We demonstrate that the complete model can reproduce attenuation of both magnitude and frequency of epileptic discharges during cooling. The compensatory mechanism suggests that cooling lowers the average and the variance of the distribution of threshold potential of firing across the population. Bifurcation study with respect to the temperature parameters of the model reveals how heterogeneous response of epileptic discharges to cooling (termination or suppression only) is exhibited. Possibility of differential temperature effects on post-synaptic potential generation of different populations is also explored.

Differential temperature sensitivity of synaptic and firing processes in a neural mass model of epileptic discharges explains heterogeneous response of experimental epilepsy to focal brain cooling

PubMed Central

Inoue, Takao; Kida, Hiroyuki; Yamakawa, Toshitaka; Suzuki, Michiyasu

2017-01-01

Experiments with drug-induced epilepsy in rat brains and epileptic human brain region reveal that focal cooling can suppress epileptic discharges without affecting the brain’s normal neurological function. Findings suggest a viable treatment for intractable epilepsy cases via an implantable cooling device. However, precise mechanisms by which cooling suppresses epileptic discharges are still not clearly understood. Cooling experiments in vitro presented evidence of reduction in neurotransmitter release from presynaptic terminals and loss of dendritic spines at post-synaptic terminals offering a possible synaptic mechanism. We show that termination of epileptic discharges is possible by introducing a homogeneous temperature factor in a neural mass model which attenuates the post-synaptic impulse responses of the neuronal populations. This result however may be expected since such attenuation leads to reduced post-synaptic potential and when the effect on inhibitory interneurons is less than on excitatory interneurons, frequency of firing of pyramidal cells is consequently reduced. While this is observed in cooling experiments in vitro, experiments in vivo exhibit persistent discharges during cooling but suppressed in magnitude. This leads us to conjecture that reduction in the frequency of discharges may be compensated through intrinsic excitability mechanisms. Such compensatory mechanism is modelled using a reciprocal temperature factor in the firing response function in the neural mass model. We demonstrate that the complete model can reproduce attenuation of both magnitude and frequency of epileptic discharges during cooling. The compensatory mechanism suggests that cooling lowers the average and the variance of the distribution of threshold potential of firing across the population. Bifurcation study with respect to the temperature parameters of the model reveals how heterogeneous response of epileptic discharges to cooling (termination or suppression only) is exhibited. Possibility of differential temperature effects on post-synaptic potential generation of different populations is also explored. PMID:28981509

Decrement of GABAA receptor-mediated inhibitory postsynaptic currents in dentate granule cells in epileptic hippocampus.

PubMed

Isokawa, M

1996-05-01

1. Inhibitory postsynaptic currents (IPSCs) were studied in hippocampal dentate granule cells (DGCs) in the pilocarpine model and human temporal lobe epilepsy, with the use of the whole cell patch-clamp recording technique in slice preparations. 2. In the pilocarpine model, hippocampal slices were prepared from rats that were allowed to experience spontaneous seizures for 2 mo. Human hippocampal specimens were obtained from epileptic patients who underwent surgical treatment for medically intractable seizures. 3. IPSCs were generated by single perforant path stimulation and recorded at a membrane potential (Vm) of 0 mV near the reversal potential of glutamate excitatory postsynaptic currents in the voltage-clamp recording. IPSCs were pharmacologically identified as gamma-aminobutyric acid-A (GABAA) IPSCs by 10 microM bicuculline methiodide. 4. During low-frequency stimulation, IPSCs were not different in amplitude among non-seizure-experienced rat hippocampi, human nonsclerotic hippocampi, seizure-experienced rat hippocampi, and human sclerotic hippocampi. In the last two groups of DGCs, current-clamp recordings indicated the presence of prolonged excitatory postsynaptic potentials (EPSPs) mediated by the N-methyl-D-aspartate (NMDA) receptor. 5. High-frequency stimulation, administered at Vm = -30 mV to activate NMDA currents, reduced GABAA IPSC amplitude specifically in seizure-experienced rat hippocampi (t = 2.5, P < 0.03) and human sclerotic hippocampi (t = 7.7, P < 0.01). This reduction was blocked by an NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV) (50 microM). The time for GABAA IPSCs to recover to their original amplitude was also shortened by the application of APV. 6. I conclude that, when intensively activated, NMDA receptor-mediated excitatory transmission may interact with GABAergic synaptic inhibition in DGCs in seizure-experienced hippocampus to transiently reduce GABA(A) receptor-channel function. Such interactions may contribute to give rise to epileptic excitation in chronically seizure-prone hippocampus.

PSPs and ERPs: applying the dynamics of post-synaptic potentials to individual units in simulation of temporally extended Event-Related Potential reading data.

PubMed

Laszlo, Sarah; Armstrong, Blair C

2014-05-01

The Parallel Distributed Processing (PDP) framework is built on neural-style computation, and is thus well-suited for simulating the neural implementation of cognition. However, relatively little cognitive modeling work has concerned neural measures, instead focusing on behavior. Here, we extend a PDP model of reading-related components in the Event-Related Potential (ERP) to simulation of the N400 repetition effect. We accomplish this by incorporating the dynamics of cortical post-synaptic potentials--the source of the ERP signal--into the model. Simulations demonstrate that application of these dynamics is critical for model elicitation of repetition effects in the time and frequency domains. We conclude that by advancing a neurocomputational understanding of repetition effects, we are able to posit an interpretation of their source that is both explicitly specified and mechanistically different from the well-accepted cognitive one. Copyright © 2014 Elsevier Inc. All rights reserved.

NLP-12 engages different UNC-13 proteins to potentiate tonic and evoked release.

PubMed

Hu, Zhitao; Vashlishan-Murray, Amy B; Kaplan, Joshua M

2015-01-21

A neuropeptide (NLP-12) and its receptor (CKR-2) potentiate tonic and evoked ACh release at Caenorhabditis elegans neuromuscular junctions. Increased evoked release is mediated by a presynaptic pathway (egl-30 Gαq and egl-8 PLCβ) that produces DAG, and by DAG binding to short and long UNC-13 proteins. Potentiation of tonic ACh release persists in mutants deficient for egl-30 Gαq and egl-8 PLCβ and requires DAG binding to UNC-13L (but not UNC-13S). Thus, NLP-12 adjusts tonic and evoked release by distinct mechanisms. Copyright © 2015 the authors 0270-6474/15/351038-05$15.00/0.

Generalized alternating stimulation: a novel method to reduce stimulus artifact in electrically evoked compound action potentials.

PubMed

Alvarez, Isaac; de la Torre, Angel; Sainz, Manuel; Roldan, Cristina; Schoesser, Hansjoerg; Spitzer, Philipp

2007-09-15

Stimulus artifact is one of the main limitations when considering electrically evoked compound action potential for clinical applications. Alternating stimulation (average of recordings obtained with anodic-cathodic and cathodic-anodic bipolar stimulation pulses) is an effective method to reduce stimulus artifact when evoked potentials are recorded. In this paper we extend the concept of alternating stimulation by combining anodic-cathodic and cathodic-anodic recordings with a weight in general different to 0.5. We also provide an automatic method to obtain an estimation of the optimal weights. Comparison with conventional alternating, triphasic stimulation and masker-probe paradigm shows that the generalized alternating method improves the quality of electrically evoked compound action potential responses.

Development of visual evoked potentials in neonates. A study using light emitting diode goggles.

PubMed Central

Chin, K C; Taylor, M J; Menzies, R; Whyte, H

1985-01-01

We used a signal averager with light emitting diode goggles as the photostimulator to study the development of the visual evoked potentials in 40 normal neonates of between 23 and 42 weeks' gestation. All except two infants of less than 24 weeks' gestation had replicable visual evoked potentials. A negative peak of latency (mean (SD), 308 (21) msec) was present in all infants, but the development of the primary positive peak depended on maturity. Only infants of 37 weeks or more had a consistent positive peak of latency (mean (SD), 220 (22) msec). The practical simplicity and reliability of this technique has distinct advantages over previous conventional recording systems. Neonatal visual evoked potentials are shown to change with maturity. PMID:4091582

Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to long-term potentiation and spatial learning.

PubMed

Nanou, Evanthia; Scheuer, Todd; Catterall, William A

2016-11-15

Many forms of short-term synaptic plasticity rely on regulation of presynaptic voltage-gated Ca 2+ type 2.1 (Ca V 2.1) channels. However, the contribution of regulation of Ca V 2.1 channels to other forms of neuroplasticity and to learning and memory are not known. Here we have studied mice with a mutation (IM-AA) that disrupts regulation of Ca V 2.1 channels by calmodulin and related calcium sensor proteins. Surprisingly, we find that long-term potentiation (LTP) of synaptic transmission at the Schaffer collateral-CA1 synapse in the hippocampus is substantially weakened, even though this form of synaptic plasticity is thought to be primarily generated postsynaptically. LTP in response to θ-burst stimulation and to 100-Hz tetanic stimulation is much reduced. However, a normal level of LTP can be generated by repetitive 100-Hz stimulation or by depolarization of the postsynaptic cell to prevent block of NMDA-specific glutamate receptors by Mg 2+ The ratio of postsynaptic responses of NMDA-specific glutamate receptors to those of AMPA-specific glutamate receptors is decreased, but the postsynaptic current from activation of NMDA-specific glutamate receptors is progressively increased during trains of stimuli and exceeds WT by the end of 1-s trains. Strikingly, these impairments in long-term synaptic plasticity and the previously documented impairments in short-term synaptic plasticity in IM-AA mice are associated with pronounced deficits in spatial learning and memory in context-dependent fear conditioning and in the Barnes circular maze. Thus, regulation of Ca V 2.1 channels by calcium sensor proteins is required for normal short-term synaptic plasticity, LTP, and spatial learning and memory in mice.

Effect of intrathecal baclofen on evoked pain perception: an evoked potentials and quantitative thermal testing study.

PubMed

Kumru, H; Kofler, M; Flores, M C; Portell, E; Robles, V; Leon, N; Vidal, J

2013-08-01

Somatic antinociceptive effects of baclofen have been demonstrated in animal models. We hypothesized that if enhanced thermal or pain sensitivity is produced by loss of gamma-aminobutyric acid (GABA)-ergic tone in the central nervous system, spinal administration of GABA agonists might be predicted to be effective in thermal and/or pain perception changes and pain-related evoked potentials in candidates for intrathecal baclofen (ITB) treatment. Eleven patients with severe spinal cord injury (SCI) who suffered from severe spasticity were evaluated during a 50-μg ITB bolus test. Warm and heat pain thresholds, evoked heat pain perception, and contact heat-evoked potentials (CHEPs) were determined above SCI level from the right and left sides. Nine age- and gender-matched healthy volunteers undergoing repeat testing without any placebo injection served as control group. In patients, heat pain perception threshold increased, and evoked pain perception and amplitude of CHEPs decreased significantly after ITB bolus application in comparison with baseline (p < 0.005), with no change in warm perception threshold. In controls, no significant changes were observed in repeat testing over time. Our findings indicate that ITB modulates heat pain perception threshold, evoked heat pain perception and heat pain-related evoked potentials without inducing warm perception threshold changes in SCI patients. This phenomenon should be taken into account in the clinical evaluation and management of pain in patients receiving baclofen. © 2012 European Federation of International Association for the Study of Pain Chapters.

Nano-CuO impairs spatial cognition associated with inhibiting hippocampal long-term potentiation via affecting glutamatergic neurotransmission in rats.

PubMed

Li, Xiaoliang; Sun, Wei; An, Lei

2018-06-01

Manufactured metal nanoparticles and their applications are continuously expanding because of their unique characteristics while their increasing use may predispose to potential health problems. Several studies have reported the adverse effects of copper oxide nanoparticles (nano-CuO) relative to ecotoxicity and cell toxicity, whereas little is known about the neurotoxicity of nano-CuO. The present study aimed to examine its effects on spatial cognition, hippocampal function, and the possible mechanisms. Male Wistar rats were used to establish an animal model, and nano-CuO was administered at a dose of 0.5 mg/kg/day for 2 weeks. The Morris water maze (MWM) test was employed to evaluate learning and memory. The long-term potentiation (LTP) from Schaffer collaterals to the hippocampal CA1 region, and the effects of nano-CuO on synases were recorded in the hippocampal CA1 neurons of rats. MWM test showed that learning and memory abilities were impaired significantly by nano-CuO ( p < 0.05). The LTP test demonstrated that the field excitatory postsynaptic potential (fEPSP) slopes were significantly lower in nano-CuO-treated groups compared with the control group ( p < 0.01). Furthermore, the data of whole-cell patch-clamp experiments showed that nano-CuO markedly depressed the frequencies of both spontaneous excitatory postsynaptic currents (sEPSCs) and miniature EPSCs (mEPSCs), indicating an effect of nano-CuO on inhibiting the release frequency of glutamate presynapticly ( p < 0.01). Meanwhile, the amplitudes of both sEPSC and mEPSC were significantly reduced in nano-CuO-treated animals, which suggested that the effect of nano-CuO modulates postsynaptic receptor kinetics ( p < 0.01). Paired pulse facilitation (PPF) ( p < 0.05) and the expression of NR2A, but not NR2B, of N-methyl-d-aspartate (NMDA) subunits ( p < 0.05), were decreased significantly. In conclusion, nano-CuO impaired glutamate transmission presynapticly and postsynapticly, which may contribute importantly to diminished LTP and other induced cognitive deficits.

Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model.

PubMed

Calon, Frédéric; Lim, Giselle P; Yang, Fusheng; Morihara, Takashi; Teter, Bruce; Ubeda, Oliver; Rostaing, Phillippe; Triller, Antoine; Salem, Norman; Ashe, Karen H; Frautschy, Sally A; Cole, Greg M

2004-09-02

Learning and memory depend on dendritic spine actin assembly and docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated fatty acid (PFA). High DHA consumption is associated with reduced Alzheimer's disease (AD) risk, yet mechanisms and therapeutic potential remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD mouse model resulted in 80%-90% losses of the p85alpha subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or presynaptic protein loss. n-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD.

Ketamine attenuates the glutamatergic neurotransmission in the ventral posteromedial nucleus slices of rats.

PubMed

Fu, Bao; Liu, Chengxi; Zhang, Yajun; Fu, Xiaoyun; Zhang, Lin; Yu, Tian

2017-08-23

Ketamine is a frequently used intravenous anesthetic, which can reversibly induce loss of consciousness (LOC). Previous studies have demonstrated that thalamocortical system is critical for information transmission and integration in the brain. The ventral posteromedial nucleus (VPM) is a critical component of thalamocortical system. Glutamate is an important excitatory neurotransmitter in the brain and may be involved in ketamine-induced LOC. The study used whole-cell patch-clamp to observe the effect of ketamine (30 μM-1000 μM) on glutamatergic neurotransmission in VPM slices. Ketamine significantly decreased the amplitude of glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs), but only higher concentration of ketamine (300 μM and 1000 μM) suppressed the frequency of sEPSCs. Ketamine (100 μM-1000 μM) also decreased the amplitude of glutamatergic miniature excitatory postsynaptic currents (mEPSCs), without altering the frequency. In VPM neurons, ketamine attenuates the glutamatergic neurotransmission mainly through postsynaptic mechanism and action potential may be involved in the process.

Functional dependence of neuroligin on a new non-PDZ intracellular domain

PubMed Central

Shipman, Seth L; Schnell, Eric; Hirai, Takaaki; Chen, Bo-Shiun; Roche, Katherine W; Nicoll, Roger A

2011-01-01

Neuroligins, a family of postsynaptic adhesion molecules, are important in synaptogenesis through a well-characterized trans-synaptic interaction with neurexin. In addition, neuroligins are thought to drive postsynaptic assembly through binding of their intracellular domain to PSD-95. However, there is little direct evidence to support the functional necessity of the neuroligin intracellular domain in postsynaptic development. We found that presence of endogenous neuroligin obscured the study of exogenous mutated neuroligin. We therefore used chained microRNAs in rat organotypic hippocampal slices to generate a reduced background of endogenous neuroligin. On this reduced background, we found that neuroligin function was critically dependent on the cytoplasmic tail. However, this function required neither the PDZ ligand nor any other previously described cytoplasmic binding domain, but rather required a previously unknown conserved region. Mutation of a single critical residue in this region inhibited neuroligin-mediated excitatory synaptic potentiation. Finally, we found a functional distinction between neuroligins 1 and 3. PMID:21532576

Neuromodulated Spike-Timing-Dependent Plasticity, and Theory of Three-Factor Learning Rules

PubMed Central

Frémaux, Nicolas; Gerstner, Wulfram

2016-01-01

Classical Hebbian learning puts the emphasis on joint pre- and postsynaptic activity, but neglects the potential role of neuromodulators. Since neuromodulators convey information about novelty or reward, the influence of neuromodulators on synaptic plasticity is useful not just for action learning in classical conditioning, but also to decide “when” to create new memories in response to a flow of sensory stimuli. In this review, we focus on timing requirements for pre- and postsynaptic activity in conjunction with one or several phasic neuromodulatory signals. While the emphasis of the text is on conceptual models and mathematical theories, we also discuss some experimental evidence for neuromodulation of Spike-Timing-Dependent Plasticity. We highlight the importance of synaptic mechanisms in bridging the temporal gap between sensory stimulation and neuromodulatory signals, and develop a framework for a class of neo-Hebbian three-factor learning rules that depend on presynaptic activity, postsynaptic variables as well as the influence of neuromodulators. PMID:26834568

Dendritic position is a major determinant of presynaptic strength

PubMed Central

de Jong, Arthur P.H.; Schmitz, Sabine K.; Toonen, Ruud F.G.

2012-01-01

Different regulatory principles influence synaptic coupling between neurons, including positional principles. In dendrites of pyramidal neurons, postsynaptic sensitivity depends on synapse location, with distal synapses having the highest gain. In this paper, we investigate whether similar rules exist for presynaptic terminals in mixed networks of pyramidal and dentate gyrus (DG) neurons. Unexpectedly, distal synapses had the lowest staining intensities for vesicular proteins vGlut, vGAT, Synaptotagmin, and VAMP and for many nonvesicular proteins, including Bassoon, Munc18, and Syntaxin. Concomitantly, distal synapses displayed less vesicle release upon stimulation. This dependence of presynaptic strength on dendritic position persisted after chronically blocking action potential firing and postsynaptic receptors but was markedly reduced on DG dendrites compared with pyramidal dendrites. These data reveal a novel rule, independent of neuronal activity, which regulates presynaptic strength according to dendritic position, with the strongest terminals closest to the soma. This gradient is opposite to postsynaptic gradients observed in pyramidal dendrites, and different cell types apply this rule to a different extent. PMID:22492722

Pain-related somatosensory evoked potentials and functional brain magnetic resonance in the evaluation of neurologic recovery after cardiac arrest: a case study of three patients.

PubMed

Zanatta, Paolo; Messerotti Benvenuti, Simone; Baldanzi, Fabrizio; Bendini, Matteo; Saccavini, Marsilio; Tamari, Wadih; Palomba, Daniela; Bosco, Enrico

2012-03-31

This case series investigates whether painful electrical stimulation increases the early prognostic value of both somatosensory-evoked potentials and functional magnetic resonance imaging in comatose patients after cardiac arrest. Three single cases with hypoxic-ischemic encephalopathy were considered. A neurophysiological evaluation with an electroencephalogram and somatosensory-evoked potentials during increased electrical stimulation in both median nerves was performed within five days of cardiac arrest. Each patient also underwent a functional magnetic resonance imaging evaluation with the same neurophysiological protocol one month after cardiac arrest. One patient, who completely recovered, showed a middle latency component at a high intensity of stimulation and the activation of all brain areas involved in cerebral pain processing. One patient in a minimally conscious state only showed the cortical somatosensory response and the activation of the primary somatosensory cortex. The last patient, who was in a vegetative state, did not show primary somatosensory evoked potentials; only the activation of subcortical brain areas occurred. These preliminary findings suggest that the pain-related somatosensory evoked potentials performed to increase the prognosis of comatose patients after cardiac arrest are associated with regional brain activity showed by functional magnetic resonance imaging during median nerves electrical stimulation. More importantly, this cases report also suggests that somatosensory evoked potentials and functional magnetic resonance imaging during painful electrical stimulation may be sensitive and complementary methods to predict the neurological outcome in the acute phase of coma. Thus, pain-related somatosensory-evoked potentials may be a reliable and a cost-effective tool for planning the early diagnostic evaluation of comatose patients.

Characterization of Motor and Somatosensory Evoked Potentials in the Yucatan Micropig Using Transcranial and Epidural Stimulation.

PubMed

Benavides, Francisco D; Santamaria, Andrea J; Bodoukhin, Nikita; Guada, Luis G; Solano, Juan P; Guest, James D

2017-09-15

Yucatan micropigs have brain and spinal cord dimensions similar to humans and are useful for certain spinal cord injury (SCI) translational studies. Micropigs are readily trained in behavioral tasks, allowing consistent testing of locomotor loss and recovery. However, there has been little description of their motor and sensory pathway neurophysiology. We established methods to assess motor and sensory cortical evoked potentials in the anesthetized, uninjured state. We also evaluated epidurally evoked motor and sensory stimuli from the T6 and T9 levels, spanning the intended contusion injury epicenter. Response detection frequency, mean latency and amplitude values, and variability of evoked potentials were determined. Somatosensory evoked potentials were reliable and best detected during stimulation of peripheral nerve and epidural stimulation by referencing the lateral cortex to midline Fz. The most reliable hindlimb motor evoked potential (MEP) occurred in tibialis anterior. We found MEPs in forelimb muscles in response to thoracic epidural stimulation likely generated from propriospinal pathways. Cranially stimulated MEPs were easier to evoke in the upper limbs than in the hindlimbs. Autopsy studies revealed substantial variations in cortical morphology between animals. This electrophysiological study establishes that neurophysiological measures can be reliably obtained in micropigs in a time frame compatible with other experimental procedures, such as SCI and transplantation. It underscores the need to better understand the motor control pathways, including the corticospinal tract, to determine which therapeutics are suitable for testing in the pig model.

The impact of short term synaptic depression and stochastic vesicle dynamics on neuronal variability

PubMed Central

Reich, Steven

2014-01-01

Neuronal variability plays a central role in neural coding and impacts the dynamics of neuronal networks. Unreliability of synaptic transmission is a major source of neural variability: synaptic neurotransmitter vesicles are released probabilistically in response to presynaptic action potentials and are recovered stochastically in time. The dynamics of this process of vesicle release and recovery interacts with variability in the arrival times of presynaptic spikes to shape the variability of the postsynaptic response. We use continuous time Markov chain methods to analyze a model of short term synaptic depression with stochastic vesicle dynamics coupled with three different models of presynaptic spiking: one model in which the timing of presynaptic action potentials are modeled as a Poisson process, one in which action potentials occur more regularly than a Poisson process (sub-Poisson) and one in which action potentials occur more irregularly (super-Poisson). We use this analysis to investigate how variability in a presynaptic spike train is transformed by short term depression and stochastic vesicle dynamics to determine the variability of the postsynaptic response. We find that sub-Poisson presynaptic spiking increases the average rate at which vesicles are released, that the number of vesicles released over a time window is more variable for smaller time windows than larger time windows and that fast presynaptic spiking gives rise to Poisson-like variability of the postsynaptic response even when presynaptic spike times are non-Poisson. Our results complement and extend previously reported theoretical results and provide possible explanations for some trends observed in recorded data. PMID:23354693

High-frequency stimulation of the temporoammonic pathway induces input-specific long-term potentiation in subicular bursting cells.

PubMed

Fidzinski, Pawel; Wawra, Matthias; Bartsch, Julia; Heinemann, Uwe; Behr, Joachim

2012-01-09

The subiculum (Sub) as a part of the hippocampal formation is thought to play a functional role in learning and memory. In addition to its major input from CA1 pyramidal cells, the subiculum receives input from the entorhinal cortex (EC) via the temporoammonic pathway. Thus far, synaptic plasticity in the subiculum was mainly investigated at CA1-Sub synapses. According to their spiking pattern, pyramidal cells in the subiculum were classified as bursting cells and non-bursting cells. In the present study, we demonstrate that subicular bursting cells show input-specific forms of long-term potentiation (LTP). At CA1-Sub synapses, bursting cells have been shown to express a presynaptic NMDA receptor-dependent LTP that depends on the activation of a cAMP-PKA cascade (Wozny et al., Journal of Physiology 2008). In contrast, at EC-Sub synapses the induction of LTP in bursting cells shows a high induction-threshold and relies on the activation of postsynaptic NMDA receptors, postsynaptic depolarization and postsynaptic Ca(2+) influx. Each form of LTP is input-specific and fails to induce heterosynaptic plasticity. Taken together, our data suggest that distinct, input-specific mechanisms govern high frequency-induced LTP at subicular bursting cells' synapses. Copyright © 2011 Elsevier B.V. All rights reserved.

Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons

PubMed Central

Zhou, Chengwen; Sun, Hongyu; Klein, Peter M.; Jensen, Frances E.

2015-01-01

Neonatal seizures are commonly caused by hypoxic and/or ischemic injury during birth and can lead to long-term epilepsy and cognitive deficits. In a rodent hypoxic seizure (HS) model, we have previously demonstrated a critical role for seizure-induced enhancement of the AMPA subtype of glutamate receptor (GluA) in epileptogenesis and cognitive consequences, in part due to GluA maturational upregulation of expression. Similarly, as the expression and function of the N-Methyl-D-aspartate (NMDA) subtype of glutamate receptor (GluN) is also developmentally controlled, we examined how early life seizures during the critical period of synaptogenesis could modify GluN development and function. In a postnatal day (P)10 rat model of neonatal seizures, we found that seizures could alter GluN2/3 subunit composition of GluNs and physiological function of synaptic GluNs. In hippocampal slices removed from rats within 48–96 h following seizures, the amplitudes of synaptic GluN-mediated evoked excitatory postsynaptic currents (eEPSCs) were elevated in CA1 pyramidal neurons. Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg2+ sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively. These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein. These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain. PMID:26441533

The effects of lindane and long-term potentiation (LTP) on pyramidal cell excitability in the rat hippocampal slice.

PubMed

Albertson, T E; Walby, W F; Stark, L G; Joy, R M

1997-01-01

An in vitro orthodromic stimulation technique was used to examine the effects of lindane and long-term potentiation (LTP) inducing stimuli, alone or in combination, on the excitatory afferent terminal of CA1 pyramidal cells and on recurrent collateral evoked inhibition using the rat hippocampal slice model. Hippocampal slices of 400 microns thickness were perfused with oxygenated artificial cerebrospinal fluid. Stimulation of Schaffer collateral/commissural fibers produced extracellular excitatory postsynaptic potential (EPSP) and/or populations spike (PS) responses recorded from electrodes in the CA1 region. A paired-pulse technique was used to measure gamma-aminobutyric acid (GABAA)-mediated recurrent inhibition before and after treatments. After both lindane and LTP, larger PS amplitudes for a given stimulus intensity were seen. The resulting leftward shift in the curve of the PS amplitude versus stimulus intensity was larger after LTP than after 25 microM lindane. Both lindane and LTP treatments reduced PS thresholds and reduced or eliminated recurrent inhibition as measured by paired-pulse stimulation at the 15 msec interval. The reduction of recurrent inhibition after both treatments was more pronounced at lower stimulus intensities. When LTP stimuli were applied after lindane exposure a further large shift to the left was seen in the PS amplitude versus stimulus intensity curve. A smaller shift to the left was seen in the PS amplitude versus stimulus intensity curve only at the higher stimuli when lindane exposure occurred after LTP. Only at low stimulus intensities were further argumentations seen in PS amplitudes when the LTP stimuli was followed by a second LTP stimuli. Previous exposure to 25 microM lindane stimuli does not block the development of a further robust LTP in this in vitro model.

The Nature and Process of Development in Averaged Visually Evoked Potentials: Discussion on Pattern Structure.

ERIC Educational Resources Information Center

Izawa, Shuji; Mizutani, Tohru

This paper examines the development of visually evoked EEG patterns in retarded and normal subjects. The paper focuses on the averaged visually evoked potentials (AVEP) in the central and occipital regions of the brain in eyes closed and eyes open conditions. Wave pattern, amplitude, and latency are examined. The first section of the paper reviews…

Phantom somatosensory evoked potentials following selective intraneural electrical stimulation in two amputees.

PubMed

Granata, Giuseppe; Di Iorio, Riccardo; Romanello, Roberto; Iodice, Francesco; Raspopovic, Stanisa; Petrini, Francesco; Strauss, Ivo; Valle, Giacomo; Stieglitz, Thomas; Čvančara, Paul; Andreu, David; Divoux, Jean-Louis; Guiraud, David; Wauters, Loic; Hiairrassary, Arthur; Jensen, Winnie; Micera, Silvestro; Rossini, Paolo Maria

2018-06-01

The aim of the paper is to objectively demonstrate that amputees implanted with intraneural interfaces are truly able to feel a sensation in the phantom hand by recording "phantom" somatosensory evoked potentials from the corresponding brain areas. We implanted four transverse intrafascicular multichannel electrodes, available with percutaneous connections to a multichannel electrical stimulator, in the median and ulnar nerves of two left trans-radial amputees. Two channels of the implants that were able to elicit sensations during intraneural nerve stimulation were chosen, in both patients, for recording somatosensory evoked potentials. We recorded reproducible evoked responses by stimulating the median and the ulnar nerves in both cases. Latencies were in accordance with the arrival of somatosensory information to the primary somatosensory cortex. Our results provide evidence that sensations generated by intraneural stimulation are truly perceived by amputees and located in the phantom hand. Moreover, our results strongly suggest that sensations perceived in different parts of the phantom hand result in different evoked responses. Somatosensory evoked potentials obtained by selective intraneural electrical stimulation in amputee patients are a useful tool to provide an objective demonstration of somatosensory feedback in new generation bidirectional prostheses. Copyright © 2018. Published by Elsevier B.V.

Effects of single cycle binaural beat duration on auditory evoked potentials.

PubMed

Mihajloski, Todor; Bohorquez, Jorge; Özdamar, Özcan

2014-01-01

Binaural beat (BB) illusions are experienced as continuous central pulsations when two sounds with slightly different frequencies are delivered to each ear. It has been shown that steady-state auditory evoked potentials (AEPs) to BBs can be captured and investigated. The authors recently developed a new method of evoking transient AEPs to binaural beats using frequency modulated stimuli. This methodology was able to create single BBs in predetermined intervals with varying carrier frequencies. This study examines the effects of the BB duration and the frequency modulating component of the stimulus on the binaural beats and their evoked potentials. Normal hearing subjects were tested with a set of four durations (25, 50, 100, and 200 ms) with two stimulation configurations, binaural dichotic (binaural beats) and diotic (frequency modulation). The results obtained from the study showed that out of the given durations, the 100 ms beat, was capable of evoking the largest amplitude responses. The frequency modulation effect showed a decrease in peak amplitudes with increasing beat duration until their complete disappearance at 200 ms. Even though, at 200 ms, the frequency modulation effects were not present, the binaural beats were still perceived and captured as evoked potentials.

Diagnostic accuracy of evoked potentials for functional impairment after contusive spinal cord injury in adult rats.

PubMed

Thirumala, Parthasarathy; Zhou, James; Krishnan, Rohan; Manem, Nihita; Umredkar, Shreya; Hamilton, D K; Balzer, Jeffrey R; Oudega, Martin

2016-03-01

Iatrogenic spinal cord injury (SCI) is a cause of potentially debilitating post-operative neurologic complications. Currently, intra-operative neurophysiological monitoring (IONM) via somatosensory evoked potentials and motor-evoked potentials is used to detect and prevent impending SCI. However, no empirically validated interventions exist to halt the progression of iatrogenic SCI once it is detected. This is in part due to the lack of a suitable translational model that mimics the circumstances surrounding iatrogenic SCI detected via IONM. Here, we evaluate a model of simulated contusive iatrogenic SCI detected via IONM in adult female Sprague-Dawley rats. We show that transient losses of somatosensory evoked potentials responses are 88.24% sensitive (95% confidence interval [CI] 63.53-98.20) and 80% specific (95% CI 51.91-95.43) for significant functional impairment following simulated iatrogenic SCI. Similarly, we show that transient losses in motor-evoked potentials responses are 70.83% sensitive (95% CI 48.91-87.33) and 100% specific (95% CI 62.91-100.00) for significant functional impairment following simulated iatrogenic SCI. These results indicate that our model is a suitable replica of the circumstances surrounding clinical iatrogenic SCI. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synaptic Impairment in Layer 1 of the Prefrontal Cortex Induced by Repeated Stress During Adolescence is Reversed in Adulthood

PubMed Central

Negrón-Oyarzo, Ignacio; Dagnino-Subiabre, Alexies; Muñoz Carvajal, Pablo

2015-01-01

Chronic stress is a risk factor for the development of psychiatric disorders, some of which involve dysfunction of the prefrontal cortex (PFC). There is a higher prevalence of these chronic stress-related psychiatric disorders during adolescence, when the PFC has not yet fully matured. In the present work we studied the effect of repeated stress during adolescence on synaptic function in the PFC in adolescence and adulthood. To this end, adolescent Sprague-Dawley rats were subjected to seven consecutive days of restraint stress. Afterward, both synaptic transmission and short- and long-term synaptic plasticity were evaluated in layer 1 of medial-PFC (mPFC) slices from adolescent and adult rats. We found that repeated stress significantly reduced the amplitude of evoked field excitatory post-synaptic potential (fEPSP) in the mPFC. Isolation of excitatory transmission reveled that lower-amplitude fEPSPs were associated with a reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated transmission. We also found that repeated stress significantly decreased long-term depression (LTD). Interestingly, AMPA/kainate receptor-mediated transmission and LTD were recovered in adult animals that experienced a three-week stress-free recovery period. The data indicates that the changes in synaptic transmission and plasticity in the mPFC induced by repeated stress during adolescence are reversed in adulthood after a stress-free period. PMID:26617490

Kindling alters entorhinal cortex-hippocampal interaction by increased efficacy of presynaptic GABA(B) autoreceptors in layer III of the entorhinal cortex.

PubMed

Gloveli, Tengis; Behr, Joachim; Dugladze, Tamar; Kokaia, Zaal; Kokaia, Merab; Heinemann, Uwe

2003-08-01

We studied the effect of kindling, a model of temporal lobe epilepsy, on the frequency-dependent information transfer from the entorhinal cortex to the hippocampus in vitro. In control rats repetitive synaptic activation of layer III projection cells resulted in a frequency dependent depression of the synaptic transfer of action potentials to the hippocampus. One-to-two-days after kindling this effect was strongly reduced. Although no substantial change in synaptic inhibition upon single electrical stimulation was detected in kindled rats, there was a significant depression in the prolonged inhibition following high frequency stimulation. In kindled animals, paired-pulse depression (PPD) of stimulus-evoked IPSCs in layer III neurons was significantly stronger than in control rats. The increase of PPD is most likely caused by an increased presynaptic GABA(B) receptor-mediated autoinhibition. In kindled animals activation of presynaptic GABA(B) receptors by baclofen (10 microM) suppressed monosynaptic IPSCs significantly more than in control rats. In contrast, activation of postsynaptic GABA(B) receptors by baclofen was accompanied by comparable changes of the membrane conductance in both animal groups. Thus, in kindled animals activation of the layer III-CA1 pathway is facilitated by an increased GABA(B) receptor-mediated autoinhibition leading to an enhanced activation of the monosynaptic EC-CA1 pathway.

Synaptic Impairment in Layer 1 of the Prefrontal Cortex Induced by Repeated Stress During Adolescence is Reversed in Adulthood.

PubMed

Negrón-Oyarzo, Ignacio; Dagnino-Subiabre, Alexies; Muñoz Carvajal, Pablo

2015-01-01

Chronic stress is a risk factor for the development of psychiatric disorders, some of which involve dysfunction of the prefrontal cortex (PFC). There is a higher prevalence of these chronic stress-related psychiatric disorders during adolescence, when the PFC has not yet fully matured. In the present work we studied the effect of repeated stress during adolescence on synaptic function in the PFC in adolescence and adulthood. To this end, adolescent Sprague-Dawley rats were subjected to seven consecutive days of restraint stress. Afterward, both synaptic transmission and short- and long-term synaptic plasticity were evaluated in layer 1 of medial-PFC (mPFC) slices from adolescent and adult rats. We found that repeated stress significantly reduced the amplitude of evoked field excitatory post-synaptic potential (fEPSP) in the mPFC. Isolation of excitatory transmission reveled that lower-amplitude fEPSPs were associated with a reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated transmission. We also found that repeated stress significantly decreased long-term depression (LTD). Interestingly, AMPA/kainate receptor-mediated transmission and LTD were recovered in adult animals that experienced a three-week stress-free recovery period. The data indicates that the changes in synaptic transmission and plasticity in the mPFC induced by repeated stress during adolescence are reversed in adulthood after a stress-free period.

Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice

PubMed Central

Paul, Kush; Venkitaramani, Deepa V; Cox, Charles L

2013-01-01

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long-lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1-type receptors seen in wild-type mice; however, such enhancement is absent in the Fmr1 knock-out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS. PMID:23148316

Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice.

PubMed

Paul, Kush; Venkitaramani, Deepa V; Cox, Charles L

2013-02-15

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long-lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1-type receptors seen in wild-type mice; however, such enhancement is absent in the Fmr1 knock-out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS.

Improving Focal Photostimulation of Cortical Neurons with Pre-derived Wavefront Correction

PubMed Central

Choy, Julian M. C.; Sané, Sharmila S.; Lee, Woei M.; Stricker, Christian; Bachor, Hans A.; Daria, Vincent R.

2017-01-01

Recent progress in neuroscience to image and investigate brain function has been made possible by impressive developments in optogenetic and opto-molecular tools. Such research requires advances in optical techniques for the delivery of light through brain tissue with high spatial resolution. The tissue causes distortions to the wavefront of the incoming light which broadens the focus and consequently reduces the intensity and degrades the resolution. Such effects are detrimental in techniques requiring focal stimulation. Adaptive wavefront correction has been demonstrated to compensate for these distortions. However, iterative derivation of the corrective wavefront introduces time constraints that limit its applicability to probe living cells. Here, we demonstrate that we can pre-determine and generalize a small set of Zernike modes to correct for aberrations of the light propagating through specific brain regions. A priori identification of a corrective wavefront is a direct and fast technique that improves the quality of the focus without the need for iterative adaptive wavefront correction. We verify our technique by measuring the efficiency of two-photon photolysis of caged neurotransmitters along the dendrites of a whole-cell patched neuron. Our results show that encoding the selected Zernike modes on the excitation light can improve light propagation through brain slices of rats as observed by the neuron's evoked excitatory post-synaptic potential in response to localized focal uncaging at the spines of the neuron's dendrites. PMID:28507508

Melatonin inhibits voltage-sensitive Ca(2+) channel-mediated neurotransmitter release.

PubMed

Choi, Tae-Yong; Kwon, Ji Eun; Durrance, Eunice Sung; Jo, Su-Hyun; Choi, Se-Young; Kim, Kyong-Tai

2014-04-04

Melatonin is involved in various neuronal functions such as circadian rhythmicity and thermoregulation. Melatonin has a wide range of pharmacologically effective concentration levels from the nanomolar to millimolar levels. Recently, the antiepileptic effect of high dose melatonin has been the focus of clinical studies; however, its detailed mechanism especially in relation to neurotransmitter release and synaptic transmission remains unclear. We studied the effect of melatonin at high concentrations on the neurotransmitter release by monitoring norepinephrine release in PC12 cells, and excitatory postsynaptic potential in rat hippocampal slices. Melatonin inhibits the 70mM K(+)-induced Ca(2+) increase at millimolar levels without effect on bradykinin-triggered Ca(2+) increase in PC12 cells. Melatonin (1mM) did not affect A2A adenosine receptor-evoked cAMP production, and classical melatonin receptor antagonists did not reverse the melatonin-induced inhibitory effect, suggesting G-protein coupled receptor independency. Melatonin inhibits the 70mM K(+)-induced norepinephrine release at a similar effective concentration range in PC12 cells. We confirmed that melatonin (100µM) inhibits excitatory synaptic transmission of the hippocampal Schaffer collateral pathway with the decrease in basal synaptic transmission and the increase in paired pulse ratio. These results show that melatonin inhibits neurotransmitter release through the blocking of voltage-sensitive Ca(2+) channels and suggest a possible mechanism for the antiepileptic effect of melatonin. Copyright © 2014 Elsevier B.V. All rights reserved.

Proteasome-independent polyubiquitin linkage regulates synapse scaffolding, efficacy, and plasticity

PubMed Central

Ma, Qi; Ruan, Hongyu; Peng, Lisheng; Zhang, Mingjie; Gack, Michaela U.

2017-01-01

Ubiquitination-directed proteasomal degradation of synaptic proteins, presumably mediated by lysine 48 (K48) of ubiquitin, is a key mechanism in synapse and neural circuit remodeling. However, more than half of polyubiquitin (polyUb) species in the mammalian brain are estimated to be non-K48; among them, the most abundant is Lys 63 (K63)-linked polyUb chains that do not tag substrates for degradation but rather modify their properties and activity. Virtually nothing is known about the role of these nonproteolytic polyUb chains at the synapse. Here we report that K63-polyUb chains play a significant role in postsynaptic protein scaffolding and synaptic strength and plasticity. We found that the postsynaptic scaffold PSD-95 (postsynaptic density protein 95) undergoes K63 polyubiquitination, which markedly modifies PSD-95’s scaffolding potentials, enables its synaptic targeting, and promotes synapse maturation and efficacy. TNF receptor-associated factor 6 (TRAF6) is identified as a direct E3 ligase for PSD-95, which, together with the E2 complex Ubc13/Uev1a, assembles K63-chains on PSD-95. In contrast, CYLD (cylindromatosis tumor-suppressor protein), a K63-specific deubiquitinase enriched in postsynaptic densities, cleaves K63-chains from PSD-95. We found that neuronal activity exerts potent control of global and synaptic K63-polyUb levels and, through NMDA receptors, drives rapid, CYLD-mediated PSD-95 deubiquitination, mobilizing and depleting PSD-95 from synapses. Silencing CYLD in hippocampal neurons abolishes NMDA-induced chemical long-term depression. Our results unveil a previously unsuspected role for nonproteolytic polyUb chains in the synapse and illustrate a mechanism by which a PSD-associated K63-linkage–specific ubiquitin machinery acts on a major postsynaptic scaffold to regulate synapse organization, function, and plasticity. PMID:28973854

Parkin Deficiency Reduces Hippocampal Glutamatergic Neurotransmission by Impairing AMPA Receptor Endocytosis.

PubMed

Cortese, Giuseppe P; Zhu, Mei; Williams, Damian; Heath, Sarah; Waites, Clarissa L

2016-11-30

Mutations in the gene encoding Parkin, an E3 ubiquitin ligase, lead to juvenile-onset Parkinson's disease by inducing the selective death of midbrain dopaminergic neurons. Accumulating evidence indicates that Parkin also has an important role in excitatory glutamatergic neurotransmission, although its precise mechanism of action remains unclear. Here, we investigate Parkin's role at glutamatergic synapses of rat hippocampal neurons. We find that Parkin-deficient neurons exhibit significantly reduced AMPA receptor (AMPAR)-mediated currents and cell-surface expression, and that these phenotypes result from decreased postsynaptic expression of the adaptor protein Homer1, which is necessary for coupling AMPAR endocytic zones with the postsynaptic density. Accordingly, Parkin loss of function leads to the reduced density of postsynaptic endocytic zones and to impaired AMPAR internalization. These findings demonstrate a novel and essential role for Parkin in glutamatergic neurotransmission, as a stabilizer of postsynaptic Homer1 and the Homer1-linked endocytic machinery necessary for maintaining normal cell-surface AMPAR levels. Mutations in Parkin, a ubiquitinating enzyme, lead to the selective loss of midbrain dopaminergic neurons and juvenile-onset Parkinson's disease (PD). Parkin loss of function has also been shown to alter hippocampal glutamatergic neurotransmission, providing a potential explanation for PD-associated cognitive impairment. However, very little is known about Parkin's specific sites or mechanisms of action at glutamatergic synapses. Here, we show that Parkin deficiency leads to decreased AMPA receptor-mediated activity due to disruption of the postsynaptic endocytic zones required for maintaining proper cell-surface AMPA receptor levels. These findings demonstrate a novel role for Parkin in synaptic AMPA receptor internalization and suggest a Parkin-dependent mechanism for hippocampal dysfunction that may explain cognitive deficits associated with some forms of PD. Copyright © 2016 the authors 0270-6474/16/3612243-16$15.00/0.

Unknown Pseudocholinesterase Deficiency in a Patient Undergoing TIVA with Planned Motor Evoked Potential Monitoring: A Case Report.

PubMed

Binkley, Candace

2016-06-01

Pseudocholinesterase abnormalities are a genetic cause of aberrant metabolism of the depolarizing muscle relaxant succinylcholine. This article examines a case where succinylcholine was chosen to facilitate intubation due to its ultra short duration and the request of the surgeon to monitor motor evoked potentials. Following succinylcholine administration the neurophysiologist was unable to obtain motor evoked potentials. This case study highlights the intraoperative and postoperative management of an elderly patient with an unknown pseudocholinesterase deficiency.

Patient autoantibodies deplete postsynaptic muscle-specific kinase leading to disassembly of the ACh receptor scaffold and myasthenia gravis in mice

PubMed Central

Cole, R N; Ghazanfari, N; Ngo, S T; Gervásio, O L; Reddel, S W; Phillips, W D

2010-01-01

The postsynaptic muscle-specific kinase (MuSK) coordinates formation of the neuromuscular junction (NMJ) during embryonic development. Here we have studied the effects of MuSK autoantibodies upon the NMJ in adult mice. Daily injections of IgG from four MuSK autoantibody-positive myasthenia gravis patients (MuSK IgG; 45 mg day−1i.p. for 14 days) caused reductions in postsynaptic ACh receptor (AChR) packing as assessed by fluorescence resonance energy transfer (FRET). IgG from the patients with the highest titres of MuSK autoantibodies caused large (51–73%) reductions in postsynaptic MuSK staining (cf. control mice; P < 0.01) and muscle weakness. Among mice injected for 14 days with control and MuSK patient IgGs, the residual level of MuSK correlated with the degree of impairment of postsynaptic AChR packing. However, the loss of postsynaptic MuSK preceded this impairment of postsynaptic AChR. When added to cultured C2 muscle cells the MuSK autoantibodies caused tyrosine phosphorylation of MuSK and the AChR β-subunit, and internalization of MuSK from the plasma membrane. The results suggest a pathogenic mechanism in which MuSK autoantibodies rapidly deplete MuSK from the postsynaptic membrane leading to progressive dispersal of postsynaptic AChRs. Moreover, maintenance of postsynaptic AChR packing at the adult NMJ would appear to depend upon physical engagement of MuSK with the AChR scaffold, notwithstanding activation of the MuSK-rapsyn system of AChR clustering. PMID:20603331

Human auditory evoked potentials in the assessment of brain function during major cardiovascular surgery.

PubMed

Rodriguez, Rosendo A

2004-06-01

Focal neurologic and intellectual deficits or memory problems are relatively frequent after cardiac surgery. These complications have been associated with cerebral hypoperfusion, embolization, and inflammation that occur during or after surgery. Auditory evoked potentials, a neurophysiologic technique that evaluates the function of neural structures from the auditory nerve to the cortex, provide useful information about the functional status of the brain during major cardiovascular procedures. Skepticism regarding the presence of artifacts or difficulty in their interpretation has outweighed considerations of its potential utility and noninvasiveness. This paper reviews the evidence of their potential applications in several aspects of the management of cardiac surgery patients. The sensitivity of auditory evoked potentials to the effects of changes in brain temperature makes them useful for monitoring cerebral hypothermia and rewarming during cardiopulmonary bypass. The close relationship between evoked potential waveforms and specific anatomic structures facilitates the assessment of the functional integrity of the central nervous system in cardiac surgery patients. This feature may also be relevant in the management of critical patients under sedation and coma or in the evaluation of their prognosis during critical care. Their objectivity, reproducibility, and relative insensitivity to learning effects make auditory evoked potentials attractive for the cognitive assessment of cardiac surgery patients. From a clinical perspective, auditory evoked potentials represent an additional window for the study of underlying cerebral processes in healthy and diseased patients. From a research standpoint, this technology offers opportunities for a better understanding of the particular cerebral deficits associated with patients who are undergoing major cardiovascular procedures.

Physiological characterization, localization and synaptic inputs of bursting and nonbursting neurons in the trigeminal principal sensory nucleus of the rat.

PubMed

Athanassiadis, T; Westberg, K-G; Olsson, K A; Kolta, A

2005-12-01

A population of neurons in the trigeminal principal sensory nucleus (NVsnpr) fire rhythmically during fictive mastication induced in the in vivo rabbit. To elucidate whether these neurons form part of the central pattern generator (CPG) for mastication, we performed intracellular recordings in brainstem slices taken from young rats. Two cell types were defined, nonbursting (63%) and bursting (37%). In response to membrane depolarization, bursting cells, which dominated in the dorsal part of the NVsnpr, fired an initial burst followed by single spikes or recurring bursts. Non-bursting neurons, scattered throughout the nucleus, fired single action potentials. Microstimulation applied to the trigeminal motor nucleus (NVmt), the reticular border zone surrounding the NVmt, the parvocellular reticular formation or the nucleus reticularis pontis caudalis (NPontc) elicited a postsynaptic potential in 81% of the neurons tested for synaptic inputs. Responses obtained were predominately excitatory and sensitive to glutamatergic antagonists DNQX and/or APV. Some inhibitory and biphasic responses were also evoked. Bicuculline methiodide or strychnine blocked the IPSPs indicating that they were mediated by GABA(A) or glycinergic receptors. About one-third of the stimulations activated both types of neurons antidromically, mostly from the masseteric motoneuron pool of NVmt and dorsal part of NPontc. In conclusion, our new findings show that some neurons in the dorsal NVsnpr display both firing properties and axonal connections which support the hypothesis that they may participate in masticatory pattern generation. Thus, the present data provide an extended basis for further studies on the organization of the masticatory CPG network.

cGMP-Dependent Protein Kinase Inhibition Extends the Upper Temperature Limit of Stimulus-Evoked Calcium Responses in Motoneuronal Boutons of Drosophila melanogaster Larvae.

PubMed

Krill, Jennifer L; Dawson-Scully, Ken

2016-01-01

While the mammalian brain functions within a very narrow range of oxygen concentrations and temperatures, the fruit fly, Drosophila melanogaster, has employed strategies to deal with a much wider range of acute environmental stressors. The foraging (for) gene encodes the cGMP-dependent protein kinase (PKG), has been shown to regulate thermotolerance in many stress-adapted species, including Drosophila, and could be a potential therapeutic target in the treatment of hyperthermia in mammals. Whereas previous thermotolerance studies have looked at the effects of PKG variation on Drosophila behavior or excitatory postsynaptic potentials at the neuromuscular junction (NMJ), little is known about PKG effects on presynaptic mechanisms. In this study, we characterize presynaptic calcium ([Ca2+]i) dynamics at the Drosophila larval NMJ to determine the effects of high temperature stress on synaptic transmission. We investigated the neuroprotective role of PKG modulation both genetically using RNA interference (RNAi), and pharmacologically, to determine if and how PKG affects presynaptic [Ca2+]i dynamics during hyperthermia. We found that PKG activity modulates presynaptic neuronal Ca2+ responses during acute hyperthermia, where PKG activation makes neurons more sensitive to temperature-induced failure of Ca2+ flux and PKG inhibition confers thermotolerance and maintains normal Ca2+ dynamics under the same conditions. Targeted motoneuronal knockdown of PKG using RNAi demonstrated that decreased PKG expression was sufficient to confer thermoprotection. These results demonstrate that the PKG pathway regulates presynaptic motoneuronal Ca2+ signaling to influence thermotolerance of presynaptic function during acute hyperthermia.

Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists

PubMed Central

Kleschevnikov, A.M.; Belichenko, P.V.; Faizi, M.; Jacobs, L.F.; Htun, K.; Shamloo, M.; Mobley, W.C.

2012-01-01

Cognitive impairment in Down syndrome (DS) is characterized by deficient learning and memory. Mouse genetic models of DS exhibit impaired cognition in hippocampally mediated behavioral tasks and reduced synaptic plasticity of hippocampal pathways. Enhanced efficiency of GABAergic neurotransmission was implicated in those changes. We have recently shown that signaling through postsynaptic GABAB receptors is significantly increased in the dentate gyrus (DG) of Ts65Dn mice, a genetic model of DS. Here we examined a role for GABAB receptors in cognitive deficits in DS by defining the effect of selective GABAB receptor antagonists on behavior and synaptic plasticity of adult Ts65Dn mice. Treatment with the GABAB receptor antagonist CGP55845 restored memory of Ts65Dn mice in the novel place recognition, novel object recognition and contextual fear conditioning tasks, but did not affect locomotion and performance in T-maze. The treatment increased hippocampal levels of brain-derived neurotrophic factor (BDNF), equally in 2N and Ts65Dn mice. In hippocampal slices, treatment with the GABAB receptor antagonists CGP55845 or CGP52432 enhanced long-term potentiation (LTP) in the Ts65Dn DG. The enhancement of LTP was accompanied by an increase in the NMDA receptor-mediated component of the tetanus-evoked responses. These findings are evidence for a contribution of GABAB receptors to changes in hippocampal-based cognition in the Ts65Dn mouse. The ability to rescue cognitive performance through treatment with selective GABAB receptor antagonists motivates studies to further explore the therapeutic potential of these compounds in people with DS. PMID:22764230

A new method for registration of kinesthetic evoked potentials for studies of proprioceptive sensitivity in normal subjects and patients with organic lesions in the brain.

PubMed

Gordeev, S A; Voronin, S G

2015-01-01

The proprioceptive sensitivity of healthy volunteers and convalescents after acute cerebrovascular episodes was studied by a new neurophysiological method for registration of kinesthetic evoked potentials emerging in response to passive 50(o) bending of the hand in the wrist joint with the angular acceleration of 350 rad/sec(2). Kinesthetic evoked potentials were recorded above the somatosensory cortex projection areas in the hemispheres contra- and ipsilateral to the stimulated limb. The patients exhibited significantly longer latencies and lesser amplitudes of the early components of response in the involved hemisphere in comparison with normal subjects. The method for registration of the kinesthetic evoked potentials allows a more detailed study of the mechanisms of kinesthetic sensitivity in health and in organic involvement of the brain.

Vertex evoked potentials in a rating-scale detection task: Relation to signal probability

NASA Technical Reports Server (NTRS)

Squires, K. C.; Squires, N. K.; Hillyard, S. A.

1974-01-01

Vertex evoked potentials were recorded from human subjects performing in an auditory detection task with rating scale responses. Three values of a priori probability of signal presentation were tested. The amplitudes of the N1 and P3 components of the vertex potential associated with correct detections of the signal were found to be systematically related to the strictness of the response criterion and independent of variations in a priori signal probability. No similar evoked potential components were found associated with signal absent judgements (misses and correct rejections) regardless of the confidence level of the judgement or signal probability. These results strongly support the contention that the form of the vertex evoked response is closely correlated with the subject's psychophysical decision regarding the presence or absence of a threshold level signal.

Induction of Anti-Hebbian LTP in CA1 Stratum Oriens Interneurons: Interactions between Group I Metabotropic Glutamate Receptors and M1 Muscarinic Receptors

PubMed Central

Savary, Etienne; Kullmann, Dimitri M.; Miles, Richard

2015-01-01

An anti-Hebbian form of LTP is observed at excitatory synapses made with some hippocampal interneurons. LTP induction is facilitated when postsynaptic interneurons are hyperpolarized, presumably because Ca2+ entry through Ca2+-permeable glutamate receptors is enhanced. The contribution of modulatory transmitters to anti-Hebbian LTP induction remains to be established. Activation of group I metabotropic receptors (mGluRs) is required for anti-Hebbian LTP induction in interneurons with cell bodies in the CA1 stratum oriens. This region receives a strong cholinergic innervation from the septum, and muscarinic acetylcholine receptors (mAChRs) share some signaling pathways and cooperate with mGluRs in the control of neuronal excitability. We therefore examined possible interactions between group I mGluRs and mAChRs in anti-Hebbian LTP at synapses which excite oriens interneurons in rat brain slices. We found that blockade of either group I mGluRs or M1 mAChRs prevented the induction of anti-Hebbian LTP by pairing presynaptic activity with postsynaptic hyperpolarization. Blocking either receptor also suppressed long-term effects of activation of the other G-protein coupled receptor on interneuron membrane potential. However, no crossed blockade was detected for mGluR or mAchR effects on interneuron after-burst potentials or on the frequency of miniature EPSPs. Paired recordings between pyramidal neurons and oriens interneurons were obtained to determine whether LTP could be induced without concurrent stimulation of cholinergic axons. Exogenous activation of mAChRs led to LTP, with changes in EPSP amplitude distributions consistent with a presynaptic locus of expression. LTP, however, required noninvasive presynaptic and postsynaptic recordings. SIGNIFICANCE STATEMENT In the hippocampus, a form of NMDA receptor-independent long-term potentiation (LTP) occurs at excitatory synapses made on some inhibitory neurons. This is preferentially induced when postsynaptic interneurons are hyperpolarized, depends on Ca2+ entry through Ca2+-permeable AMPA receptors, and has been labeled anti-Hebbian LTP. Here we show that this form of LTP also depends on activation of both group I mGluR and M1 mAChRs. We demonstrate that these G-protein coupled receptors (GPCRs) interact, because the blockade of one receptor suppresses long-term effects of activation of the other GPCR on both LTP and interneuron membrane potential. This LTP was also detected in paired recordings, although only when both presynaptic and postsynaptic recordings did not perturb the intracellular medium. Changes in EPSP amplitude distributions in dual recordings were consistent with a presynaptic locus of expression. PMID:26446209

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes

NASA Astrophysics Data System (ADS)

Jayant, Krishna; Hirtz, Jan J.; Plante, Ilan Jen-La; Tsai, David M.; de Boer, Wieteke D. A. M.; Semonche, Alexa; Peterka, Darcy S.; Owen, Jonathan S.; Sahin, Ozgur; Shepard, Kenneth L.; Yuste, Rafael

2017-05-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ∼15-30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5-1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures.

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes

PubMed Central

Jayant, Krishna; Hirtz, Jan J.; Plante, Ilan Jen-La; Tsai, David M.; De Boer, Wieteke D. A. M.; Semonche, Alexa; Peterka, Darcy S.; Owen, Jonathan S.; Sahin, Ozgur; Shepard, Kenneth L.; Yuste, Rafael

2017-01-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ~15–30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5–1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures. PMID:27941898

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes.

PubMed

Jayant, Krishna; Hirtz, Jan J; Plante, Ilan Jen-La; Tsai, David M; De Boer, Wieteke D A M; Semonche, Alexa; Peterka, Darcy S; Owen, Jonathan S; Sahin, Ozgur; Shepard, Kenneth L; Yuste, Rafael

2017-05-01

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ∼15-30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5-1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures.

Effects of core body temperature on changes in spinal somatosensory-evoked potential in acute spinal cord compression injury: an experimental study in the rat.

PubMed

Jou, I M

2000-08-01

Acute spinal cord injury was induced by a clip compression model in rats to approximate spinal cord injury encountered in spinal surgery. Spinal somatosensory-evoked potential neuromonitoring was used to study the electrophysiologic change. To compare and correlate changes in evoked potential after acute compression at different core temperatures with postoperative neurologic function and histologic change, to evaluate current intraoperative neuromonitoring warning criteria for neural damage, and to confirm the protective effect of hypothermia in acute spinal cord compression injury by electrophysiologic, histologic, and clinical observation. With the increase in aggressive correction of spinal deformities, and the invasiveness of surgical instruments, the incidence of neurologic complication appears to have increased despite the availability of sensitive intraoperative neuromonitoring techniques designed to alert surgeons to impending neural damage. Many reasons have been given for the frequent failures of neuromonitoring, but the influence of temperature-a very important and frequently encountered factor-on evoked potential has not been well documented. Specifically, decrease in amplitude and elongation of latency seem not to have been sufficiently taken into account when intraoperative neuromonitoring levels were interpreted and when acceptable intraoperative warning criteria were determined. Experimental acute spinal cord injury was induced in rats by clip compression for two different intervals and at three different core temperatures. Spinal somatosensory-evoked potential, elicited by stimulating the median nerve and recorded from the cervical interspinous C2-C3, was monitored immediately before and after compression, and at 15-minute intervals for 1 hour. Spinal somatosensory-evoked potential change is almost parallel to temperature-based amplitude reduction and latency elongation. Significant neurologic damage induced by acute compression of the cervical spinal cord produced a degree of effect on the amplitude of spinal somatosensory-evoked potential in normothermic conditions that differed from the effect in moderately hypothermic conditions. Using the same electromonitoring criteria,moderately hypothermic groups showed a significantly higher false-negative rate statistically (35%) than normothermic groups (10%). Systemic cooling may protect against the detrimental effects of aggressive spinal surgical procedures. There is still not enough published information available to establish statistically and ethically acceptable intraoperative neuromonitoring warning and intervention criteria conclusively. Therefore, an urgent need exists for further investigation. Although a reduction of more than 50% in evoked potential still seems acceptable as an indicator of impending neural function loss, maintenance of more than 50% of baseline evoked potential is no guarantee of normal postoperative neural function, especially at lower than normal temperatures.

[The modified method registration of kinesthetic evoked potentials and its application for research of proprioceptive sensitivity disorders at spondylogenic cervical myelopathy].

PubMed

Gordeev, S A; Voronin, S G

2016-01-01

To analyze the efficacy of modified (passive radiocarpal articulation flexion/extension) and «standard» (passive radiocarpal articulation flexion) methods of kinesthetic evoked potentials for proprioceptive sensitivity assessment in healthy subjects and patients with spondylotic cervical myelopathy. The study included 14 healthy subjects (4 women and 10 men, mean age 54.1±10.5 years) and 8 patients (2 women and 6 men, mean age 55.8±10.9 years) with spondylotic cervical myelopathy. Muscle-joint sensation was examined during the clinical study. A modified method of kinesthetic evoked potentials was developed. This method differed from the "standard" one by the organization of a cycle including several passive movements,where each new movement differed from the preceding one by the direction. The modified method of kinesthetic evoked potentials ensures more reliable kinesthetic sensitivity assessment due to movement variability. Asignificant increaseof the latent periods of the early components of the response was found in patients compared to healthy subjects. The modified method of kinesthetic evoked potentials can be used for objective diagnosis of proprioceptive sensitivity disorders in patients with spondylotic cervical myelopathy.

Feasibility and performance evaluation of generating and recording visual evoked potentials using ambulatory Bluetooth based system.

PubMed

Ellingson, Roger M; Oken, Barry

2010-01-01

Report contains the design overview and key performance measurements demonstrating the feasibility of generating and recording ambulatory visual stimulus evoked potentials using the previously reported custom Complementary and Alternative Medicine physiologic data collection and monitoring system, CAMAS. The methods used to generate visual stimuli on a PDA device and the design of an optical coupling device to convert the display to an electrical waveform which is recorded by the CAMAS base unit are presented. The optical sensor signal, synchronized to the visual stimulus emulates the brain's synchronized EEG signal input to CAMAS normally reviewed for the evoked potential response. Most importantly, the PDA also sends a marker message over the wireless Bluetooth connection to the CAMAS base unit synchronized to the visual stimulus which is the critical averaging reference component to obtain VEP results. Results show the variance in the latency of the wireless marker messaging link is consistent enough to support the generation and recording of visual evoked potentials. The averaged sensor waveforms at multiple CPU speeds are presented and demonstrate suitability of the Bluetooth interface for portable ambulatory visual evoked potential implementation on our CAMAS platform.

Visual evoked potential in RCS rats with Okayama University-type retinal prosthesis (OUReP™) implantation.

PubMed

Alamusi; Matsuo, Toshihiko; Hosoya, Osamu; Uchida, Tetsuya

2017-06-01

Photoelectric dye-coupled polyethylene film, designated Okayama University type-retinal prosthesis or OUReP™, generates light-evoked surface electric potentials and stimulates neurons. The dye-coupled films or plain films were implanted subretinally in both eyes of 10 Royal College of Surgeons rats with hereditary retinal dystrophy at the age of 6 weeks. Visual evoked potentials in response to monocular flashing light stimuli were recorded from cranially-fixed electrodes, 4 weeks and 8 weeks after the implantation. After the recording, subretinal film implantation was confirmed histologically in 7 eyes with dye-coupled films and 7 eyes with plain films. The recordings from these 7 eyes in each group were used for statistical analysis. The amplitudes of visual evoked potentials in the consecutive time points from 125 to 250 ms after flash were significantly larger in the 7 eyes with dye-coupled film implantation, compared to the 7 eyes with plain film implantation at 8 weeks after the implantation (P < 0.05, repeated-measure ANOVA). The photoelectric dye-coupled polyethylene film, as retinal prosthesis, gave rise to visual evoked potential in response to flashing light.

Voltage-clamp analysis of the potentiation of the slow Ca2+-activated K+ current in hippocampal pyramidal neurons.

PubMed

Borde, M; Bonansco, C; Fernández de Sevilla, D; Le Ray, D; Buño, W

2000-01-01

Exploring the principles that govern activity-dependent changes in excitability is an essential step to understand the function of the nervous system, because they act as a general postsynaptic control mechanism that modulates the flow of synaptic signals. We show an activity-dependent potentiation of the slow Ca2+-activated K+ current (sl(AHP)) which induces sustained decreases in the excitability in CA1 pyramidal neurons. We analyzed the sl(AHP) using the slice technique and voltage-clamp recordings with sharp or patch-electrodes. Using sharp electrodes-repeated activation with depolarizing pulses evoked a prolonged (8-min) potentiation of the amplitude (171%) and duration (208%) of the sl(AHP). Using patch electrodes, early after entering the whole-cell configuration (<20 min), responses were as those reported above. However, although the sl(AHP) remained unchanged, its potentiation was markedly reduced in later recordings, suggesting that the underlying mechanisms were rapidly eliminated by intracellular dialysis. Inhibition of L-type Ca2+ current by nifedipine (20 microM) markedly reduced the sl(AHP) (79%) and its potentiation (55%). Ryanodine (20 microM) that blocks the release of intracellular Ca2+ also reduced sl(AHP) (29%) and its potentiation (25%). The potentiation of the sl(AHP) induced a marked and prolonged (>50%; approximately equals 8 min) decrease in excitability. The results suggest that sl(AHP) is potentiated as a result of an increased intracellular Ca2+ concentration ([Ca2+]i) following activation of voltage-gated L-type Ca2+ channels, aided by the subsequent release of Ca2+ from intracellular stores. Another possibility is that repeated activation increases the Ca2+-binding capacity of the channels mediating the sl(AHP). This potentiation of the sl(AHP) could be relevant in hippocampal physiology, because the changes in excitability it causes may regulate the induction threshold of the long-term potentiation of synaptic efficacy. Moreover, the potentiation would act as a protective mechanism by reducing excitability and preventing the accumulation of intracellular Ca2+ to toxic levels when intense synaptic activation occurs.

Responses to Gamma-Aminobutyric Acid of Rat Visual Cortical Neurons in Tissue Slices

DTIC Science & Technology

1986-04-01

depolarizing afterpotentials ( DAPs ; Figure 3). The afterhyperpolarization (AHP) was defined as the hyperpolarization that follow one or more orthodromic...action potentials or action potentials elicited during a depolarizing current pulse (Figure 3). DAPs and AHPs were measured from the RMP. The term...inhibitory postsynaptic potential, DAP = depolarizing afterpotential, AHP= afterhyperpolarization. Dashed lines indicate the RMP. Asterisks indicate

Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release

PubMed Central

Zhang, Yonghong; Matt, Lucas; Patriarchi, Tommaso; Malik, Zulfiqar A; Chowdhury, Dhrubajyoti; Park, Deborah K; Renieri, Alessandra; Ames, James B; Hell, Johannes W

2014-01-01

Postsynaptic density protein-95 (PSD-95) is a central element of the postsynaptic architecture of glutamatergic synapses. PSD-95 mediates postsynaptic localization of AMPA receptors and NMDA receptors and plays an important role in synaptic plasticity. PSD-95 is released from postsynaptic membranes in response to Ca2+ influx via NMDA receptors. Here, we show that Ca2+/calmodulin (CaM) binds at the N-terminus of PSD-95. Our NMR structure reveals that both lobes of CaM collapse onto a helical structure of PSD-95 formed at its N-terminus (residues 1–16). This N-terminal capping of PSD-95 by CaM blocks palmitoylation of C3 and C5, which is required for postsynaptic PSD-95 targeting and the binding of CDKL5, a kinase important for synapse stability. CaM forms extensive hydrophobic contacts with Y12 of PSD-95. The PSD-95 mutant Y12E strongly impairs binding to CaM and Ca2+-induced release of PSD-95 from the postsynaptic membrane in dendritic spines. Our data indicate that CaM binding to PSD-95 serves to block palmitoylation of PSD-95, which in turn promotes Ca2+-induced dissociation of PSD-95 from the postsynaptic membrane. PMID:24705785

Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release.

PubMed

Zhang, Yonghong; Matt, Lucas; Patriarchi, Tommaso; Malik, Zulfiqar A; Chowdhury, Dhrubajyoti; Park, Deborah K; Renieri, Alessandra; Ames, James B; Hell, Johannes W

2014-06-17

Postsynaptic density protein-95 (PSD-95) is a central element of the postsynaptic architecture of glutamatergic synapses. PSD-95 mediates postsynaptic localization of AMPA receptors and NMDA receptors and plays an important role in synaptic plasticity. PSD-95 is released from postsynaptic membranes in response to Ca(2+) influx via NMDA receptors. Here, we show that Ca(2+)/calmodulin (CaM) binds at the N-terminus of PSD-95. Our NMR structure reveals that both lobes of CaM collapse onto a helical structure of PSD-95 formed at its N-terminus (residues 1-16). This N-terminal capping of PSD-95 by CaM blocks palmitoylation of C3 and C5, which is required for postsynaptic PSD-95 targeting and the binding of CDKL5, a kinase important for synapse stability. CaM forms extensive hydrophobic contacts with Y12 of PSD-95. The PSD-95 mutant Y12E strongly impairs binding to CaM and Ca(2+)-induced release of PSD-95 from the postsynaptic membrane in dendritic spines. Our data indicate that CaM binding to PSD-95 serves to block palmitoylation of PSD-95, which in turn promotes Ca(2+)-induced dissociation of PSD-95 from the postsynaptic membrane. © 2014 The Authors.

Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions

PubMed Central

Tomasetti, Carmine; Iasevoli, Felice; Buonaguro, Elisabetta Filomena; De Berardis, Domenico; Fornaro, Michele; Fiengo, Annastasia Lucia Carmela; Martinotti, Giovanni; Orsolini, Laura; Valchera, Alessandro; Di Giannantonio, Massimo; de Bartolomeis, Andrea

2017-01-01

Dopamine-glutamate interplay dysfunctions have been suggested as pathophysiological key determinants of major psychotic disorders, above all schizophrenia and mood disorders. For the most part, synaptic interactions between dopamine and glutamate signaling pathways take part in the postsynaptic density, a specialized ultrastructure localized under the membrane of glutamatergic excitatory synapses. Multiple proteins, with the role of adaptors, regulators, effectors, and scaffolds compose the postsynaptic density network. They form structural and functional crossroads where multiple signals, starting at membrane receptors, are received, elaborated, integrated, and routed to appropriate nuclear targets. Moreover, transductional pathways belonging to different receptors may be functionally interconnected through postsynaptic density molecules. Several studies have demonstrated that psychopharmacologic drugs may differentially affect the expression and function of postsynaptic genes and proteins, depending upon the peculiar receptor profile of each compound. Thus, through postsynaptic network modulation, these drugs may induce dopamine-glutamate synaptic remodeling, which is at the basis of their long-term physiologic effects. In this review, we will discuss the role of postsynaptic proteins in dopamine-glutamate signals integration, as well as the peculiar impact of different psychotropic drugs used in clinical practice on postsynaptic remodeling, thereby trying to point out the possible future molecular targets of “synapse-based” psychiatric therapeutic strategies. PMID:28085108

Enhanced AMPA Receptor Function Promotes Cerebellar Long-Term Depression Rather than Potentiation

ERIC Educational Resources Information Center

van Beugen, Boeke J.; Qiao, Xin; Simmons, Dana H.; De Zeeuw, Chris I.; Hansel, Christian

2014-01-01

Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar…

Local classifiers for evoked potentials recorded from behaving rats.

PubMed

Jakuczun, Wit; Kublik, Ewa; Wójcik, Daniel K; Wróbel, Andrzej

2005-01-01

Dynamic states of the brain determine the way information is processed in local neural networks. We have applied classical conditioning paradigm in order to study whether habituated and aroused states can be differentiated in single barrel column of rat's somatosensory cortex by means of analysis of field potentials evoked by stimulation of a single vibrissa. A new method using local classifiers is presented which allows for reliable and meaningful classification of single evoked potentials which might be consequently attributed to different functional states of the cortical column.

Absence of both auditory evoked potentials and auditory percepts dependent on timing cues.

PubMed

Starr, A; McPherson, D; Patterson, J; Don, M; Luxford, W; Shannon, R; Sininger, Y; Tonakawa, L; Waring, M

1991-06-01

An 11-yr-old girl had an absence of sensory components of auditory evoked potentials (brainstem, middle and long-latency) to click and tone burst stimuli that she could clearly hear. Psychoacoustic tests revealed a marked impairment of those auditory perceptions dependent on temporal cues, that is, lateralization of binaural clicks, change of binaural masked threshold with changes in signal phase, binaural beats, detection of paired monaural clicks, monaural detection of a silent gap in a sound, and monaural threshold elevation for short duration tones. In contrast, auditory functions reflecting intensity or frequency discriminations (difference limens) were only minimally impaired. Pure tone audiometry showed a moderate (50 dB) bilateral hearing loss with a disproportionate severe loss of word intelligibility. Those auditory evoked potentials that were preserved included (1) cochlear microphonics reflecting hair cell activity; (2) cortical sustained potentials reflecting processing of slowly changing signals; and (3) long-latency cognitive components (P300, processing negativity) reflecting endogenous auditory cognitive processes. Both the evoked potential and perceptual deficits are attributed to changes in temporal encoding of acoustic signals perhaps occurring at the synapse between hair cell and eighth nerve dendrites. The results from this patient are discussed in relation to previously published cases with absent auditory evoked potentials and preserved hearing.

Structural and molecular remodeling of dendritic spine substructures during long-term potentiation

PubMed Central

Bosch, Miquel; Castro, Jorge; Saneyoshi, Takeo; Matsuno, Hitomi; Sur, Mriganka; Hayashi, Yasunori

2014-01-01

SUMMARY Synapses store information by long-lasting modifications of their structure and molecular composition, but the precise chronology of these changes has not been studied at single synapse resolution in real time. Here we describe the spatiotemporal reorganization of postsynaptic substructures during long-term potentiation (LTP) at individual dendritic spines. Proteins translocated to the spine in four distinct patterns through three sequential phases. In the initial phase, the actin cytoskeleton was rapidly remodeled while active cofilin was massively transported to the spine. In the stabilization phase, cofilin formed a stable complex with F-actin, was persistently retained at the spine, and consolidated spine expansion. In contrast, the postsynaptic density (PSD) was independently remodeled, as PSD scaffolding proteins did not change their amount and localization until a late protein synthesis-dependent third phase. Our findings show how and when spine substructures are remodeled during LTP and explain why synaptic plasticity rules change over time. PMID:24742465

The postsynaptic t-SNARE Syntaxin 4 controls traffic of Neuroligin 1 and Synaptotagmin 4 to regulate retrograde signaling.

PubMed

Harris, Kathryn P; Zhang, Yao V; Piccioli, Zachary D; Perrimon, Norbert; Littleton, J Troy

2016-05-25

Postsynaptic cells can induce synaptic plasticity through the release of activity-dependent retrograde signals. We previously described a Ca(2+)-dependent retrograde signaling pathway mediated by postsynaptic Synaptotagmin 4 (Syt4). To identify proteins involved in postsynaptic exocytosis, we conducted a screen for candidates that disrupted trafficking of a pHluorin-tagged Syt4 at Drosophila neuromuscular junctions (NMJs). Here we characterize one candidate, the postsynaptic t-SNARE Syntaxin 4 (Syx4). Analysis of Syx4 mutants reveals that Syx4 mediates retrograde signaling, modulating the membrane levels of Syt4 and the transsynaptic adhesion protein Neuroligin 1 (Nlg1). Syx4-dependent trafficking regulates synaptic development, including controlling synaptic bouton number and the ability to bud new varicosities in response to acute neuronal stimulation. Genetic interaction experiments demonstrate Syx4, Syt4, and Nlg1 regulate synaptic growth and plasticity through both shared and parallel signaling pathways. Our findings suggest a conserved postsynaptic SNARE machinery controls multiple aspects of retrograde signaling and cargo trafficking within the postsynaptic compartment.

Chronic restraint stress impairs endocannabinoid mediated suppression of GABAergic signaling in the hippocampus of adult male rats.

PubMed

Hu, Wen; Zhang, Mingyue; Czéh, Boldizsár; Zhang, Weiqi; Flügge, Gabriele

2011-07-15

Chronic stress, a risk factor for the development of psychiatric disorders, is known to induce alterations in neuronal networks in many brain areas. Previous studies have shown that chronic stress changes the expression of the cannabinoid receptor 1 (CB1) in the brains of adult rats, but neurophysiological consequences of these changes remained unclear. Here we demonstrate that chronic restraint stress causes a dysfunction in CB1 mediated modulation of GABAergic transmission in the hippocampus. Using an established protocol, adult male Sprague Dawley rats were daily restrained for 21 days and whole-cell voltage clamp was performed at CA1 pyramidal neurons. When recording carbachol-evoked inhibitory postsynaptic currents (IPSCs) which presumably originate from CB1 expressing cholecystokinin (CCK) interneurons, we found that depolarization-induced suppression of inhibition (DSI) was impaired by the stress. DSI is a form of short-term plasticity at GABAergic synapses that is known to be CB1 mediated and has been suggested to be involved in hippocampal information encoding. Chronic stress attenuated the depolarization-induced suppression of the frequency of carbachol-evoked IPSCs. Incubation with a CB1 receptor antagonist prevented this DSI effect in control but not in chronically stressed animals. The stress-induced impairment of CB1-mediated short-term plasticity at GABAergic synapses may underlie cognitive deficits which are commonly observed in animal models of stress as well as in patients with stress-related psychiatric disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

Intraglomerular inhibition shapes the strength and temporal structure of glomerular output

PubMed Central

Shao, Zuoyi; Puche, Adam C.; Liu, Shaolin

2012-01-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MCs) and external tufted cells (ETCs). ETCs, in turn, provide feedforward excitatory input to MCs. MC and ETCs are also regulated by inhibition: intraglomerular and interglomerular inhibitory circuits act at MC and ETC apical dendrites; granule cells (GCs) inhibit MC lateral dendrites via the MC→GC→MC circuit. We investigated the contribution of intraglomerular inhibition to MC and ETCs responses to ON input. ON input evokes initial excitation followed by early, strongly summating inhibitory postsynaptic currents (IPSCs) in MCs; this is followed by prolonged, intermittent IPSCs. The N-methyl-d-aspartate receptor antagonist dl-amino-5-phosphovaleric acid, known to suppress GABA release by GCs, reduced late IPSCs but had no effect on early IPSCs. In contrast, selective intraglomerular block of GABAA receptors eliminated all early IPSCs and caused a 5-fold increase in ON-evoked MC spiking and a 10-fold increase in response duration. ETCs also receive intraglomerular inhibition; blockade of inhibition doubled ETC spike responses. By reducing ETC excitatory drive and directly inhibiting MCs, intraglomerular inhibition is a key factor shaping the strength and temporal structure of MC responses to sensory input. Sensory input generates an intraglomerular excitation-inhibition sequence that limits MC spike output to a brief temporal window. Glomerular circuits may dynamically regulate this input-output window to optimize MC encoding across sniff-sampled inputs. PMID:22592311

Intraglomerular inhibition shapes the strength and temporal structure of glomerular output.

PubMed

Shao, Zuoyi; Puche, Adam C; Liu, Shaolin; Shipley, Michael T

2012-08-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MCs) and external tufted cells (ETCs). ETCs, in turn, provide feedforward excitatory input to MCs. MC and ETCs are also regulated by inhibition: intraglomerular and interglomerular inhibitory circuits act at MC and ETC apical dendrites; granule cells (GCs) inhibit MC lateral dendrites via the MC→GC→MC circuit. We investigated the contribution of intraglomerular inhibition to MC and ETCs responses to ON input. ON input evokes initial excitation followed by early, strongly summating inhibitory postsynaptic currents (IPSCs) in MCs; this is followed by prolonged, intermittent IPSCs. The N-methyl-d-aspartate receptor antagonist dl-amino-5-phosphovaleric acid, known to suppress GABA release by GCs, reduced late IPSCs but had no effect on early IPSCs. In contrast, selective intraglomerular block of GABA(A) receptors eliminated all early IPSCs and caused a 5-fold increase in ON-evoked MC spiking and a 10-fold increase in response duration. ETCs also receive intraglomerular inhibition; blockade of inhibition doubled ETC spike responses. By reducing ETC excitatory drive and directly inhibiting MCs, intraglomerular inhibition is a key factor shaping the strength and temporal structure of MC responses to sensory input. Sensory input generates an intraglomerular excitation-inhibition sequence that limits MC spike output to a brief temporal window. Glomerular circuits may dynamically regulate this input-output window to optimize MC encoding across sniff-sampled inputs.

Intraoperative Functional Mapping and Monitoring during Glioma Surgery

PubMed Central

SAITO, Taiichi; MURAGAKI, Yoshihiro; MARUYAMA, Takashi; TAMURA, Manabu; NITTA, Masayuki; OKADA, Yoshikazu

2015-01-01

Glioma surgery represents a significant advance with respect to improving resection rates using new surgical techniques, including intraoperative functional mapping, monitoring, and imaging. Functional mapping under awake craniotomy can be used to detect individual eloquent tissues of speech and/or motor functions in order to prevent unexpected deficits and promote extensive resection. In addition, monitoring the patient’s neurological findings during resection is also very useful for maximizing the removal rate and minimizing deficits by alarming that the touched area is close to eloquent regions and fibers. Assessing several types of evoked potentials, including motor evoked potentials (MEPs), sensory evoked potentials (SEPs) and visual evoked potentials (VEPs), is also helpful for performing surgical monitoring in patients under general anesthesia (GA). We herein review the utility of intraoperative mapping and monitoring the assessment of neurological findings, with a particular focus on speech and the motor function, in patients undergoing glioma surgery. PMID:25744346

Transcranial electric motor evoked potential monitoring during spine surgery: is it safe?

PubMed

Schwartz, Daniel M; Sestokas, Anthony K; Dormans, John P; Vaccaro, Alexander R; Hilibrand, Alan S; Flynn, John M; Li, P Mark; Shah, Suken A; Welch, William; Drummond, Denis S; Albert, Todd J

2011-06-01

Retrospective review. To report on the safety of repetitive transcranial electric stimulation (RTES) for eliciting motor-evoked potentials during spine surgery. Theoretical concerns over the safety of RTES have hindered broader acceptance of transcranial electric motor-evoked potentials (tceMEP), despite successful implementation of spinal cord monitoring with tceMEPs in many large spine centers, as well as their apparent superiority over mixed-nerve somatosensory-evoked potentials (SSEP) for detection of spinal cord injury. The records of 18,862 consecutive patients who met inclusion criteria and underwent spine surgery with tceMEP monitoring were reviewed for RTES-related complications. This large retrospective review identified only 26 (0.14%) cases with RTES-related complications; all but one of these were tongue lacerations, most of which were self-limiting. The results demonstrate that RTES is a highly safe modality for monitoring spinal cord motor tract function intraoperatively.

Innovative neurophysiological methods in itch research: long-latency evoked potentials after electrical and thermal stimulation in patients with atopic dermatitis.

PubMed

Yudina, Marina M; Toropina, Galina G; Lvov, Andrey; Gieler, Uwe

2011-10-01

The aim of this study was to examine the findings of innovative neurophysiological methods of itch research. Short-latency and pain-related somatosensory-evoked potentials after electrical stimulation, as well as long-latency evoked potentials after thermal stimulation were studied in 38 patients with atopic dermatitis (AD) and 26 healthy volunteers. Quantitative Sensory Testing of thermal perception was performed in 22 patients with AD from the main AD group and in 15 healthy volunteers. Brain hyperactivity to electrical stimuli, delayed thermal-evoked potentials and elevated thermal thresholds were revealed in patients with AD compared with healthy controls. The data indicate small nerve fibre dysfunction in patients with AD, which may contribute to the pathogenesis of AD and chronic itch. The study demonstrates objective approaches to assess the function of small nerve fibres in patients with chronic itch.

Recording Visual Evoked Potentials and Auditory Evoked P300 at 9.4T Static Magnetic Field

PubMed Central

Hahn, David; Boers, Frank; Shah, N. Jon

2013-01-01

Simultaneous recording of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) has shown a number of advantages that make this multimodal technique superior to fMRI alone. The feasibility of recording EEG at ultra-high static magnetic field up to 9.4T was recently demonstrated and promises to be implemented soon in fMRI studies at ultra high magnetic fields. Recording visual evoked potentials are expected to be amongst the most simple for simultaneous EEG/fMRI at ultra-high magnetic field due to the easy assessment of the visual cortex. Auditory evoked P300 measurements are of interest since it is believed that they represent the earliest stage of cognitive processing. In this study, we investigate the feasibility of recording visual evoked potentials and auditory evoked P300 in a 9.4T static magnetic field. For this purpose, EEG data were recorded from 26 healthy volunteers inside a 9.4T MR scanner using a 32-channel MR compatible EEG system. Visual stimulation and auditory oddball paradigm were presented in order to elicit evoked related potentials (ERP). Recordings made outside the scanner were performed using the same stimuli and EEG system for comparison purposes. We were able to retrieve visual P100 and auditory P300 evoked potentials at 9.4T static magnetic field after correction of the ballistocardiogram artefact using independent component analysis. The latencies of the ERPs recorded at 9.4T were not different from those recorded at 0T. The amplitudes of ERPs were higher at 9.4T when compared to recordings at 0T. Nevertheless, it seems that the increased amplitudes of the ERPs are due to the effect of the ultra-high field on the EEG recording system rather than alteration in the intrinsic processes that generate the electrophysiological responses. PMID:23650538

Recording visual evoked potentials and auditory evoked P300 at 9.4T static magnetic field.

PubMed

Arrubla, Jorge; Neuner, Irene; Hahn, David; Boers, Frank; Shah, N Jon

2013-01-01

Simultaneous recording of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) has shown a number of advantages that make this multimodal technique superior to fMRI alone. The feasibility of recording EEG at ultra-high static magnetic field up to 9.4 T was recently demonstrated and promises to be implemented soon in fMRI studies at ultra high magnetic fields. Recording visual evoked potentials are expected to be amongst the most simple for simultaneous EEG/fMRI at ultra-high magnetic field due to the easy assessment of the visual cortex. Auditory evoked P300 measurements are of interest since it is believed that they represent the earliest stage of cognitive processing. In this study, we investigate the feasibility of recording visual evoked potentials and auditory evoked P300 in a 9.4 T static magnetic field. For this purpose, EEG data were recorded from 26 healthy volunteers inside a 9.4 T MR scanner using a 32-channel MR compatible EEG system. Visual stimulation and auditory oddball paradigm were presented in order to elicit evoked related potentials (ERP). Recordings made outside the scanner were performed using the same stimuli and EEG system for comparison purposes. We were able to retrieve visual P100 and auditory P300 evoked potentials at 9.4 T static magnetic field after correction of the ballistocardiogram artefact using independent component analysis. The latencies of the ERPs recorded at 9.4 T were not different from those recorded at 0 T. The amplitudes of ERPs were higher at 9.4 T when compared to recordings at 0 T. Nevertheless, it seems that the increased amplitudes of the ERPs are due to the effect of the ultra-high field on the EEG recording system rather than alteration in the intrinsic processes that generate the electrophysiological responses.

Surgical monitoring with auditory evoked potentials.

PubMed

Lüders, H

1988-07-01

This comprehensive review of surgical monitoring with auditory evoked potentials (AEPs) includes a detailed discussion of techniques used for recording brainstem auditory evoked potentials, direct eight-nerve potentials, and electrocochleograms. The normal waveform of these different potentials is discussed, and the typical patterns of abnormalities seen with different insults to the peripheral or central auditory pathways are presented. The mechanisms most probably responsible for changes in AEPs during surgical procedures are analyzed. A critical analysis is made of what represents a significant change in AEPs. Also considered is the predictive value of intrasurgical changes of AEPs. Finally, attempts are made to determine whether AEPs monitoring can assist the surgeon in the prevention of postsurgical complications.

Docosahexaenoic Acid Protects from Dendritic Pathology in an Alzheimer’s Disease Mouse Model

PubMed Central

Calon, Frédéric; Lim, Giselle P.; Yang, Fusheng; Morihara, Takashi; Teter, Bruce; Ubeda, Oliver; Rostaing, Phillippe; Triller, Antoine; Salem, Norman; Ashe, Karen H.; Frautschy, Sally A.; Cole, Greg M.

2005-01-01

Learning and memory depend on dendritic spine actin assembly and docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated fatty acid (PFA). High DHA consumption is associated with reduced Alzheimer’s disease (AD) risk, yet mechanisms and therapeutic potential remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD mouse model resulted in 80%–90% losses of the p85α subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or pre-synaptic protein loss. N-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD. PMID:15339646

Paired-pulse facilitation and depression at unitary synapses in rat hippocampus: quantal fluctuation affects subsequent release.

PubMed Central

Debanne, D; Guérineau, N C; Gähwiler, B H; Thompson, S M

1996-01-01

1. Excitatory synaptic transmission between pairs of monosynaptically coupled pyramidal cells was examined in rat hippocampal slice cultures. Action potentials were elicited in single CA3 pyramidal cells impaled with microelectrodes and unitary excitatory postsynaptic currents (EPSCs) were recorded in whole-cell voltage-clamped CA1 or CA3 cells. 2. The amplitude of successive unitary EPSCs in response to single action potentials varied. The amplitude of EPSCs was altered by adenosine or changes in the [Mg2+]/[CA2+] ratio. We conclude that single action potentials triggered the release of multiple quanta of glutamate. 3. When two action potentials were elicited in the presynaptic cell, the amplitude of the second EPSC was inversely related to the amplitude of the first. Paired-pulse facilitation (PPF) was observed when the first EPSC was small, i.e. the second EPSC was larger than the first, whereas paired-pulse depression (PPD) was observed when the first EPSC was large. 4. The number of trials displaying PPD was greater when release probability was increased, and smaller when release probability was decreased. 5. PPD was not postsynaptically mediated because it was unaffected by decreasing ionic flux with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or receptor desensitization with aniracetam. 6. PPF was maximal at an interstimulus interval of 70 ms and recovered within 500 ms. Recovery from PPD occurred within 5 s. 7. We propose that multiple release sites are formed by the axon of a CA3 pyramidal cell and a single postsynaptic CA1 or CA3 cell. PPF is observed if the first action potential fails to release transmitter at most release sites. PPD is observed if the first action potential successfully triggers release at most release sites. 8. Our observations of PPF are consistent with the residual calcium hypothesis. We conclude that PPD results from a decrease in quantal content, perhaps due to short-term depletion of readily releasable vesicles. PMID:9011608

Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala.

PubMed

Du, Jianyang; Reznikov, Leah R; Price, Margaret P; Zha, Xiang-ming; Lu, Yuan; Moninger, Thomas O; Wemmie, John A; Welsh, Michael J

2014-06-17

Stimulating presynaptic terminals can increase the proton concentration in synapses. Potential receptors for protons are acid-sensing ion channels (ASICs), Na(+)- and Ca(2+)-permeable channels that are activated by extracellular acidosis. Those observations suggest that protons might be a neurotransmitter. We found that presynaptic stimulation transiently reduced extracellular pH in the amygdala. The protons activated ASICs in lateral amygdala pyramidal neurons, generating excitatory postsynaptic currents. Moreover, both protons and ASICs were required for synaptic plasticity in lateral amygdala neurons. The results identify protons as a neurotransmitter, and they establish ASICs as the postsynaptic receptor. They also indicate that protons and ASICs are a neurotransmitter/receptor pair critical for amygdala-dependent learning and memory.

Micro-field evoked potentials recorded from the porcine sub-dural cortical surface utilizing a microelectrode array.

PubMed

Kitzmiller, Joseph P; Hansford, Derek J; Fortin, Linda D; Obrietan, Karl H; Bergdall, Valerie K; Beversdorf, David Q

2007-05-15

A sub-dural surface microelectrode array designed to detect micro-field evoked potentials has been developed. The device is comprised of an array of 350-microm square gold contacts, with bidirectional spacing of 150 microm, contained within a polyimide Kapton material. Cytotoxicity testing suggests that the device is suitable for use with animal and human patients. Implementation of the device in animal studies revealed that reliable evoked potentials could be acquired. Further work will be needed to determine how these micro-field potentials, which demonstrate selectivity for one eye, relate to the distribution of the ocular dominance columns of the occipital cortex.

Micro-Field Evoked Potentials Recorded from the Porcine Sub-Dural Cortical Surface Utilizing a Microelectrode Array

PubMed Central

Kitzmiller, Joseph P.; Hansford, Derek J.; Fortin, Linda D.; Obrietan, Karl H.; Bergdall, Valerie K.

2007-01-01

A sub-dural surface microelectrode array designed to detect microfield evoked potentials has been developed. The device is comprised of an array of 350-micron square gold contacts, with bi-directional spacing of 150 microns, contained within a polyimide Kapton material. Cytotoxicity testing suggests that the device is suitable for use with animal and human patients. Implementation of the device in animal studies revealed that reliable evoked potentials could be acquired. Further work will be needed to determine how these microfield potentials, which demonstrate selectivity for one eye, relate to the distribution of the ocular dominance columns of the occipital cortex. PMID:17298849

Brain Transcriptome Profiles in Mouse Model Simulating Features of Post-traumatic Stress Disorder

DTIC Science & Technology

2015-02-28

comorbid-related signaling pathways indicate the pervasive and multisystem effects of aggressor exposure in mice, potentially mirroring the pathologic...11,12]. Impaired extinction of fear- potentiated startle and en- hanced cue conditioning in these brain regions (of trau- matized patients and animal...lead to either a long-term synap- tic potentiation (LTP) increase in synaptic strength and in- crease in excitatory post-synaptic potential

Interside Latency Differences in Brainstem Auditory and Somatosensory Evoked Potentials. Defining Upper Limits to Determine Asymmetry.

PubMed

Moncho, Dulce; Poca, Maria A; Minoves, Teresa; Ferré, Alejandro; Sahuquillo, Juan

2015-10-01

Limits of the interside differences are invaluable when interpreting asymmetry in brainstem auditory evoked potentials and somatosensory evoked potentials (SEP) recordings. The aim of this study was to analyze the normal upper limits of interside latency differences of brainstem auditory evoked potentials and SEP from the posterior tibial nerve and median nerve to determine asymmetry. The authors performed a prospective study in 56 healthy subjects aged 15 to 64 years with no neurological or hearing disorders. They analyzed (1) the latencies of I, III, and V waves and I-III, III-V, and I-V intervals and the amplitude ratios V/I and IV/I for brainstem auditory evoked potentials bilaterally; (2) the latencies of N8, N22, N28, and P37 waves and the interval N22-P37 and the amplitude P37 for posterior tibial nerve SEP bilaterally; and (3) the latencies and amplitudes of N9, N13, and N20 waves and N9-N13 and N13-N20 intervals for median nerve SEP bilaterally. The interside differences for these parameters were calculated and analyzed. The authors obtained an upper limit for the interside latency differences from brainstem auditory evoked potentials that was significantly lower than the previously published data. However, the upper limits of interside latency differences for SEP were similar to those previously reported. The findings of this study should be considered when laboratories analyze asymmetry using the normative data published by another center, however temporarily, in organizing new laboratories.

Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia.

PubMed

Ewing, Samuel G; Grace, Anthony A

2013-02-01

Existing antipsychotic drugs are most effective at treating the positive symptoms of schizophrenia but their relative efficacy is low and they are associated with considerable side effects. In this study deep brain stimulation of the ventral hippocampus was performed in a rodent model of schizophrenia (MAM-E17) in an attempt to alleviate one set of neurophysiological alterations observed in this disorder. Bipolar stimulating electrodes were fabricated and implanted, bilaterally, into the ventral hippocampus of rats. High frequency stimulation was delivered bilaterally via a custom-made stimulation device and both spectral analysis (power and coherence) of resting state local field potentials and amplitude of auditory evoked potential components during a standard inhibitory gating paradigm were examined. MAM rats exhibited alterations in specific components of the auditory evoked potential in the infralimbic cortex, the core of the nucleus accumbens, mediodorsal thalamic nucleus, and ventral hippocampus in the left hemisphere only. DBS was effective in reversing these evoked deficits in the infralimbic cortex and the mediodorsal thalamic nucleus of MAM-treated rats to levels similar to those observed in control animals. In contrast stimulation did not alter evoked potentials in control rats. No deficits or stimulation-induced alterations were observed in the prelimbic and orbitofrontal cortices, the shell of the nucleus accumbens or ventral tegmental area. These data indicate a normalization of deficits in generating auditory evoked potentials induced by a developmental disruption by acute high frequency, electrical stimulation of the ventral hippocampus. Copyright © 2012 Elsevier B.V. All rights reserved.

Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia

PubMed Central

Ewing, Samuel G.; Grace, Anthony A.

2012-01-01

Existing antipsychotic drugs are most effective at treating the positive symptoms of schizophrenia, but their relative efficacy is low and they are associated with considerable side effects. In this study deep brain stimulation of the ventral hippocampus was performed in a rodent model of schizophrenia (MAM-E17) in an attempt to alleviate one set of neurophysiological alterations observed in this disorder. Bipolar stimulating electrodes were fabricated and implanted, bilaterally, into the ventral hippocampus of rats. High frequency stimulation was delivered bilaterally via a custom-made stimulation device and both spectral analysis (power and coherence) of resting state local field potentials and amplitude of auditory evoked potential components during a standard inhibitory gating paradigm were examined. MAM rats exhibited alterations in specific components of the auditory evoked potential in the infralimbic cortex, the core of the nucleus accumbens, mediodorsal thalamic nucleus, and ventral hippocampus in the left hemisphere only. DBS was effective in reversing these evoked deficits in the infralimbic cortex and the mediodorsal thalamic nucleus of MAM-treated rats to levels similar to those observed in control animals. In contrast stimulation did not alter evoked potentials in control rats. No deficits or stimulation-induced alterations were observed in the prelimbic and orbitofrontal cortices, the shell of the nucleus accumbens or ventral tegmental area. These data indicate a normalization of deficits in generating auditory evoked potentials induced by a developmental disruption by acute high frequency, electrical stimulation of the ventral hippocampus. PMID:23269227

Temporal-pattern recognition by single neurons in a sensory pathway devoted to social communication behavior

PubMed Central

Carlson, Bruce A.

2010-01-01

Sensory systems often encode stimulus information into the temporal pattern of action potential activity. However, little is known about how the information contained within these patterns is extracted by postsynaptic neurons. Similar to temporal coding by sensory neurons, social information in mormyrid fish is encoded into the temporal patterning of an electric organ discharge (EOD). In the current study, sensitivity to temporal patterns of electrosensory stimuli was found to arise within the midbrain posterior exterolateral nucleus (ELp). Whole-cell patch recordings from ELp neurons in vivo revealed three patterns of interpulse interval (IPI) tuning: low-pass neurons tuned to long intervals, high-pass neurons tuned to short intervals and band-pass neurons tuned to intermediate intervals. Many neurons within each class also responded preferentially to either increasing or decreasing IPIs. Playback of electric signaling patterns recorded from freely behaving fish revealed that the IPI and direction tuning of ELp neurons resulted in selective responses to particular social communication displays characterized by distinct IPI patterns. The postsynaptic potential responses of many neurons indicated a combination of excitatory and inhibitory synaptic input, and the IPI tuning of ELp neurons was directly related to rate-dependent changes in the direction and amplitude of postsynaptic potentials. These results suggest that differences in the dynamics of short-term synaptic plasticity in excitatory and inhibitory pathways may tune central sensory neurons to particular temporal patterns of presynaptic activity. This may represent a general mechanism for the processing of behaviorally-relevant stimulus information encoded into temporal patterns of activity by sensory neurons. PMID:19641105

Temporal-pattern recognition by single neurons in a sensory pathway devoted to social communication behavior.

PubMed

Carlson, Bruce A

2009-07-29

Sensory systems often encode stimulus information into the temporal pattern of action potential activity. However, little is known about how the information contained within these patterns is extracted by postsynaptic neurons. Similar to temporal coding by sensory neurons, social information in mormyrid fish is encoded into the temporal patterning of an electric organ discharge. In the current study, sensitivity to temporal patterns of electrosensory stimuli was found to arise within the midbrain posterior exterolateral nucleus (ELp). Whole-cell patch recordings from ELp neurons in vivo revealed three patterns of interpulse interval (IPI) tuning: low-pass neurons tuned to long intervals, high-pass neurons tuned to short intervals, and bandpass neurons tuned to intermediate intervals. Many neurons within each class also responded preferentially to either increasing or decreasing IPIs. Playback of electric signaling patterns recorded from freely behaving fish revealed that the IPI and direction tuning of ELp neurons resulted in selective responses to particular social communication displays characterized by distinct IPI patterns. The postsynaptic potential responses of many neurons indicated a combination of excitatory and inhibitory synaptic input, and the IPI tuning of ELp neurons was directly related to rate-dependent changes in the direction and amplitude of postsynaptic potentials. These results suggest that differences in the dynamics of short-term synaptic plasticity in excitatory and inhibitory pathways may tune central sensory neurons to particular temporal patterns of presynaptic activity. This may represent a general mechanism for the processing of behaviorally relevant stimulus information encoded into temporal patterns of activity by sensory neurons.

A cephalic projection neuron involved in locomotion is dye coupled to the dopaminergic neural network in the medicinal leech.

PubMed

Crisp, Kevin M; Mesce, Karen A

2004-12-01

It is widely appreciated that the selection and modulation of locomotor circuits are dependent on the actions of higher-order projection neurons. In the leech, Hirudo medicinalis, locomotion is modulated by a number of cephalic projection neurons that descend from the subesophageal ganglion in the head. Specifically, descending brain interneuron Tr2 functions as a command-like neuron that can terminate or sometimes trigger fictive swimming. In this study, we demonstrate that Tr2 is dye coupled to the dopaminergic neural network distributed in the head brain. These findings represent the first anatomical evidence in support of dopamine (DA) playing a role in the modulation of locomotion in the leech. In addition, we have determined that bath application of DA to the brain and entire nerve cord reliably and rapidly terminates swimming in all preparations exhibiting fictive swimming. By contrast, DA application to nerve cords expressing ongoing fictive crawling does not inhibit this motor rhythm. Furthermore, we show that Tr2 receives rhythmic feedback from the crawl central pattern generator. For example, Tr2 receives inhibitory post-synaptic potentials during the elongation phase of each crawl cycle. When crawling is not expressed, spontaneous inhibitory post-synaptic potentials in Tr2 correlate in time with spontaneous excitatory post-synaptic potentials in the CV motor neuron, a circular muscle excitor that bursts during the elongation phase of crawling. Our data are consistent with the idea that DA biases the nervous system to produce locomotion in the form of crawling.

The anorexic agents, sibutramine and fenfluramine, depress GABAB-induced inhibitory postsynaptic potentials in rat mesencephalic dopaminergic cells

PubMed Central

Ledonne, Ada; Sebastianelli, Luca; Federici, Mauro; Bernardi, Giorgio; Mercuri, Nicola Biagio

2009-01-01

Background and purpose Nutrition is the result of a complex interaction among environmental, homeostatic and reward-related processes. Accumulating evidence supports key roles for the dopaminergic neurons of the ventral midbrain in regulating feeding behaviour. For this reason, in the present study, we have investigated the electrophysiological effects of two centrally acting anorexic agents, fenfluramine and sibutramine, on these cells. Experimental approach Rat midbrain slices were used to make intracellular recordings from dopaminergic neurons of the substantia nigra and the ventral tegmental area. Gamma-aminobutyric acid (GABA)-mediated synaptic transmission was assessed from the inhibitory postsynaptic potentials (IPSPs) mediated by GABAA and GABAB receptors. Key results Fenfluramine and sibutramine reduced, concentration-dependently, the GABAB IPSPs, without affecting the GABAA-mediated potentials. This effect is presynaptic, as postsynaptic membrane responses induced by application of a GABAB receptor agonist, baclofen, were not affected by the two drugs. Furthermore, the selective 5-hydroxytriptamine 1B (5-HT1B) receptor antagonist, SB216641, blocked the reduction of GABAB IPSPs caused by fenfluramine and sibutramine, indicating that the receptor mediating this effect is 5-HT1B. Conclusions and implications Two anorexic agents, fenfluramine and sibutramine, induced the activation of 5-HT1B receptors located on presynaptic GABAergic terminals, thus reducing the release of GABA. This action can alter the strength of synaptic afferents that modify the activity of dopaminergic neurons, inducing neuronal excitation. Our results reveal an additional mechanism of action for fenfluramine and sibutramine that might contribute to reducing food intake, by influencing the pleasurable and motor aspects of feeding behaviour. PMID:19298257

Evoked potentials are useful for diagnosis of neuromyelitis optica spectrum disorder.

PubMed

Ohnari, Keiko; Okada, Kazumasa; Takahashi, Toshiyuki; Mafune, Kosuke; Adachi, Hiroaki

2016-05-15

Neuromyelitis optica spectrum disorder (NMOSD) has been differentiated from relapsing-remitting multiple sclerosis (RRMS) by clinical, laboratory, and pathological findings, including the presence of the anti-aquaporin 4 antibody. Measurement of evoked potentials (EPs) is often used for the diagnosis of RRMS, although the possibility of applying EPs to the diagnosis of NMOSD has not been investigated in detail. Eighteen patients with NMOSD and 28 patients with RRMS were included in this study. The patients' neurological symptoms and signs were examined and their EPs were recorded. Characteristic findings were absence of visual evoked potentials and absence of motor evoked potentials in the lower extremities in patients with NMOSD, and a delay in these potentials in patients with RRMS. Most patients with NMOSD did not present abnormal subclinical EPs, whereas many patients with RRMS did. None of the patients with NMOSD showed abnormalities in auditory brainstem responses. NMOSD can be differentiated from RRMS by EP data obtained in the early stages of these diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

SOMATOSENSORY EVOKED POTENTIALS

EPA Science Inventory

Somatosensory evoked potentials (SEPs) have been used by neuroscientists for many years. The versatility of the method is attested to be the differing purposes to which it has been applied. Initially, SEPs were used to uncover basic principles of sensory processing. A casual glan...

In Vivo Imaging of Human Sarcomere Twitch Dynamics in Individual Motor Units

PubMed Central

Sanchez, Gabriel N.; Sinha, Supriyo; Liske, Holly; Chen, Xuefeng; Nguyen, Viet; Delp, Scott L.; Schnitzer, Mark J.

2017-01-01

SUMMARY Motor units comprise a pre-synaptic motor neuron and multiple post-synaptic muscle fibers. Many movement disorders disrupt motor unit contractile dynamics and the structure of sarcomeres, skeletal muscle’s contractile units. Despite the motor unit’s centrality to neuromuscular physiology, no extant technology can image sarcomere twitch dynamics in live humans. We created a wearable microscope equipped with a microendoscope for minimally invasive observation of sarcomere lengths and contractile dynamics in any major skeletal muscle. By electrically stimulating twitches via the microendoscope and visualizing the sarcomere displacements, we monitored single motor unit contractions in soleus and vastus lateralis muscles of healthy individuals. Control experiments verified that these evoked twitches involved neuromuscular transmission and faithfully reported muscle force generation. In post-stroke patients with spasticity of the biceps brachii, we found involuntary microscopic contractions and sarcomere length abnormalities. The wearable microscope facilitates exploration of many basic and disease-related neuromuscular phenomena never visualized before in live humans. PMID:26687220

Stargazin regulates AMPA receptor trafficking through adaptor protein complexes during long-term depression

NASA Astrophysics Data System (ADS)

Matsuda, Shinji; Kakegawa, Wataru; Budisantoso, Timotheus; Nomura, Toshihiro; Kohda, Kazuhisa; Yuzaki, Michisuke

2013-11-01

Long-term depression (LTD) underlies learning and memory in various brain regions. Although postsynaptic AMPA receptor trafficking mediates LTD, its underlying molecular mechanisms remain largely unclear. Here we show that stargazin, a transmembrane AMPA receptor regulatory protein, forms a ternary complex with adaptor proteins AP-2 and AP-3A in hippocampal neurons, depending on its phosphorylation state. Inhibiting the stargazin-AP-2 interaction disrupts NMDA-induced AMPA receptor endocytosis, and inhibiting that of stargazin-AP-3A abrogates the late endosomal/lysosomal trafficking of AMPA receptors, thereby upregulating receptor recycling to the cell surface. Similarly, stargazin’s interaction with AP-2 or AP-3A is necessary for low-frequency stimulus-evoked LTD in CA1 hippocampal neurons. Thus, stargazin has a crucial role in NMDA-dependent LTD by regulating two trafficking pathways of AMPA receptors—transport from the cell surface to early endosomes and from early endosomes to late endosomes/lysosomes—through its sequential binding to AP-2 and AP-3A.

In Vivo Imaging of Human Sarcomere Twitch Dynamics in Individual Motor Units.

PubMed

Sanchez, Gabriel N; Sinha, Supriyo; Liske, Holly; Chen, Xuefeng; Nguyen, Viet; Delp, Scott L; Schnitzer, Mark J

2015-12-16

Motor units comprise a pre-synaptic motor neuron and multiple post-synaptic muscle fibers. Many movement disorders disrupt motor unit contractile dynamics and the structure of sarcomeres, skeletal muscle's contractile units. Despite the motor unit's centrality to neuromuscular physiology, no extant technology can image sarcomere twitch dynamics in live humans. We created a wearable microscope equipped with a microendoscope for minimally invasive observation of sarcomere lengths and contractile dynamics in any major skeletal muscle. By electrically stimulating twitches via the microendoscope and visualizing the sarcomere displacements, we monitored single motor unit contractions in soleus and vastus lateralis muscles of healthy individuals. Control experiments verified that these evoked twitches involved neuromuscular transmission and faithfully reported muscle force generation. In post-stroke patients with spasticity of the biceps brachii, we found involuntary microscopic contractions and sarcomere length abnormalities. The wearable microscope facilitates exploration of many basic and disease-related neuromuscular phenomena never visualized before in live humans. Copyright © 2015 Elsevier Inc. All rights reserved.

[The effect of atropine on the ultrastructural postsynaptic plasticity of the associative type in the rat neocortex].

PubMed

Khludova, G G; Gusev, P A

1998-01-01

The effect of muscarinic antagonist atropine on thickness of postsynaptic density of axodendritic synapses was studied in the sensorimotor region of the brain cortex of rats during paired repeated microapplication of glutamate and acetylcholine. In the applied conditioning paradigm atropine significantly decreased morphological dimensions of the postsynaptic density, however, the control values were not reached. This finding testifies to participation of both muscarinic and nicotinic cholinoreceptors in associative postsynaptic plasticity.

Gating characteristics control glutamate receptor distribution and trafficking in vivo.

PubMed

Petzoldt, Astrid G; Lee, Yü-Hien; Khorramshahi, Omid; Reynolds, Eric; Plested, Andrew J R; Herzel, Hanspeter; Sigrist, Stephan J

2014-09-08

Glutamate-releasing synapses dominate excitatory release in the brain. Mechanisms governing their assembly are of major importance for circuit development and long-term plasticity underlying learning and memory. AMPA/Kainate-type glutamate receptors (GluRs) are tetrameric ligand-gated ion channels that open their ion-conducting pores in response to binding of the neurotransmitter. Changes in subunit composition of postsynaptic GluRs are highly relevant for plasticity and development of glutamatergic synapses [1-4]. To date, posttranslational modifications, mostly operating via the intracellular C-terminal domains (CTDs) of GluRs, are presumed to be the major regulator of trafficking [5]. In recent years, structural and electrophysiological analyses have improved our understanding of GluR gating mechanism [6-11]. However, whether conformational changes subsequent to glutamate binding may per se be able to influence GluR trafficking has remained an unaddressed question. Using a Drosophila system allowing for extended visualization of GluR trafficking in vivo, we here provide evidence that mutations changing the gating behavior alter GluR distribution and trafficking. GluR mutants associated with reduced charge transfer segregated from coexpressed wild-type GluRs on the level of individual postsynaptic densities. Segregation was lost upon blocking of evoked glutamate release. Photobleaching experiments suggested increased mobility of mutants with reduced charge transfer, which accumulated prematurely during early steps of synapse assembly, but failed to further increase their level in accordance with assembly of the presynaptic scaffold. In summary, gating characteristics seem to be a new variable for the understanding of GluR trafficking relevant to both development and plasticity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Early exposure to general anesthesia with isoflurane downregulates inhibitory synaptic neurotransmission in the rat thalamus

PubMed Central

Joksovic, Pavle M.; Lunardi, Nadia; Jevtovic-Todorovic, Vesna; Todorovic, Slobodan M.

2015-01-01

Recent evidence supports the idea that common general anesthetics (GAs) such as isoflurane (Iso) and nitrous oxide (N2O; laughing gas) are neurotoxic and may harm the developing mammalian brain, including the thalamus; however, to date very little is known about how developmental exposure to GAs may affect synaptic transmission in the thalamus which, in turn, controls the function of thalamocortical circuitry. To address this issue we used in vitro patch-clamp recordings of evoked inhibitory postsynaptic currents (eIPSCs) from intact neurons of the nucleus reticularis thalami (nRT) in brain slices from rat pups (postnatal age P10-P18) exposed at age of P7 to clinically relevant GA combinations of Iso and N2O. We found that rats exposed to a combination of 0.75% Iso and 75% N2O display lasting reduction in the amplitude and faster decays of eIPSCs. Exposure to sub-anesthetic concentrations of 75% N2O alone or 0.75% Iso alone at P7 did not affect the amplitude of eIPSCs; however, Iso alone, but not N2O, significantly accelerated decay of eIPSCs. Anesthesia with 1.5% Iso alone decreased amplitudes, caused faster decay and decreased the paired-pulse ratio of eIPSCs. We conclude that anesthesia at P7 with Iso alone or in combination with N2O causes plasticity of eIPSCs in nRT neurons by both presynaptic and postsynaptic mechanisms. We hypothesize that changes in inhibitory synaptic transmission in the thalamus induced by GAs may contribute to altered neuronal excitability and consequently abnormal thalamocortical oscillations later in life. PMID:26048671

RDX Binds to the GABAA Receptor–Convulsant Site and Blocks GABAA Receptor–Mediated Currents in the Amygdala: A Mechanism for RDX-Induced Seizures

PubMed Central

Williams, Larry R.; Aroniadou-Anderjaska, Vassiliki; Qashu, Felicia; Finne, Huckelberry; Pidoplichko, Volodymyr; Bannon, Desmond I.; Braga, Maria F. M.

2011-01-01

Background Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a high-energy, trinitrated cyclic compound that has been used worldwide since World War II as an explosive in both military and civilian applications. RDX can be released in the environment by way of waste streams generated during the manufacture, use, and disposal of RDX-containing munitions and can leach into groundwater from unexploded munitions found on training ranges. For > 60 years, it has been known that exposure to high doses of RDX causes generalized seizures, but the mechanism has remained unknown. Objective We investigated the mechanism by which RDX induces seizures. Methods and results By screening the affinity of RDX for a number of neurotransmitter receptors, we found that RDX binds exclusively to the picrotoxin convulsant site of the γ-aminobutyric acid type A (GABAA) ionophore. Whole-cell in vitro recordings in the rat basolateral amygdala (BLA) showed that RDX reduces the frequency and amplitude of spontaneous GABAA receptor–mediated inhibitory postsynaptic currents and the amplitude of GABA-evoked postsynaptic currents. In extracellular field recordings from the BLA, RDX induced prolonged, seizure-like neuronal discharges. Conclusions These results suggest that binding to the GABAA receptor convulsant site is the primary mechanism of seizure induction by RDX and that reduction of GABAergic inhibitory transmission in the amygdala is involved in the generation of RDX-induced seizures. Knowledge of the molecular site and the mechanism of RDX action with respect to seizure induction can guide therapeutic strategies, allow more accurate development of safe thresholds for exposures, and help prevent the development of new explosives or other munitions that could pose similar health risks. PMID:21362589

Updated energy budgets for neural computation in the neocortex and cerebellum

PubMed Central

Howarth, Clare; Gleeson, Padraig; Attwell, David

2012-01-01

The brain's energy supply determines its information processing power, and generates functional imaging signals. The energy use on the different subcellular processes underlying neural information processing has been estimated previously for the grey matter of the cerebral and cerebellar cortex. However, these estimates need reevaluating following recent work demonstrating that action potentials in mammalian neurons are much more energy efficient than was previously thought. Using this new knowledge, this paper provides revised estimates for the energy expenditure on neural computation in a simple model for the cerebral cortex and a detailed model of the cerebellar cortex. In cerebral cortex, most signaling energy (50%) is used on postsynaptic glutamate receptors, 21% is used on action potentials, 20% on resting potentials, 5% on presynaptic transmitter release, and 4% on transmitter recycling. In the cerebellar cortex, excitatory neurons use 75% and inhibitory neurons 25% of the signaling energy, and most energy is used on information processing by non-principal neurons: Purkinje cells use only 15% of the signaling energy. The majority of cerebellar signaling energy use is on the maintenance of resting potentials (54%) and postsynaptic receptors (22%), while action potentials account for only 17% of the signaling energy use. PMID:22434069

A comparison of auditory evoked potentials to acoustic beats and to binaural beats.

PubMed

Pratt, Hillel; Starr, Arnold; Michalewski, Henry J; Dimitrijevic, Andrew; Bleich, Naomi; Mittelman, Nomi

2010-04-01

The purpose of this study was to compare cortical brain responses evoked by amplitude modulated acoustic beats of 3 and 6 Hz in tones of 250 and 1000 Hz with those evoked by their binaural beats counterparts in unmodulated tones to indicate whether the cortical processes involved differ. Event-related potentials (ERPs) were recorded to 3- and 6-Hz acoustic and binaural beats in 2000 ms duration 250 and 1000 Hz tones presented with approximately 1 s intervals. Latency, amplitude and source current density estimates of ERP components to beats-evoked oscillations were determined and compared across beat types, beat frequencies and base (carrier) frequencies. All stimuli evoked tone-onset components followed by oscillations corresponding to the beat frequency, and a subsequent tone-offset complex. Beats-evoked oscillations were higher in amplitude in response to acoustic than to binaural beats, to 250 than to 1000 Hz base frequency and to 3 Hz than to 6 Hz beat frequency. Sources of the beats-evoked oscillations across all stimulus conditions located mostly to left temporal lobe areas. Differences between estimated sources of potentials to acoustic and binaural beats were not significant. The perceptions of binaural beats involve cortical activity that is not different than acoustic beats in distribution and in the effects of beat- and base frequency, indicating similar cortical processing. Copyright 2010 Elsevier B.V. All rights reserved.

Pindolol antagonises G-protein activation at both pre- and postsynaptic serotonin 5-HT1A receptors: a.

PubMed

Newman-Tancredi, A; Chaput, C; Touzard, M; Millan, M J

2001-04-01

The arylalkylamine, pindolol, may potentiate the clinical actions of antidepressant agents. Although it is thought to act via blockade of 5-HT1A autoreceptors, its efficacy at these sites remains controversial. Herein, we evaluated the actions of pindolol at 5-HT1A autoreceptors and specific populations of postsynaptic 5-HT1A receptors employing [35S]GTPgammaS autoradiography, a measure of receptor-mediated G-protein activation. Both 8-OH-DPAT (1 microM) and 5-HT (10 microM) elicited a pronounced increase in [35S]GTPyS binding in the dorsal raphe nucleus, which contains serotonergic cell bodies bearing 5-HT1A autoreceptors. Pindolol abolished their actions. In the dentate gyrus, lateral septum and entorhinal cortex, structures enriched in postsynaptic 5-HT1A receptors, 8-OH-DPAT (1 microM) and 5-HT (10 microM) also elicited a marked increase in [35S]GTPgammaS binding which was likewise blocked by pindolol. The antagonism of 5-HT-induced [35S]GTPgammaS labelling in the dentate gyrus was shown to be concentration-dependent, yielding a pIC50 of 5.82. Pindolol did not, itself, affect [35S]GTPgammaS binding in any brain region examined. In conclusion, these data suggest that, as characterised by [35S]GTPgammaS autoradiography, and compared with 5-HT and 8-OH-DPAT, pindolol possesses low efficacy at both pre- and postsynaptic 5-HT1A receptors.

Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis.

PubMed

Musella, Alessandra; Sepman, Helena; Mandolesi, Georgia; Gentile, Antonietta; Fresegna, Diego; Haji, Nabila; Conrad, Andrea; Lutz, Beat; Maccarrone, Mauro; Centonze, Diego

2014-04-01

Type-1 cannabinoid receptors (CB1R) are important regulators of the neurodegenerative damage in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). In GABAergic striatal neurons, CB1R stimulation exerts protective effects by limiting inflammation-induced potentiation of glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Here we show that CB1R located on GABAergic or on glutamatergic neurons are differentially involved in the pre- and postsynaptic alterations of sEPSCs caused by EAE in the striatum. After induction of EAE, mice selectively lacking CB1R on GABAergic neurons (GABA-CB1R-KO) showed exacerbated alterations of sEPSC duration in GABAergic medium spiny neurons (MSN). On the other hand, EAE-induced alterations of corticostriatal sEPSC frequency were exacerbated only in mice lacking CB1R on glutamatergic neurons (Glu-CB1R-KO), indicating that this subset of receptors controls the effects of inflammation on glutamate release. While EAE severity was enhanced in whole CB1R-KO mice, GABA-CB1R-KO and Glu-CB1R-KO mice had similar motor deficits as the respective wild-type (WT) counterparts. Our results provide further evidence that CB1R are involved in EAE pathophysiology, and suggest that both pre- and postsynaptic alterations of glutamate transmission are important to drive excitotoxic neurodegeneration typical of this disorder. Copyright © 2014 Elsevier Ltd. All rights reserved.

Interactions of cervico-ocular and vestibulo-ocular fast-phase signals in the control of eye position in rabbits.

PubMed Central

Barmack, N H; Errico, P; Ferraresi, A; Pettorossi, V E

1989-01-01

1. Eye movements in unanaesthetized rabbits were studied during horizontal neck-proprioceptive stimulation (movement of the body with respect to the fixed head), when this stimulation was given alone and when it was given simultaneously with vestibular stimulation (rotation of the head-body). The effect of neck-proprioceptive stimulation on modifying the anticompensatory fast-phase eye movements (AFPs) evoked by vestibular stimulation was studied with a 'conditioning-test' protocol; the 'conditioning' stimulus was a neck-proprioceptive signal evoked by a step-like change in body position with respect to the head and the 'test' stimulus was a vestibular signal evoked by a step rotation of the head-body. 2. The influence of eye position and direction of slow eye movements on the occurrence of compensatory fast-phase eye movements (CFPs) evoked by neck-proprioceptive stimulation was also examined. 3. The anticompensatory fast phase (AFP) evoked by vestibular stimulation was attenuated by a preceding neck-proprioceptive stimulus which when delivered alone evoked compensatory slow-phase eye movements (CSP) in the same direction as the CSP evoked by vestibular stimulation. Conversely, the vestibularly evoked AFP was potentiated by a neck-proprioceptive stimulus which evoked CSPs opposite to that of vestibularly evoked CSPs. 4. Eccentric initial eye positions increased the probability of occurrence of midline-directed compensatory fast-phase eye movements (CFPs) evoked by appropriate neck-proprioceptive stimulation. 5. The gain of the horizontal cervico-ocular reflex (GHCOR) was measured from the combined changes in eye position resulting from AFPs and CSPs. GHCOR was potentiated during simultaneous vestibular stimulation. This enhancement of GHCOR occurred at neck-proprioceptive stimulus frequencies which, in the absence of conjoint vestibular stimulation, do not evoke CSPs. PMID:2795479

Influence of rotating shift work on visual reaction time and visual evoked potential.

PubMed

R V, Hemamalini; N, Krishnamurthy; A, Saravanan

2014-10-01

The present day life style is changing the circadian rhythm of the body especially in rotating night shift workers. The impact of this prolongs their reaction time. Night shift also interferes with the circadian variation of pupil size which may affect the visual evoked potential. To compare the visual reaction time, visual evoked potential (VEP) in rotating night shift workers & day workers and also to correlate the changes in visual reaction time with visual evoked potential. Forty healthy male security guards & staff (25 - 35 y) who did rotating night shifts at least for six months & 40 d workers (25 - 35 y) who did not do night shift in last two years were involved in the study. Visual reaction time and the latency & amplitude of VEP were recorded. Kolmogorov- Smirnov test for normalcy showed the latencies & amplitude of VEP to be normally distributed. Student's unpaired t test showed significant difference (p<0.05) in the visual time and in the latencies of VEP between night shift & day workers. There was no significant difference in the amplitude of VEP. Night shift workers who are prone to circadian rhythm alteration will have prolonged visual reaction time & visual evoked potential abnormalities. Implementation of Bright Light Therapy would be beneficial to the night shift worker.

Evaluation of afferent pain pathways in adrenomyeloneuropathic patients.

PubMed

Yagüe, Sara; Veciana, Misericordia; Casasnovas, Carlos; Ruiz, Montserrat; Pedro, Jordi; Valls-Solé, Josep; Pujol, Aurora

2018-03-01

Patients with adrenomyeloneuropathy may have dysfunctions of visual, auditory, motor and somatosensory pathways. We thought on examining the nociceptive pathways by means of laser evoked potentials (LEPs), to obtain additional information on the pathophysiology of this condition. In 13 adrenomyeloneuropathic patients we examined LEPs to leg, arm and face stimulation. Normative data were obtained from 10 healthy subjects examined in the same experimental conditions. We also examined brainstem auditory evoked potentials (BAEPs), pattern reversal full-field visual evoked potentials (VEPs), motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs). Upper and lower limb MEPs and SEPs, as well as BAEPs, were abnormal in all patients, while VEPs were abnormal in 3 of them (23.1%). LEPs revealed abnormalities to stimulation of the face in 4 patients (30.7%), the forearm in 4 patients (30.7%) and the leg in 10 patients (76.9%). The pathologic process of adrenomyeloneuropathy is characterized by a preferential involvement of auditory, motor and somatosensory tracts and less severely of the visual and nociceptive pathways. This non-inflammatory distal axonopathy preferably damages large myelinated spinal tracts but there is also partial involvement of small myelinated fibres. LEPs studies can provide relevant information about afferent pain pathways involvement in adrenomyeloneuropathic patients. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Electropysiologic evaluation of the visual pathway in patients with multiple sclerosis.

PubMed

Rodriguez-Mena, Diego; Almarcegui, Carmen; Dolz, Isabel; Herrero, Raquel; Bambo, Maria P; Fernandez, Javier; Pablo, Luis E; Garcia-Martin, Elena

2013-08-01

To evaluate the ability of visual evoked potentials and pattern electroretinograms (PERG) to detect subclinical axonal damage in patients during the early diagnostic stage of multiple sclerosis (MS). The authors also compared the ability of optical coherence tomography (OCT), PERG, and visual evoked potentials to detect axonal loss in MS patients and correlated the functional and structural properties of the retinal nerve fiber layer. Two hundred twenty-eight eyes of 114 subjects (57 MS patients and 57 age- and sex-matched healthy controls) were included. The visual pathway was evaluated based on functional and structural assessments. All patients underwent a complete ophthalmic examination that included assessment of visual acuity, ocular motility, intraocular pressure, visual field, papillary morphology, OCT, visual evoked potentials, and PERG. Visual evoked potentials (P100 latency and amplitude), PERG (N95 amplitude and N95/P50 ratio), and OCT parameters differed significantly between MS patients and healthy subjects. Moderate significant correlations were found between visual evoked potentials or PERG parameters and OCT measurements. Axonal damage in ganglion cells of the visual pathway can be detected based on structural measures provided by OCT in MS patients and by the N95 component and N95/P50 index of PERG, thus providing good correlation between function and structure.

Premature infants display increased noxious-evoked neuronal activity in the brain compared to healthy age-matched term-born infants.

PubMed

Slater, Rebeccah; Fabrizi, Lorenzo; Worley, Alan; Meek, Judith; Boyd, Stewart; Fitzgerald, Maria

2010-08-15

This study demonstrates that infants who are born prematurely and who have experienced at least 40days of intensive or special care have increased brain neuronal responses to noxious stimuli compared to healthy newborns at the same postmenstrual age. We have measured evoked potentials generated by noxious clinically-essential heel lances in infants born at term (8 infants; born 37-40weeks) and in infants born prematurely (7 infants; born 24-32weeks) who had reached the same postmenstrual age (mean age at time of heel lance 39.2+/-1.2weeks). These noxious-evoked potentials are clearly distinguishable from shorter latency potentials evoked by non-noxious tactile sensory stimulation. While the shorter latency touch potentials are not dependent on the age of the infant at birth, the noxious-evoked potentials are significantly larger in prematurely-born infants. This enhancement is not associated with specific brain lesions but reflects a functional change in pain processing in the brain that is likely to underlie previously reported changes in pain sensitivity in older ex-preterm children. Our ability to quantify and measure experience-dependent changes in infant cortical pain processing will allow us to develop a more rational approach to pain management in neonatal intensive care. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Association of Membrane Rafts and Postsynaptic Density: Proteomics, Biochemical, and Ultrastructural Analyses

PubMed Central

Suzuki, Tatsuo; Zhang, Jingping; Miyazawa, Shoko; Liu, Qian; Farzan, Michael R.; Yao, Wei-Dong

2011-01-01

Postsynaptic membrane rafts are believed to play important roles in synaptic signaling, plasticity, and maintenance. However, their molecular identities remain elusive. Further, how they interact with the well-established signaling specialization, the postsynaptic density (PSD), is poorly understood. We previously detected a number of conventional PSD proteins in detergent-resistant membranes (DRMs). Here, we have performed LC-MS/MS (liquid chromatography coupled with tandem mass spectrometry) analyses on postsynaptic membrane rafts and PSDs. Our comparative analysis identified an extensive overlap of protein components in the two structures. This overlapping could be explained, at least partly, by a physical association of the two structures. Meanwhile, a significant number of proteins displayed biased distributions to either rafts or PSDs, suggesting distinct roles for the two postsynaptic specializations. Using biochemical and electron microscopic methods, we directly detected membrane raft-PSD complexes. In vitro reconstitution experiments indicated that the formation of raft-PSD complexes was not due to the artificial reconstruction of once-solubilized membrane components and PSD structures, supporting that these complexes occurred in vivo. Taking together, our results provide evidence that postsynaptic membrane rafts and PSDs may be physically associated. Such association could be important in postsynaptic signal integration, synaptic function, and maintenance. PMID:21797867

Presynaptic establishment of the synaptic cleft extracellular matrix is required for post-synaptic differentiation

PubMed Central

Rohrbough, Jeffrey; Rushton, Emma; Woodruff, Elvin; Fergestad, Tim; Vigneswaran, Krishanthan; Broadie, Kendal

2007-01-01

Formation and regulation of excitatory glutamatergic synapses is essential for shaping neural circuits throughout development. In a Drosophila genetic screen for synaptogenesis mutants, we identified mind the gap (mtg), which encodes a secreted, extracellular N-glycosaminoglycan-binding protein. MTG is expressed neuronally and detected in the synaptic cleft, and is required to form the specialized transsynaptic matrix that links the presynaptic active zone with the post-synaptic glutamate receptor (GluR) domain. Null mtg embryonic mutant synapses exhibit greatly reduced GluR function, and a corresponding loss of localized GluR domains. All known post-synaptic signaling/scaffold proteins functioning upstream of GluR localization are also grossly reduced or mislocalized in mtg mutants, including the dPix–dPak–Dock cascade and the Dlg/PSD-95 scaffold. Ubiquitous or neuronally targeted mtg RNA interference (RNAi) similarly reduce post-synaptic assembly, whereas post-synaptically targeted RNAi has no effect, indicating that presynaptic MTG induces and maintains the post-synaptic pathways driving GluR domain formation. These findings suggest that MTG is secreted from the presynaptic terminal to shape the extracellular synaptic cleft domain, and that the cleft domain functions to mediate transsynaptic signals required for post-synaptic development. PMID:17901219

Functional Differences between Global Pre- and Postsynaptic Inhibition in the Drosophila Olfactory Circuit.

PubMed

Oizumi, Masafumi; Satoh, Ryota; Kazama, Hokto; Okada, Masato

2012-01-01

The Drosophila antennal lobe is subdivided into multiple glomeruli, each of which represents a unique olfactory information processing channel. In each glomerulus, feedforward input from olfactory receptor neurons (ORNs) is transformed into activity of projection neurons (PNs), which represent the output. Recent investigations have indicated that lateral presynaptic inhibitory input from other glomeruli controls the gain of this transformation. Here, we address why this gain control acts "pre"-synaptically rather than "post"-synaptically. Postsynaptic inhibition could work similarly to presynaptic inhibition with regard to regulating the firing rates of PNs depending on the stimulus intensity. We investigate the differences between pre- and postsynaptic gain control in terms of odor discriminability by simulating a network model of the Drosophila antennal lobe with experimental data. We first demonstrate that only presynaptic inhibition can reproduce the type of gain control observed in experiments. We next show that presynaptic inhibition decorrelates PN responses whereas postsynaptic inhibition does not. Due to this effect, presynaptic gain control enhances the accuracy of odor discrimination by a linear decoder while its postsynaptic counterpart only diminishes it. Our results provide the reason gain control operates "pre"-synaptically but not "post"-synaptically in the Drosophila antennal lobe.

Interplay between low threshold voltage-gated K+ channels and synaptic inhibition in neurons of the chicken nucleus laminaris along its frequency axis

PubMed Central

Hamlet, William R.; Liu, Yu-Wei; Tang, Zheng-Quan; Lu, Yong

2014-01-01

Central auditory neurons that localize sound in horizontal space have specialized intrinsic and synaptic cellular mechanisms to tightly control the threshold and timing for action potential generation. However, the critical interplay between intrinsic voltage-gated conductances and extrinsic synaptic conductances in determining neuronal output are not well understood. In chicken, neurons in the nucleus laminaris (NL) encode sound location using interaural time difference (ITD) as a cue. Along the tonotopic axis of NL, there exist robust differences among low, middle, and high frequency (LF, MF, and HF, respectively) neurons in a variety of neuronal properties such as low threshold voltage-gated K+ (LTK) channels and depolarizing inhibition. This establishes NL as an ideal model to examine the interactions between LTK currents and synaptic inhibition across the tonotopic axis. Using whole-cell patch clamp recordings prepared from chicken embryos (E17–E18), we found that LTK currents were larger in MF and HF neurons than in LF neurons. Kinetic analysis revealed that LTK currents in MF neurons activated at lower voltages than in LF and HF neurons, whereas the inactivation of the currents was similar across the tonotopic axis. Surprisingly, blockade of LTK currents using dendrotoxin-I (DTX) tended to broaden the duration and increase the amplitude of the depolarizing inhibitory postsynaptic potentials (IPSPs) in NL neurons without dependence on coding frequency regions. Analyses of the effects of DTX on inhibitory postsynaptic currents led us to interpret this unexpected observation as a result of primarily postsynaptic effects of LTK currents on MF and HF neurons, and combined presynaptic and postsynaptic effects in LF neurons. Furthermore, DTX transferred subthreshold IPSPs to spikes. Taken together, the results suggest a critical role for LTK currents in regulating inhibitory synaptic strength in ITD-coding neurons at various frequencies. PMID:24904297

AMPA receptor activation controls type I metabotropic glutamate receptor signalling via a tyrosine kinase at parallel fibre-Purkinje cell synapses.

PubMed

Auger, Céline; Ogden, David

2010-08-15

Metabotropic glutamate receptors type 1 (mGluR1s) and ionotropic AMPA receptors (AMPARs) are colocalized at parallel fibre (PF) to Purkinje cell synapses of the cerebellum. Single stimulation of PFs activates fast AMPAR excitatory postsynaptic currents, whereas the activation of mGluR1s requires burst stimulation. mGluR1s signal through several pathways in Purkinje cells and the most prominent is the activation of a slow EPSC (sEPSC). To separate the two synaptic currents, studies of the sEPSC have commonly been performed in the presence of AMPA/KA receptor antagonists. We show here in rat cerebellar slices that inhibition of the fast EPSC by AMPAR antagonists strongly and selectively potentiates the mGluR1 sEPSC, showing a negative regulation of mGluR1 by AMPAR. This effect is observed with low concentrations of NBQX (300 nM to 1 microM), with the selective AMPAR antagonist GYKI 53655 and also with gamma-DGG, a low affinity glutamate receptor antagonist. When photorelease of glutamate from MNI-glutamate was used to study the postsynaptic responses in isolation, AMPAR inhibition produced a similar potentiation of the mGluR1 sEPSC, showing that the interaction is postsynaptic. Finally, perfusion of the postsynaptic cell with PP1, an inhibitor of src-family tyrosine kinase, increased the amplitude of the mGluR1 sEPSC and occluded the effect of AMPAR inhibition. Thus, at PF to Purkinje cell synapses, AMPAR activation inhibits the mGluR1 sEPSC via activation of a src-family tyrosine kinase. Consequently mGluR1 signalling will be more sensitive to spillover of glutamate than to local synaptic release. Furthermore, it will be enhanced at silent PF synapses which are the majority in Purkinje cells.

Interplay between low threshold voltage-gated K(+) channels and synaptic inhibition in neurons of the chicken nucleus laminaris along its frequency axis.

PubMed

Hamlet, William R; Liu, Yu-Wei; Tang, Zheng-Quan; Lu, Yong

2014-01-01

Central auditory neurons that localize sound in horizontal space have specialized intrinsic and synaptic cellular mechanisms to tightly control the threshold and timing for action potential generation. However, the critical interplay between intrinsic voltage-gated conductances and extrinsic synaptic conductances in determining neuronal output are not well understood. In chicken, neurons in the nucleus laminaris (NL) encode sound location using interaural time difference (ITD) as a cue. Along the tonotopic axis of NL, there exist robust differences among low, middle, and high frequency (LF, MF, and HF, respectively) neurons in a variety of neuronal properties such as low threshold voltage-gated K(+) (LTK) channels and depolarizing inhibition. This establishes NL as an ideal model to examine the interactions between LTK currents and synaptic inhibition across the tonotopic axis. Using whole-cell patch clamp recordings prepared from chicken embryos (E17-E18), we found that LTK currents were larger in MF and HF neurons than in LF neurons. Kinetic analysis revealed that LTK currents in MF neurons activated at lower voltages than in LF and HF neurons, whereas the inactivation of the currents was similar across the tonotopic axis. Surprisingly, blockade of LTK currents using dendrotoxin-I (DTX) tended to broaden the duration and increase the amplitude of the depolarizing inhibitory postsynaptic potentials (IPSPs) in NL neurons without dependence on coding frequency regions. Analyses of the effects of DTX on inhibitory postsynaptic currents led us to interpret this unexpected observation as a result of primarily postsynaptic effects of LTK currents on MF and HF neurons, and combined presynaptic and postsynaptic effects in LF neurons. Furthermore, DTX transferred subthreshold IPSPs to spikes. Taken together, the results suggest a critical role for LTK currents in regulating inhibitory synaptic strength in ITD-coding neurons at various frequencies.

Recording and assessment of evoked potentials with electrode arrays.

PubMed

Miljković, N; Malešević, N; Kojić, V; Bijelić, G; Keller, T; Popović, D B

2015-09-01

In order to optimize procedure for the assessment of evoked potentials and to provide visualization of the flow of action potentials along the motor systems, we introduced array electrodes for stimulation and recording and developed software for the analysis of the recordings. The system uses a stimulator connected to an electrode array for the generation of evoked potentials, an electrode array connected to the amplifier, A/D converter and computer for the recording of evoked potentials, and a dedicated software application. The method has been tested for the assessment of the H-reflex on the triceps surae muscle in six healthy humans. The electrode array with 16 pads was positioned over the posterior aspect of the thigh, while the recording electrode array with 16 pads was positioned over the triceps surae muscle. The stimulator activated all the pads of the stimulation electrode array asynchronously, while the signals were recorded continuously at all the recording sites. The results are topography maps (spatial distribution of evoked potentials) and matrices (spatial visualization of nerve excitability). The software allows the automatic selection of the lowest stimulation intensity to achieve maximal H-reflex amplitude and selection of the recording/stimulation pads according to predefined criteria. The analysis of results shows that the method provides rich information compared with the conventional recording of the H-reflex with regard the spatial distribution.

Anxiety affects the amplitudes of red and green color-elicited flash visual evoked potentials in humans.

PubMed

Hosono, Yuki; Kitaoka, Kazuyoshi; Urushihara, Ryo; Séi, Hiroyoshi; Kinouchi, Yohsuke

2014-01-01

It has been reported that negative emotional changes and conditions affect the visual faculties of humans at the neural level. On the other hand, the effects of emotion on color perception in particular, which are based on evoked potentials, are unknown. In the present study, we investigated whether different anxiety levels affect the color information processing for each of 3 wavelengths by using flash visual evoked potentials (FVEPs) and State-Trait Anxiety Inventory. In results, significant positive correlations were observed between FVEP amplitudes and state or trait anxiety scores in the long (sensed as red) and middle (sensed as green) wavelengths. On the other hand, short-wavelength-evoked FVEPs were not correlated with anxiety level. Our results suggest that negative emotional conditions may affect color sense processing in humans.

High frequency bone conduction auditory evoked potentials in the guinea pig: Assessing cochlear injury after ossicular chain manipulation.

PubMed

Bergin, M J; Bird, P A; Vlajkovic, S M; Thorne, P R

2015-12-01

Permanent high frequency (>4 kHz) sensorineural hearing loss following middle ear surgery occurs in up to 25% of patients. The aetiology of this loss is poorly understood and may involve transmission of supra-physiological forces down the ossicular chain to the cochlea. Investigating the mechanisms of this injury using animal models is challenging, as evaluating cochlear function with evoked potentials is confounded when ossicular manipulation disrupts the normal air conduction (AC) pathway. Bone conduction (BC) using clinical bone vibrators in small animals is limited by poor transducer output at high frequencies sensitive to trauma. The objectives of the present study were firstly to evaluate a novel high frequency bone conduction transducer with evoked auditory potentials in a guinea pig model, and secondly to use this model to investigate the impact of middle ear surgical manipulation on cochlear function. We modified a magnetostrictive device as a high frequency BC transducer and evaluated its performance by comparison with a calibrated AC transducer at frequencies up to 32 kHz using the auditory brainstem response (ABR), compound action potential (CAP) and summating potential (SP). To mimic a middle ear traumatising stimulus, a rotating bur was brought in to contact with the incudomalleal complex and the effect on evoked cochlear potentials was observed. BC-evoked potentials followed the same input-output function pattern as AC potentials for all ABR frequencies. Deterioration in CAP and SP thresholds was observed after ossicular manipulation. It is possible to use high frequency BC to evoke responses from the injury sensitive basal region of the cochlea and so not rely on AC with the potential confounder of conductive hearing loss. Ongoing research explores how these findings evolve over time, and ways in which injury may be reduced and the cochlea protected during middle ear surgery. Copyright © 2015 Elsevier B.V. All rights reserved.

The role of the postsynaptic density in the pathology of the fragile X syndrome.

PubMed

Kindler, Stefan; Kreienkamp, Hans-Jürgen

2012-01-01

The protein repertoire of excitatory synapses controls dendritic spine morphology, synaptic plasticity and higher brain functions. In brain neurons, the RNA-associated fragile X mental retardation protein (FMRP) binds in vivo to various transcripts encoding key postsynaptic components and may thereby substantially regulate the molecular composition of dendritic spines. In agreement with this notion functional loss of FMRP in patients affected by the fragile X syndrome (FXS) causes cognitive impairment. Here we address our current understanding of the functional role of individual postsynaptic proteins. We discuss how FMRP controls the abundance of select proteins at postsynaptic sites, which signaling pathways regulate the local activity of FMRP at synapses, and how altered levels of postsynaptic proteins may contribute to FXS pathology.

Predicting Presynaptic and Postsynaptic Neurotoxins by Developing Feature Selection Technique

PubMed Central

Yang, Yunchun; Zhang, Chunmei; Chen, Rong; Huang, Po

2017-01-01

Presynaptic and postsynaptic neurotoxins are proteins which act at the presynaptic and postsynaptic membrane. Correctly predicting presynaptic and postsynaptic neurotoxins will provide important clues for drug-target discovery and drug design. In this study, we developed a theoretical method to discriminate presynaptic neurotoxins from postsynaptic neurotoxins. A strict and objective benchmark dataset was constructed to train and test our proposed model. The dipeptide composition was used to formulate neurotoxin samples. The analysis of variance (ANOVA) was proposed to find out the optimal feature set which can produce the maximum accuracy. In the jackknife cross-validation test, the overall accuracy of 94.9% was achieved. We believe that the proposed model will provide important information to study neurotoxins. PMID:28303250

The effects of neck flexion on cerebral potentials evoked by visual, auditory and somatosensory stimuli and focal brain blood flow in related sensory cortices

PubMed Central

2012-01-01

Background A flexed neck posture leads to non-specific activation of the brain. Sensory evoked cerebral potentials and focal brain blood flow have been used to evaluate the activation of the sensory cortex. We investigated the effects of a flexed neck posture on the cerebral potentials evoked by visual, auditory and somatosensory stimuli and focal brain blood flow in the related sensory cortices. Methods Twelve healthy young adults received right visual hemi-field, binaural auditory and left median nerve stimuli while sitting with the neck in a resting and flexed (20° flexion) position. Sensory evoked potentials were recorded from the right occipital region, Cz in accordance with the international 10–20 system, and 2 cm posterior from C4, during visual, auditory and somatosensory stimulations. The oxidative-hemoglobin concentration was measured in the respective sensory cortex using near-infrared spectroscopy. Results Latencies of the late component of all sensory evoked potentials significantly shortened, and the amplitude of auditory evoked potentials increased when the neck was in a flexed position. Oxidative-hemoglobin concentrations in the left and right visual cortices were higher during visual stimulation in the flexed neck position. The left visual cortex is responsible for receiving the visual information. In addition, oxidative-hemoglobin concentrations in the bilateral auditory cortex during auditory stimulation, and in the right somatosensory cortex during somatosensory stimulation, were higher in the flexed neck position. Conclusions Visual, auditory and somatosensory pathways were activated by neck flexion. The sensory cortices were selectively activated, reflecting the modalities in sensory projection to the cerebral cortex and inter-hemispheric connections. PMID:23199306

Transcranial Motor-Evoked Potentials Are More Readily Acquired Than Somatosensory-Evoked Potentials in Children Younger Than 6 Years.

PubMed

McIntyre, Ian W; Francis, Lisa; McAuliffe, John J

2016-01-01

There is a general belief that somatosensory-evoked potentials (SSEPs) are more easily obtained than transcranial motor-evoked potentials (TcMEPs) in children younger than 6 years. We tested this assumption and the assumption that motor-evoked potentials are rarely obtained in children younger than 2 years. The records of all patients who were monitored during surgical procedures between April 1, 2010, and June 30, 2013, were reviewed and those who were younger than 72 months at the time of surgery were identified and analyzed for the rate of obtaining clinically useful SSEPs and motor-evoked potentials. Subgroup analysis was performed by age. A total of 146 patients were identified, 9 had SSEPs without TcMEPs monitored, 117 had both TcMEPs and SSEPs monitored, and the remainder had only electromyographic monitoring. All patients who were to have TcMEPs recorded received a total IV anesthetic. Among the 117 patients who had both SSEPs and TcMEPs monitored, clinically relevant TcMEPs were obtained more frequently than SSEPs (110/117 vs 89/117; χ = 14.82; P = 0.00012). There were significant differences between the rates of obtaining SSEPs and TcMEPs in the 0- to 23-month (P = 0.0038) and 24- to 47-month (P = 0.0056) age groups. Utilization of a double-train stimulation technique facilitated obtaining TcMEPs in the youngest patients. TcMEPs can be obtained more easily than SSEPs in patients younger than 72 months if a permissive anesthetic technique is used. The success rate for obtaining TcMEPs can be further enhanced by the use of a temporal facilitation (double-train) stimulation technique.

Utility of Brainstem Trigeminal Evoked Potentials in Patients With Primary Trigeminal Neuralgia Treated by Microvascular Decompression.

PubMed

Zhu, Jin; Zhang, Xin; Zhao, Hua; Tang, Yin-Da; Ying, Ting-Ting; Li, Shi-Ting

2017-09-01

To investigate the characteristics of brainstem trigeminal evoked potentials (BTEP) waveform in patients with and without trigeminal neuralgia (TN), and to discuss the utility of BTEP in patients with primary TN treated by microvascular decompression (MVD). A retrospective review of 43 patients who underwent BTEP between January 2016 and June 2016, including 33 patients with TN who underwent MVD and 10 patients without TN. Brainstem trigeminal evoked potentials characteristics of TN and non-TN were summarized, in particular to compare the BTEP changes between pre- and post-MVD, and to discover the relationship between BTEP changes and surgical outcome. Brainstem trigeminal evoked potentials can be recorded in patients without trigeminal neuralgia. Abnormal BTEP could be recorded when different branches were stimulated. After decompression, the original W2, W3 disappeared and then replaced by a large wave in most patients, or original wave poorly differentiated improved in some patients, showed as shorter latency and (or) amplitude increased. Brainstem trigeminal evoked potentials waveform of healthy side in patients with trigeminal neuralgia was similar to the waveform of patients without TN. In 3 patients, after decompression the W2, W3 peaks increased, and the latency, duration, IPLD did not change significantly. Until discharge, 87.9% (29/33) of the patients presented complete absence of pain without medication (BNI I) and 93.9% (31/33) had good pain control without medication (BNI I-II). Brainstem trigeminal evoked potentials can reflect the conduction function of the trigeminal nerve to evaluate the functional level of the trigeminal nerve conduction pathway. The improvement and restoration of BTEP waveforms are closely related to the postoperative curative effect.

Steady-state pattern electroretinogram and short-duration transient visual evoked potentials in glaucomatous and healthy eyes.

PubMed

Amarasekera, Dilru C; Resende, Arthur F; Waisbourd, Michael; Puri, Sanjeev; Moster, Marlene R; Hark, Lisa A; Katz, L Jay; Fudemberg, Scott J; Mantravadi, Anand V

2018-01-01

This study evaluates two rapid electrophysiological glaucoma diagnostic tests that may add a functional perspective to glaucoma diagnosis. This study aimed to determine the ability of two office-based electrophysiological diagnostic tests, steady-state pattern electroretinogram and short-duration transient visual evoked potentials, to discern between glaucomatous and healthy eyes. This is a cross-sectional study in a hospital setting. Forty-one patients with glaucoma and 41 healthy volunteers participated in the study. Steady-state pattern electroretinogram and short-duration transient visual evoked potential testing was conducted in glaucomatous and healthy eyes. A 64-bar-size stimulus with both a low-contrast and high-contrast setting was used to compare steady-state pattern electroretinogram parameters in both groups. A low-contrast and high-contrast checkerboard stimulus was used to measure short-duration transient visual evoked potential parameters in both groups. Steady-state pattern electroretinogram parameters compared were MagnitudeD, MagnitudeD/Magnitude ratio, and the signal-to-noise ratio. Short-duration transient visual evoked potential parameters compared were amplitude and latency. MagnitudeD was significantly lower in glaucoma patients when using a low-contrast (P = 0.001) and high-contrast (P < 0.001) 64-bar-size steady-state pattern electroretinogram stimulus. MagnitudeD/Magnitude ratio and SNR were significantly lower in the glaucoma group when using a high-contrast 64-bar-size stimulus (P < 0.001 and P = 0.010, respectively). Short-duration transient visual evoked potential amplitude and latency were not significantly different between the two groups. Steady-state pattern electroretinogram was effectively able to discern between glaucomatous and healthy eyes. Steady-state pattern electroretinogram may thus have a role as a clinically useful electrophysiological diagnostic tool. © 2017 Royal Australian and New Zealand College of Ophthalmologists.

Multifocal Visual Evoked Potential in Eyes With Temporal Hemianopia From Chiasmal Compression: Correlation With Standard Automated Perimetry and OCT Findings.

PubMed

Sousa, Rafael M; Oyamada, Maria K; Cunha, Leonardo P; Monteiro, Mário L R

2017-09-01

To verify whether multifocal visual evoked potential (mfVEP) can differentiate eyes with temporal hemianopia due to chiasmal compression from healthy controls. To assess the relationship between mfVEP, standard automated perimetry (SAP), and Fourier domain-optical coherence tomography (FD-OCT) macular and peripapillary retinal nerve fiber layer (RNFL) thickness measurements. Twenty-seven eyes with permanent temporal visual field (VF) defects from chiasmal compression on SAP and 43 eyes of healthy controls were submitted to mfVEP and FD-OCT scanning. Multifocal visual evoked potential was elicited using a stimulus pattern of 60 sectors and the responses were averaged for the four quadrants and two hemifields. Optical coherence tomography macular measurements were averaged in quadrants and halves, while peripapillary RNFL thickness was averaged in four sectors around the disc. Visual field loss was estimated in four quadrants and each half of the 24-2 strategy test points. Multifocal visual evoked potential measurements in the two groups were compared using generalized estimated equations, and the correlations between mfVEP, VF, and OCT findings were quantified. Multifocal visual evoked potential-measured temporal P1 and N2 amplitudes were significantly smaller in patients than in controls. No significant difference in amplitude was observed for nasal parameters. A significant correlation was found between mfVEP amplitudes and temporal VF loss, and between mfVEP amplitudes and the corresponding OCT-measured macular and RNFL thickness parameters. Multifocal visual evoked potential amplitude parameters were able to differentiate eyes with temporal hemianopia from controls and were significantly correlated with VF and OCT findings, suggesting mfVEP is a useful tool for the detection of visual abnormalities in patients with chiasmal compression.

Rhesus macaque model of chronic opiate dependence and neuro-AIDS: longitudinal assessment of auditory brainstem responses and visual evoked potentials

PubMed Central

Riazi, Mariam; Marcario, Joanne K; Samson, Frank K.; Kenjale, Himanshu; Adany, Istvan; Staggs, Vincent; Ledford, Emily; Marquis, Janet; Narayan, Opendra; Cheney, Paul D.

2013-01-01

Our work characterizes the effects of opiate (morphine) dependence on auditory brainstem and visual evoked responses in a rhesus macaque model of neuro-AIDS utilizing a chronic continuous drug delivery paradigm. The goal of this study was to clarify whether morphine is protective, or if it exacerbates simian immunodeficiency virus (SIV) related systemic and neurological disease. Our model employs a macrophage tropic CD4/CCR5 co-receptor virus, SIVmac239 (R71/E17), which crosses the blood brain barrier shortly after inoculation and closely mimics the natural disease course of human immunodeficiency virus (HIV) infection. The cohort was divided into 3 groups: morphine only, SIV only, and SIV + morphine. Evoked potential (EP) abnormalities in sub-clinically infected macaques were evident as early as eight weeks post-inoculation. Prolongations in EP latencies were observed in SIV-infected macaques across all modalities. Animals with the highest CSF viral loads and clinical disease showed more abnormalities than those with sub-clinical disease, confirming our previous work (Raymond et al, 1998, 1999, 2000). Although some differences were observed in auditory and visual evoked potentials in morphine treated compared to untreated SIV-infected animals, the effects were relatively small and not consistent across evoked potential type. However, morphine treated animals with subclinical disease had a clear tendency toward higher virus loads in peripheral and CNS tissues (Marcario et al., 2008) suggesting that if had been possible to follow all animals to end-stage disease, a clearer pattern of evoked potential abnormality might have emerged. PMID:19283490

Voltage-Gated Calcium Influx Modifies Cholinergic Inhibition of Inner Hair Cells in the Immature Rat Cochlea.

PubMed

Zachary, Stephen; Nowak, Nathaniel; Vyas, Pankhuri; Bonanni, Luke; Fuchs, Paul Albert

2018-06-20

Until postnatal day (P) 12, inner hair cells of the rat cochlea are invested with both afferent and efferent synaptic connections. With the onset of hearing at P12, the efferent synapses disappear, and afferent (ribbon) synapses operate with greater efficiency. This change coincides with increased expression of voltage-gated potassium channels, the loss of calcium-dependent electrogenesis, and the onset of graded receptor potentials driven by sound. The transient efferent synapses include near-membrane postsynaptic cisterns thought to regulate calcium influx through the hair cell's α9-containing and α10-containing nicotinic acetylcholine receptors. This influx activates small-conductance Ca 2+ -activated K + (SK) channels. Serial-section electron microscopy of inner hair cells from two 9-d-old (male) rat pups revealed many postsynaptic efferent cisterns and presynaptic afferent ribbons whose average minimal separation in five cells ranged from 1.1 to 1.7 μm. Efferent synaptic function was studied in rat pups (age, 7-9 d) of either sex. The duration of these SK channel-mediated IPSCs was increased by enhanced calcium influx through L-type voltage-gated channels, combined with ryanodine-sensitive release from internal stores-presumably the near-membrane postsynaptic cistern. These data support the possibility that inner hair cell calcium electrogenesis modulates the efficacy of efferent inhibition during the maturation of inner hair cell synapses. SIGNIFICANCE STATEMENT Strict calcium buffering is essential for cellular function. This problem is especially acute for compact hair cells where increasing cytoplasmic calcium promotes the opposing functions of closely adjoining afferent and efferent synapses. The near-membrane postsynaptic cistern at efferent synapses segregates synaptic calcium signals by acting as a dynamic calcium store. The hair cell serves as an informative model for synapses with postsynaptic cisterns (C synapses) found in central neurons. Copyright © 2018 the authors 0270-6474/18/385677-11$15.00/0.

Stimulus novelty, task relevance and the visual evoked potential in man

NASA Technical Reports Server (NTRS)

Courchesne, E.; Hillyard, S. A.; Galambos, R.

1975-01-01

The effect of task relevance on P3 (waveform of human evoked potential) waves and the methodologies used to deal with them are outlined. Visual evoked potentials (VEPs) were recorded from normal adult subjects performing in a visual discrimination task. Subjects counted the number of presentations of the numeral 4 which was interposed rarely and randomly within a sequence of tachistoscopically flashed background stimuli. Intrusive, task-irrelevant (not counted) stimuli were also interspersed rarely and randomly in the sequence of 2s; these stimuli were of two types: simples, which were easily recognizable, and novels, which were completely unrecognizable. It was found that the simples and the counted 4s evoked posteriorly distributed P3 waves while the irrelevant novels evoked large, frontally distributed P3 waves. These large, frontal P3 waves to novels were also found to be preceded by large N2 waves. These findings indicate that the P3 wave is not a unitary phenomenon but should be considered in terms of a family of waves, differing in their brain generators and in their psychological correlates.

Investigation of brachial plexus traction lesions by peripheral and spinal somatosensory evoked potentials.

PubMed Central

Jones, S J

1979-01-01

Peripheral, spinal and cortical somatosensory evoked potentials were recorded in 26 patients with unilateral traction injuries of the brachial plexus ganglia. Of 10 cases explored surgically the recordings correctly anticipated the major site of the lesion in eight. PMID:422958

Normalization of auditory evoked potential and visual evoked potential in patients with idiot savant.

PubMed

Chen, X; Zhang, M; Wang, J; Lou, F; Liang, J

1999-03-01

To investigate the variations of auditory evoked potentials (AEP) and visual evoked potentials (VEP) of patients with idiot savant (IS) syndrome. Both AEP and VEP were recorded from 7 patients with IS syndrome, 21 mentally retarded (MR) children without the syndrome and 21 normally age-matched controls, using a Dantec concerto SEEG-16 BEAM instrument. Both AEP and VEP of MR group showed significantly longer latencies (P1 and P2 latencies of AEP, P < 0.01; N1 and N2 latencies of VEP, P < 0.01/0.05), lower P2 amplitudes (P < 0.01) and higher P3 amplitudes (P < 0.01), as compared with normal controls. But none of above-mentioned changes was found with IS group. Almost all MR patients (90.1%) presented P4 component in both AEP and VEP, which was also in sharp contrast with its incidence in other 2 groups (IS: 14.3%; normal controls: 9.5%). Patients with idiot savant syndrome presented normalized AEP and VEP.

[Executive functioning and evoked potentials P300 pre- and post- treatment in attention deficit hyperactivity disorder].

PubMed

Roca, Patricia; Mulas, Fernando; Gandia, Rubén; Ortiz-Sánchez, Pedro; Abad, Luis

2013-02-22

Evoked potentials P300 and the analysis of executive functions have shown their utility in the monitoring of patients with symptoms of attention deficit hyperactivity disorder (ADHD). Neuropsychological profiles and evoked potentials P300 have been analysed for two groups of children with an ADHD treatment with atomoxetine and methylphenidate respectively. Correlations between P300 and the selected neuropsychological parameters are studied, and the differences between basal values and 1 year follow-up are analysed. Two groups were performed: a group of 22 children ADHD in the atomoxetine condition, and a group of 24 children ADHD in the methylphenidate condition. The results show a global improvement of all the parameters, in terms of executive function and P300 values in both, the atomoxetine and the methylphenidate group. Executive functions and evoked potentials P300 reflect an underlying processing and they are very useful in the clinical practice. This exploratory study shows the importance of designing personalized objective variables-based treatments.