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1

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

Microsoft Academic Search

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

S. L. Cochran

1995-01-01

2

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

NASA Technical Reports Server (NTRS)

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).

Cochran, S. L.

1995-01-01

3

Octopaminergic modulation of synaptic transmission between an identified sensory afferent and flight motoneuron in the locust.  

PubMed

The role of the biogenic amine octopamine in modulating cholinergic synaptic transmission between the locust forewing stretch receptor neuron (fSR) and the first basalar motoneuron (BA1) was investigated. The amines 5-hydroxytryptamine (5-HT, serotonin) and dopamine were also studied. Bath application of octopamine, 5-HT, and dopamine at concentrations of 10(-4) M reversibly decreased the amplitude of monosynaptic excitatory postsynaptic potentials (EPSPs) evoked in BA1 by electrically stimulating the fSR axon. These effects occurred without any detectable change in either input resistance or membrane potential of BA1. The amines also reversibly decreased the amplitude of responses to acetylcholine (ACh) pressure-applied to the soma of BA1. The muscarinic antagonist scopolamine (10(-6) M) had no significant effect on the octopamine-induced decrease in ACh responses. These observations suggest that these amines potentially could physiologically depress cholinergic transmission between fSR and BA1, at least in part, by altering nicotinic rather than muscarinic cholinergic receptor function. Although the octopaminergic agonists naphazoline and tolazoline both mimicked the actions of octopamine, the receptor responsible for octopamine-mediated modulation could not be characterized since amine receptor antagonists tested on the preparation had complex actions. Confocal immunocytochemistry revealed intense octopamine immunoreactivity in the anterior lateral association center, thus confirming the presence of octopamine in neuropil regions containing fSR/BA1 synapses and therefore supporting a role for this amine in the modulation of synaptic transmission between the fSR and BA1. 5-HT-immunoreactivity, conversely, was concentrated within the ventral association centers; very little staining was observed in the dorsal neuropil regions in which fSR/BA1 synapses are located. PMID:12761824

Leitch, Beulah; Judge, Sarah; Pitman, Robert M

2003-07-14

4

Influence of L-serine-O-phosphate on synaptic transmission in afferent synapses of the ampullae of Lorenzini of skates  

Microsoft Academic Search

The method of superfusion of the basal membranes of the ampullae of Lorenzini of skates was used to investigate the influence of L-serine-O-phosphate (SOP) on the background and evoked activity of afferent nerve fibers, as well as on the effects of application of agonists: exciting amino acids — L-glutamate (L-GLU), kainate (KA), quisqualte (Q), and N-methyl-D-aspartate (NMDA). It was found

G. N. Akoev; Yu. N. Andrianov; I. V. Ryzhova; N. O. Sherman

1991-01-01

5

Synaptic processes in thoracic ?-motoneurons evoked by segmental afferent stimulation  

Microsoft Academic Search

Synaptic processes in various functional groups of thoracic motoneurons (Th9-Th11) evoked by stimulation of segmental nerves were investigated in anesthetized and decerebrate cats. No reciprocal relations were found between these groups of motoneurons. Only excitatory mono- and polysynaptic responses were recorded in the motoneurons of the principal intercostal nerve following stimulation of the homonymous nerve. Activation of the afferents of

N. N. Preobrazhenskii; A. P. Gokin; I. S. Bezhenary

1970-01-01

6

Synaptic Transmission Correlates of General Mental Ability  

ERIC Educational Resources Information Center

Nerve conduction velocity (NCV) and efficiency of synaptic transmission are two possible biological mechanisms that may underpin intelligence. Direct assessments of NCV, without synaptic transmission, show few substantial or reliable correlations with cognitive abilities ["Intelligence" 16 (1992) 273]. We therefore assessed the latencies of…

McRorie, Margaret; Cooper, Colin

2004-01-01

7

Ultrastructural analysis of the synaptic connectivity of TRPV1-expressing primary afferent terminals in the rat trigeminal caudal nucleus.  

PubMed

Trigeminal primary afferents that express the transient receptor potential vanilloid 1 (TRPV1) are important for the transmission of orofacial nociception. However, little is known about how the TRPV1-mediated nociceptive information is processed at the first relay nucleus in the central nervous system (CNS). To address this issue, we studied the synaptic connectivity of TRPV1-positive (+) terminals in the rat trigeminal caudal nucleus (Vc) by using electron microscopic immunohistochemistry and analysis of serial thin sections. Whereas the large majority of TRPV1+ terminals made synaptic contacts of an asymmetric type with one or two postsynaptic dendrites, a considerable fraction also participated in complex glomerular synaptic arrangements. A few TRPV1+ terminals received axoaxonic contacts from synaptic endings that contained pleomorphic synaptic vesicles and were immunolabeled for glutamic acid decarboxylase, the synthesizing enzyme for the inhibitory neurotransmitter ?-aminobutyric acid (GABA). We classified the TRPV1+ terminals into an S-type, containing less than five dense-core vesicles (DCVs), and a DCV-type, containing five or more DCVs. The number of postsynaptic dendrites was similar between the two types of terminals; however, whereas axoaxonic contacts were frequent on the S-type, the DCV-type did not receive axoaxonic contacts. In the sensory root of the trigeminal ganglion, TRPV1+ axons were mostly unmyelinated, and a small fraction was small myelinated. These results suggest that the TRPV1-mediated nociceptive information from the orofacial region is processed in a specific manner by two distinct types of synaptic arrangements in the Vc, and that the central input of a few TRPV1+ afferents is presynaptically modulated via a GABA-mediated mechanism. PMID:20878780

Yeo, Eun Jin; Cho, Yi Sul; Paik, Sang Kyoo; Yoshida, Atsushi; Park, Mae Ja; Ahn, Dong Kuk; Moon, Cheil; Kim, Yun Sook; Bae, Yong Chul

2010-10-15

8

Recovery of afferent function and synaptic strength in hippocampal CA1 following traumatic brain injury.  

PubMed

Cortical contusion injury can result in the partial loss of ipsilateral CA3 neurons within 48 h, leading to a proportional reduction in the number of afferent fibers to CA1 stratum radiatum. While the loss of afferent input to CA1 exhibits a remarkable, albeit incomplete, recovery over the next few weeks, little is known about the functional status of presynaptic afferents during the depletion and recovery phases following injury. Here, we prepared hippocampal slices from adult Sprague Dawley rats at 2, 7, and 14 days after lateral cortical contusion injury and measured fiber volley (FV) amplitudes extracellularly in CA1 stratum radiatum. Field excitatory post-synaptic potentials (EPSPs) were also measured and plotted as a function of FV amplitude to assess relative synaptic strength of residual and/or regenerated synaptic contacts. At 2 days post-injury, FV amplitude and synaptic strength were markedly reduced in the ipsilateral, relative to the contralateral, hippocampus. FV amplitude in ipsilateral CA1 showed a complete recovery by 7 days, indicative of a post-injury sprouting response. Synaptic strength in ipsilateral CA1 also showed a dramatic recovery over this time; however, EPSP-to-FV curves remained slightly suppressed at both the 7 and 14 day time points. Despite these deficits, ipsilateral slices retained the capacity to express long-term potentiation, indicating that at least some mechanisms for synaptic plasticity remain intact, or are compensated for. These results are in agreement with anatomical evidence showing a profound deafferentation, followed by a remarkable re-enervation, of ipsilateral CA1 in the first few weeks after traumatic brain injury. Although plasticity mechanisms appear to remain intact, synaptic strength deficits in CA1 could limit information throughput in the hippocampus, leading to persistent memory dysfunction. PMID:19604098

Norris, Christopher M; Scheff, Stephen W

2009-12-01

9

Synaptic inputs to trigeminal primary afferent neurons cause firing and modulate intrinsic oscillatory activity.  

PubMed

In this paper, we investigated the influence of synapses on the cell bodies of trigeminal muscle spindle afferents that lie in the trigeminal mesencephalic nucleus (NVmes), using intracellular recordings in brain stem slices of young rats. Three types of synaptic responses could be evoked by electrical stimulation of the adjacent supratrigeminal, motor, and main sensory nuclei and the intertrigeminal area: monophasic depolarizing postsynaptic potentials (PSPs), biphasic PSPs, and all or none action potentials without underlying excitatory PSPs (EPSPs). Many PSPs and spikes were abolished by bath-application of 6,7-dinitroquinoxaline (DNQX) alone or combined with D,L-2-amino-5-phosphonovaleric acid (APV), suggesting that they are mediated by non-N-methyl-D-aspartate (NMDA) and NMDA glutamatergic receptors, while some action potentials were sensitive to bicuculline, indicating involvement of GABAA receptors. A number of cells showed spontaneous membrane potential oscillations, and stimulation of synaptic inputs increased the amplitude of the oscillations for several cycles, which often triggered repetitive firing. Furthermore, the oscillatory rhythm was reset by the stimulation. Our results show that synaptic inputs to muscle primary afferent neurons in NVmes from neighboring areas are mainly excitatory and that they cause firing. In addition, the inputs synchronize intrinsic oscillations, which may lead to sustained, synchronous firing in a subpopulation of afferents. This may be of importance during rapid biting and during the mastication of very hard or tough foods. PMID:15381749

Verdier, Dorly; Lund, James P; Kolta, Arlette

2004-10-01

10

Astrocytes Optimize the Synaptic Transmission of Information  

PubMed Central

Chemical synapses transmit information via the release of neurotransmitter-filled vesicles from the presynaptic terminal. Using computational modeling, we predict that the limited availability of neurotransmitter resources in combination with the spontaneous release of vesicles limits the maximum degree of enhancement of synaptic transmission. This gives rise to an optimal tuning that depends on the number of active zones. There is strong experimental evidence that astrocytes that enwrap synapses can modulate the probabilities of vesicle release through bidirectional signaling and hence regulate synaptic transmission. For low-fidelity hippocampal synapses, which typically have only one or two active zones, the predicted optimal values lie close to those determined by experimentally measured astrocytic feedback, suggesting that astrocytes optimize synaptic transmission of information.

Nadkarni, Suhita; Jung, Peter; Levine, Herbert

2008-01-01

11

Effect of dalargin, a synthetic leu-enkephalin analogue on synaptic transmission in the Lorenzini ampullae of rays  

Microsoft Academic Search

Effects of dalargin, a synthetic leu-enkephalin analogue and its antagonist naloxone on synaptic transmission in afferent synapses of ray electroreceptors were investigated using an isolated preparation of Lorenzini ampullae from Black sea rays. It was shown that dalargin (10-6–10-10 mole liter) both decreased background activity and evoked activity of an afferent fiber in a dose-dependent manner. Naloxone (10-5 mole\\/liter) also

Yu. N. Andrianov; G. N. Akoev; H. A. Braun; I. V. Ryzhova; K. Fogt; N. O. Sherman

1993-01-01

12

Mannose-Specific Recognition Mediates Two Aspects of Synaptic Growth of Leech Sensory Afferents: Collateral Branching and Proliferation of Synaptic Vesicle Clusters  

Microsoft Academic Search

The developmental role of carbohydrate markers in the genesis of neuronal networks was studied using leech sensory afferents as a model. Leech sensory afferents express a mannose-containing epitope on their cell surface that is recognized by monoclonal antibody Lan3-2. Previously, the elaboration of sensory arbors in the synaptic neuropil of CNS ganglia was experimentally shown to depend on this mannose

Mei-Hui Tai; Birgit Zipser

1998-01-01

13

Synaptic transfer from outer hair cells to type II afferent fibers in the rat cochlea.  

PubMed

Type II cochlear afferents receive glutamatergic synaptic excitation from outer hair cells (OHCs) in the rat cochlea. However, it remains uncertain whether this connection is capable of providing auditory information to the brain. The functional efficacy of this connection depends in part on the number of presynaptic OHCs, their probability of transmitter release, and the effective electrical distance for spatial summation in the type II fiber. The present work addresses these questions using whole-cell recordings from the spiral process of type II afferents that run below OHCs in the apical turn of young (5-9 d postnatal) rat cochlea. A "high potassium puffer" was used to elicit calcium action potentials from individual OHCs and thereby show that the average probability of transmitter release was 0.26 (range 0.02-0.73). Electron microscopy showed relatively few vesicles tethered to ribbons in equivalent OHCs. A "receptive field" map for individual type II fibers was constructed by successively puffing onto OHCs along the cochlear spiral, up to 180 ?m from the recording pipette. These revealed a conservative estimate of 7 presynaptic OHCs per type II fiber (range 1-11). EPSCs evoked from presynaptic OHCs separated by >100 ?m did not differ in amplitude or waveform, implying that the type II fiber's length constant exceeded the length of the synaptic input zone. Together these data suggest that type II fibers could communicate centrally by maximal activation of their entire pool of presynaptic OHCs. PMID:22787038

Weisz, Catherine J C; Lehar, Mohamed; Hiel, Hakim; Glowatzki, Elisabeth; Fuchs, Paul Albert

2012-07-11

14

Electric Dipole Theory of Chemical Synaptic Transmission  

PubMed Central

In this paper we propose that chemicals such as acetylcholine are electric dipoles which when oriented and arranged in a large array could produce an electric field strong enough to drive positive ions over the junction barrier of the post-synaptic membrane and thus initiate excitation or produce depolarization. This theory is able to explain a great number of facts such as cleft size, synaptic delay, nonregeneration, subthreshold integration, facilitation with repetition, and the calcium and magnesium effects. It also shows why and how acetylcholine could act as excitatory or inhibitory transmitters under different circumstances. Our conclusion is that the nature of synaptic transmission is essentially electrical, be it mediated by electrical or chemical transmitters.

Wei, Ling Y.

1968-01-01

15

What is transmitted in "synaptic transmission"?  

NSDL National Science Digital Library

Even students that obtain a high grade in neurophysiology often carry away a serious misconception concerning the final result of the complex set of events that follows the arrival of an action potential at the presynaptic terminal. The misconception consists in considering that "at a synapse, information is passed on from one neuron to the next" is equivalent to (and often expressed explicitly as) "the action potential passes from one neuron to the next." More than half of four groups of students who were asked to comment on an excerpt from a recent physiology textbook that openly stated the misconception had no clear objection to the text presented. We propose that the first culprit in generating this misconception is the term "synaptic transmission," which promotes the notion of transferring something or passing something along (implicitly unchanged). To avoid establishing this misconception, the first simple suggestion is to use words like "synaptic integration" rather than "synaptic transmission" right from the start. More generally, it would be important to focus on the function of synaptic events rather than on rote listing of all the numerous steps that are known to occur, which are so complex as to saturate the mind of the student.

Erik Montagna (Institute of Chemistry); Adriana M. S. de Azevedo (Institute of Biomedical Sciences, University of São Paulo); Camilla Romano (Facoltà di Medicina e Chirurgia); Ronald Ranvaud (Institute of Biomedical Sciences, University of São Paulo)

2010-06-01

16

Synaptic properties of the mammillary and cortical afferents to the anterodorsal thalamic nucleus in the mouse.  

PubMed

Input to sensory thalamic nuclei can be classified as either driver or modulator, based on whether or not the information conveyed determines basic postsynaptic receptive field properties. Here we demonstrate that this distinction can also be applied to inputs received by nonsensory thalamic areas. Using flavoprotein autofluorescence imaging, we developed two slice preparations that contain the afferents to the anterodorsal thalamic nucleus (AD) from the lateral mammillary body and the cortical afferents arriving through the internal capsule, respectively. We examined the synaptic properties of these inputs and found that the mammillothalamic pathway exhibits paired-pulse depression, lack of a metabotropic glutamate component, and an all-or-none response pattern, which are all signatures of a driver pathway. On the other hand, the cortical input exhibits graded paired-pulse facilitation and the capacity to activate metabotropic glutamatergic responses, all features of a modulatory pathway. Our results extend the notion of driving and modulating inputs to the AD, indicating that it is a first-order relay nucleus and suggesting that these criteria may be general to the whole of thalamus. PMID:19535593

Petrof, Iraklis; Sherman, S Murray

2009-06-17

17

Effects of Divalent Ions and Drugs on Synaptic Transmission in Phasic Electroreceptors in a Mormyrid Fish  

PubMed Central

We recorded impulses in afferent nerve fibers innervating two kinds of phasic electroreceptors in a mormyrid fish. We used an isolated preparation of skin, receptors, and sensory nerves to estimate synaptic delays, and to change solution in contact with the receptor-nerve synapse. The minimum delays between stimuli and sensory nerve responses, which must be slightly larger than synaptic delays, are about 0.7 msec in medium receptors and about 0.25 msec in large receptors. This result supports previous suggestions that transmission is chemically mediated in medium receptors and electrically mediated in large receptors. Furthermore, Mg+2 depresses synaptic transmission in medium receptors, and has little effect on transmission in large receptors. A complex dependence of response on both Mg+2 and Ca+2 masks divalent ion dependence of transmission, but a large excess of Mg+2 cannot completely block transmission in medium electroreceptors. L-glutamate, and not cholinergic drugs, produces a sequence of excitation and depression of medium receptor response which indicates that a similar chemical is the transmitter in the afferent synapse.

Steinbach, A. B.; Bennett, M. V. L.

1971-01-01

18

Enhanced transmission at a spinal synapse triggered in vivo by an injury signal independent of altered synaptic activity.  

PubMed

Peripheral nerve crush initiates a robust increase in transmission strength at spinal synapses made by axotomized group IA primary sensory neurons. To study the injury signal that initiates synaptic enhancement in vivo, we designed experiments to manipulate the enlargement of EPSPs produced in spinal motoneurons (MNs) by IA afferents 3 d after nerve crush in anesthetized adult rats. If nerve crush initiates IA EPSP enlargement as proposed by reducing impulse-evoked transmission in crushed IA afferents, then restoring synaptic activity should eliminate enlargement. Daily electrical stimulation of the nerve proximal to the crush site did, in fact, eliminate enlargement but was, surprisingly, just as effective when the action potentials evoked in crushed afferents were prevented from propagating into the spinal cord. Consistent with its independence from altered synaptic activity, we found that IA EPSP enlargement was also eliminated by colchicine blockade of axon transport in the crushed nerve. Together with the observation that colchicine treatment of intact nerves had no short-term effect on IA EPSPs, we conclude that enhancement of IA-MN transmission is initiated by some yet to be identified positive injury signal generated independent of altered synaptic activity. The results establish a new set of criteria that constrain candidate signaling molecules in vivo to ones that develop quickly at the peripheral injury site, move centrally by axon transport, and initiate enhanced transmission at the central synapses of crushed primary sensory afferents through a mechanism that can be modulated by action potential activity restricted to the axons of crushed afferents. PMID:18032657

Bichler, Edyta K; Nakanishi, Stan T; Wang, Qing-Bo; Pinter, Martin J; Rich, Mark M; Cope, Timothy C

2007-11-21

19

Synaptic actions of peripheral nerve impulses upon Deiters neurones via the climbing fibre afferents.  

PubMed

1. The cerebellar integration of sensory inputs to Deiters neurones was studied in cats under Nembutal anaesthesia.2. Stimulation of peripheral nerves produced in the Deiters neurones a sequence of an initial excitatory post-synaptic potential (e.p.s.p.) and a later inhibitory post-synaptic potential (i.p.s.p.), or a relatively small e.p.s.p.3. The Deiters neurones were classified as forelimb (FL)- or hind limb (HL)-type cells according to the location of the most effective peripheral nerve. In the FL cells stimulation of the forelimb nerves produced the e.p.s.p.-i.p.s.p. sequence (dominant response), while stimulation of the hind limb nerves was ineffective or produced the small e.p.s.p. (non-dominant response). In contrast, in the HL cells the non-dominant response was evoked from the forelimb nerves, and the dominant response from the hind limb nerves.4. The stimulus intensity-response relation indicates that Group I and II muscle afferents and low and high threshold cutaneous afferents contribute to the dominant and non-dominant responses.5. Antidromic identification of these Deiters neurones revealed that 90% of the HL cells and 85% of the FL cells project to the lumbo-sacral and cervico-thoracic segments of the spinal cord, respectively, while 10% of the HL cells and 15% of the FL cells innervate the cervico-thoracic and lumbo-sacral segments, respectively.6. The mean latency of the e.p.s.p. evoked from the forelimb nerves was 14 msec in the FL cells and 13 msec in the HL cells, and the latency of the e.p.s.p. evoked from the hind limb nerves was 17 msec in the FL cells and 18 msec in the HL cells. The later i.p.s.p. regularly followed the onset of the e.p.s.p. with a delay of 3-5 msec.7. The dominant and non-dominant responses in both types of cells exhibited the following three characteristic features: (i) a strong depression after conditioning stimulation of the inferior olive, (ii) an increase of the inferior olivary excitability during the responses, and (iii) a striking frequency depression with stimulation at relatively low frequency (5-10/sec).8. Consequently it was concluded that all of the responses were produced through the climbing fibres originating from the inferior olive, the i.p.s.p.s due to inhibition from Purkyne cells activated by the climbing fibres and the e.p.s.p.s due to excitation from the collaterals of the climbing fibres. PMID:4563727

Allen, G I; Sabah, N H; Toyama, K

1972-10-01

20

Potentiation of electrical and chemical synaptic transmission mediated by endocannabinoids  

PubMed Central

SUMMARY Endocannabinoids are well established as inhibitors of chemical synaptic transmission via presynaptic activation of the cannabinoid type 1 receptor (CB1R). Contrasting this notion, we show that dendritic release of endocannabinoids mediates potentiation of synaptic transmission at mixed (electrical and chemical) synaptic contacts on the goldfish Mauthner cell. Remarkably, the observed enhancement was not restricted to the glutamatergic component of the synaptic response but also included a parallel increase in electrical transmission. This novel effect involved the activation of CB1 receptors and was indirectly mediated via the release of dopamine from nearby varicosities, which in turn led to potentiation of the synaptic response via a cAMP-dependent protein kinase-mediated postsynaptic mechanism. Thus, endocannabinoid release can potentiate synaptic transmission and its functional roles include the regulation of gap junction-mediated electrical synapses. Similar interactions between endocannabinoid and dopaminergic systems may be widespread and potentially relevant for the motor and rewarding effects of cannabis derivatives.

Cachope, Roger; Mackie, Ken; Triller, Antoine; O'Brien, John; Pereda, Alberto E.

2009-01-01

21

Potentiation of electrical and chemical synaptic transmission mediated by endocannabinoids.  

PubMed

Endocannabinoids are well established as inhibitors of chemical synaptic transmission via presynaptic activation of the cannabinoid type 1 receptor (CB1R). Contrasting this notion, we show that dendritic release of endocannabinoids mediates potentiation of synaptic transmission at mixed (electrical and chemical) synaptic contacts on the goldfish Mauthner cell. Remarkably, the observed enhancement was not restricted to the glutamatergic component of the synaptic response but also included a parallel increase in electrical transmission. This effect involved the activation of CB1 receptors and was indirectly mediated via the release of dopamine from nearby varicosities, which in turn led to potentiation of the synaptic response via a cAMP-dependent protein kinase-mediated postsynaptic mechanism. Thus, endocannabinoid release can potentiate synaptic transmission, and its functional roles include the regulation of gap junction-mediated electrical synapses. Similar interactions between endocannabinoid and dopaminergic systems may be widespread and potentially relevant for the motor and rewarding effects of cannabis derivatives. PMID:18093525

Cachope, Roger; Mackie, Ken; Triller, Antoine; O'Brien, John; Pereda, Alberto E

2007-12-20

22

Inhibitory synaptic transmission governs inspiratory motoneuron synchronization.  

PubMed

Neurons within the intact respiratory network produce bursts of action potentials that cause inspiration or expiration. Within inspiratory bursts, activity is synchronized on a shorter timescale to generate clusters of action potentials that occur in a set frequency range and are called synchronous oscillations. We investigated how GABA and glycine modulate synchronous oscillations and respiratory rhythm during postnatal development. We recorded inspiratory activity from hypoglossal nerves using the in vitro rhythmically active mouse medullary slice preparation from P0-P11 mice. Average oscillation frequency increased with postnatal development, from 17 +/- 12 Hz in P0-P6 mice (n = 15) to 38 +/- 7 Hz in P7-P11 mice (n = 37) (P < 0.0001). Bath application of GABAA and GlyR antagonists significantly reduced oscillation power in neonates (P0-P6) and juveniles (P7-P10) and increased peak integrated activity in both age groups. To test whether elevating slice excitability is sufficient to reduce oscillation power, Substance P was bath applied alone. Substance P, although increasing peak integrated activity, had no significant effect on oscillation power. Prolonging the time course of GABAergic synaptic currents with zolpidem decreased the median oscillation frequency in P9-P10 mouse slices. These data demonstrate that oscillation frequency increases with postnatal development and that both GABAergic and glycinergic transmission contribute to synchronization of activity. Further, the time course of synaptic GABAergic currents is a determinant of oscillation frequency. PMID:16510772

Sebe, Joy Y; van Brederode, Johannes F; Berger, Albert J

2006-07-01

23

Effects of excitatory amino acid antagonists on synaptic transmission in the ampullae of Lorenzini of the skate Raja clavata  

Microsoft Academic Search

1.The effects of excitatory amino acid antagonists on synaptic transmission in the ampullae of Lorenzini of the skate Raja clavata were studied.2.At concentrations of 10-3 to 10-6M, l-glutamic acid diethylester (GDEE) and l-glutamic acid dimethylester (GDME) decreased the resting afferent discharge frequency as well as the electrically evoked activities and depressed the responses to application of excitatory amino acids.3.d-a-Aminoadipic acid

G. N. Akoev; G. N. Andrianov; B. Bromm; T. Szabo

1991-01-01

24

Double-Dissociation of the Catecholaminergic Modulation of Synaptic Transmission in the Oval Bed Nucleus of the Stria Terminalis  

PubMed Central

The bed nucleus of the stria terminalis (BST) is a cluster of nuclei within the extended amygdala, a forebrain macrostructure with extensive projection to motor nuclei of the hindbrain. The subnuclei of the BST coordinate autonomic, neuroendocrine, and somatomotor functions and receive robust neuromodulatory monoaminergic afferents, including 5-HT-, noradrenaline (NA)-, and dopamine (DA)-containing terminals. In contrast to 5-HT and NA, little is known about how DA modulates neuronal activity or synaptic transmission in the BST. DA-containing afferents to the BST originate in the ventral tegmental area, the periaqueducal gray, and the retrorubral field. They form a fairly diffuse input to the dorsolateral BST with dense terminal fields in the oval (ovBST) and juxtacapsular (jxBST) nuclei. The efferent-afferent connectivity of the BST suggests that it may play a key role in motivated behaviors, consistent with recent evidence that the dorso-lateral BST is a target for drugs of abuse. This study describes the effects of DA on synaptic transmission in the ovBST. Whole cell voltage clamp recordings were performed on ovBST neurons in brain slices from adult rats in the presence or absence of exogenous DA and receptor-targeted agonists and antagonists. The results showed that DA selectively and exclusively reduced inhibitory synaptic transmission in the ovBST in a dose-dependent and D2-like dopamine receptor-dependent manner. DA also modulated excitatory synaptic transmission in a dose-dependent dependent manner. However, this effect was mediated by ?2-noradrenergic receptors. Thus these data reveal a double dissociation in catecholaminergic regulation of excitatory and inhibitory synaptic transmission in the ovBST and may shed light on the mechanisms involved in neuropathological behaviors such as stress-induced relapse to consumption of drugs of abuse.

Krawczyk, Michal; Georges, Francois; Sharma, Robyn; Mason, Xenos; Berthet, Amandine; Bezard, Erwan; Dumont, Eric C.

2014-01-01

25

Independent transmission of convergent visceral primary afferents in the solitary tract nucleus  

PubMed Central

Cranial primary afferents from the viscera enter the brain at the solitary tract nucleus (NTS), where their information is integrated for homeostatic reflexes. The organization of sensory inputs is poorly understood, despite its critical impact on overall reflex performance characteristics. Single afferents from the solitary tract (ST) branch within NTS and make multiple contacts onto individual neurons. Many neurons receive more than one ST input. To assess the potential interaction between converging afferents and proximal branching near to second-order neurons, we probed near the recorded soma in horizontal slices from rats with focal electrodes and minimal shocks. Remote ST shocks evoked monosynaptic excitatory postsynaptic currents (EPSCs), and nearby focal shocks also activated monosynaptic EPSCs. We tested the timing and order of stimulation to determine whether focal shocks influenced ST responses and vice versa in single neurons. Focal-evoked EPSC response profiles closely resembled ST-EPSC characteristics. Mean synaptic jitters, failure rates, depression, and phenotypic segregation by capsaicin responsiveness were indistinguishable between focal and ST-evoked EPSCs. ST-EPSCs failed to affect focal-EPSCs within neurons, indicating that release sites and synaptic terminals were functionally independent and isolated from cross talk or neurotransmitter overflow. In only one instance, focal shocks intercepted and depleted the ST axon generating evoked EPSCs. Despite large numbers of functional contacts, multiple afferents do not appear to interact, and ST axon branches may be limited to close to the soma. Thus single or multiple primary afferents and their presynaptic active release sites act independently when they contact single second-order NTS neurons.

Andresen, Michael C.

2013-01-01

26

Neuropharmacological analysis of synaptic transmission in the Lorenzinian ampulla of the skate Raja clavata  

Microsoft Academic Search

Dissected ampullae of Lorenzini of the skate (Raja clavata) were studied with the aim of determining the synaptic transmitter between electroreceptor cell and afferent fibre. Resting activity and stimulus-evoked activity in response to electrical pulses were recorded in single afferent units at constant perfusion with normal and test solutions containing different putative neurotransmitters. Presynaptic transmitter release was blocked by Mg2+

G. Akoev; G. N. Andrianov; T. Szabo; B. Bromm

1991-01-01

27

Synaptic transmission at retinal ribbon synapses  

PubMed Central

The molecular organization of ribbon synapses in photoreceptors and ON bipolar cells is reviewed in relation to the process of neurotransmitter release. The interactions between ribbon synapse-associated proteins, synaptic vesicle fusion machinery and the voltage-gated calcium channels that gate transmitter release at ribbon synapses are discussed in relation to the process of synaptic vesicle exocytosis. We describe structural and mechanistic specializations that permit the ON bipolar cell to release transmitter at a much higher rate than the photoreceptor does, under in vivo conditions. We also consider the modulation of exocytosis at photoreceptor synapses, with an emphasis on the regulation of calcium channels.

Heidelberger, Ruth; Thoreson, Wallace B.; Witkovsky, Paul

2006-01-01

28

Kinetic model of excitatory synaptic transmission to cerebellar Purkinje cells.  

PubMed

We present a minimal kinetic model for excitatory synaptic transmission to cerebellar Purkinje cells. The main components are a kinetic model for a single glutamate receptor, which is calibrated with the help of patch clamp data, and a mean field approximation for the dynamics of a population of channels, which generate an EPSC. The resulting minimal model of the parallel fiber-Purkinje cell synapse is used to estimate the dynamics of glutamate in the synaptic cleft and to clarify the role of receptor desensitization in synaptic transmission. We also apply the model to different aspects of synaptic modulation, like long-term depression and potentiation by pharmacological application of ampakines. In the framework of the minimal model these effects can be understood as the result of modified receptor kinetics. PMID:9379674

Marienhagen, J; Keller, B U; Zippelius, A

1997-09-21

29

Odor-Specific Habituation Arises from Interaction of Afferent Synaptic Adaptation and Intrinsic Synaptic Potentiation in Olfactory Cortex  

ERIC Educational Resources Information Center

Segmentation of target odorants from background odorants is a fundamental computational requirement for the olfactory system and is thought to be behaviorally mediated by olfactory habituation memory. Data from our laboratory have shown that odor-specific adaptation in piriform neurons, mediated at least partially by synaptic adaptation between…

Linster, Christiane; Menon, Alka V.; Singh, Christopher Y.; Wilson, Donald A.

2009-01-01

30

Rapid Suppression of Inhibitory Synaptic Transmission by Retinoic Acid  

PubMed Central

In brain, properly balanced synaptic excitation and inhibition is critically important for network stability and efficient information processing. Here, we show that retinoic acid (RA), a synaptic signaling molecule whose synthesis is activated by reduced neural activity, induces rapid internalization of synaptic GABAA receptors in mouse hippocampal neurons, leading to significant reduction of inhibitory synaptic transmission. Similar to its action at excitatory synapses, action of RA at inhibitory synapses requires protein translation and is mediated by a nontranscriptional function of the RA-receptor RAR?. Different from RA action at excitatory synapses, however, RA at inhibitory synapses causes a loss instead of the gain of a synaptic protein (i.e., GABAARs). Moreover, the removal of GABAARs from the synapses and the reduction of synaptic inhibition do not require the execution of RA's action at excitatory synapses (i.e., downscaling of synaptic inhibition is intact when upscaling of synaptic excitation is blocked). Thus, the action of RA at inhibitory and excitatory synapses diverges significantly after the step of RAR?-mediated protein synthesis, and the regulations of GABAAR and AMPAR trafficking are independent processes. When both excitatory and inhibitory synapses are examined together in the same neuron, the synaptic excitation/inhibition ratio is significantly enhanced by RA. Importantly, RA-mediated downscaling of synaptic inhibition is completely absent in Fmr1 knock-out neurons. Thus, RA acts as a central organizer for coordinated homeostatic plasticity in both excitatory and inhibitory synapses, and impairment of this overall process alters the excitatory/inhibitory balance of a circuit and likely represents a major feature of fragile X-syndrome.

Sarti, Federica; Zhang, Zhenjie; Schroeder, Jessica

2013-01-01

31

Estrogen Facilitates Spinal Cord Synaptic Transmission via Membrane-bound Estrogen Receptors  

PubMed Central

Recent evidence suggests that estrogen is synthesized in the spinal dorsal horn and plays a role in nociceptive processes. However, the cellular and molecular mechanisms underlying these effects remain unclear. Using electrophysiological, biochemical, and morphological techniques, we here demonstrate that 17?-estradiol (E2), a major form of estrogen, can directly modulate spinal cord synaptic transmission by 1) enhancing NMDA receptor-mediated synaptic transmission in dorsal horn neurons, 2) increasing glutamate release from primary afferent terminals, 3) increasing dendritic spine density in cultured spinal cord dorsal horn neurons, and 4) potentiating spinal cord long term potentiation (LTP) evoked by high frequency stimulation (HFS) of Lissauer's tract. Notably, E2-BSA, a ligand that acts only on membrane estrogen receptors, can mimic E2-induced facilitation of HFS-LTP, suggesting a nongenomic action of this neurosteroid. Consistently, cell surface biotinylation demonstrated that three types of ERs (ER?, ER?, and GPER1) are localized on the plasma membrane of dorsal horn neurons. Furthermore, the ER? and ER? antagonist ICI 182,780 completely abrogates the E2-induced facilitation of LTP. ER? (but not ER?) activation can recapitulate E2-induced persistent increases in synaptic transmission (NMDA-dependent) and dendritic spine density, indicating a critical role of ER? in spinal synaptic plasticity. E2 also increases the phosphorylation of ERK, PKA, and NR2B, and spinal HFS-LTP is prevented by blockade of PKA, ERK, or NR2B activation. Finally, HFS increases E2 release in spinal cord slices, which can be prevented by aromatase inhibitor androstatrienedione, suggesting activity-dependent local synthesis and release of endogenous E2.

Zhang, Yan; Xiao, Xiao; Zhang, Xiao-Meng; Zhao, Zhi-Qi; Zhang, Yu-Qiu

2012-01-01

32

Measuring action potential-evoked transmission at individual synaptic contacts  

PubMed Central

In the neuronal culture experimental system, the total synaptic connection between two neurons can consist of large numbers of synaptic sites, each behaving probabilistically. Studies of synaptic function with paired recordings typically consider the summed response across all of these sites and from this infer the average response. Understanding of synaptic transmission and plasticity could be improved by examination of activity at as few synaptic sites as possible. To this end, we develop a system for recording responses from individual contacts. It relies on a precisely regulated pneumatic/hydrostatic pressure system to create a microenvironment within which individual synapses are active, and an acoustic signature method to monitor the stability of this microenvironment noninvasively. With this method we are able to record action potential-evoked postsynaptic currents consistent with individual quanta. The approach does not distort synaptic current waveforms and permits stable recording for several hours. The method is applied to address mechanisms of short-term plasticity, the variability of latency at individual synaptic sites and, in a preliminary experiment, the independence of nearby synapses on the same axon.

Nauen, David W; Bi, Guo-Qiang

2014-01-01

33

Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus.  

PubMed

Several neurodegenerative disorders are associated with impaired cholesterol homeostasis in the nervous system where cholesterol is known to play a role in modulating synaptic activity and stabilizing membrane microdomains. In the present report, we investigated the effects of methyl-beta-cyclodextrin-induced cholesterol depletion on synaptic transmission and on the expression of 1) paired-pulse facilitation (PPF); 2) paired-pulse inhibition (PPI) and 3) long-term potentiation (LTP) in the CA1 hippocampal region. Results demonstrated that cyclodextrin strongly reduced synaptic transmission and blocked the expression of LTP, but did not affect PPF and PPI. The role of glutamatergic and GABAergic receptors in these cholesterol depletion-mediated effects was evaluated pharmacologically. Data indicate that, in cholesterol depleted neurons, modulation of synaptic transmission and synaptic plasticity phenomena are sustained by AMPA-, kainate-and NMDA-receptors but not by GABA-receptors. The involvement of AMPA-and kainate-receptors was confirmed by fluorimetric analysis of intracellular calcium concentrations in hippocampal cell cultures. These data suggest that modulation of receptor activity by manipulation of membrane lipids is a possible therapeutic strategy in neurodegenerative disease. PMID:18559278

Frank, C; Rufini, S; Tancredi, V; Forcina, R; Grossi, D; D'Arcangelo, G

2008-08-01

34

Synaptic transmission in neurological disorders dissected by a quantitative approach  

PubMed Central

Synaptic transmission depends on several molecular and geometric components, such as the location of vesicular release, the number of released neurotransmitter molecules, the number and type of receptors, as well as the synapse organization. Our goal here is to illustrate how synaptic modeling allows extracting quantitative information in the context of neurological diseases and associated therapies. Combining electrophysiology with simulation tools, we first evaluate the reduction in synaptically released glutamate molecules induced by a ketogenic diet. In a second part, because the scaffolding molecule Shank3 is disrupted at the postsynaptic density in Autism Spectral Disorders, we present a numerical simulation of the synaptic response where this disruption leads to an alteration of the excitatory AMPA receptor trafficking. The take home message is that combining recent experimental findings with modeling approaches allows obtaining precise quantitative properties of what was still unapproachable a decade ago.

Freche, Dominik; Lee, Chun-Yao; Rouach, Nathalie; Holcman, David

2012-01-01

35

Fine structure and synaptic architecture of HRP-labelled primary afferent terminations in lamina IIi of the rat dorsal horn.  

PubMed

The fine structure and synaptic architecture of the afferent terminations in dorsal horn lamina II are studied using a combined light and electron microscopic procedure after anterograde labelling with horseradish peroxidase. Vibratome parasagittal sections, stained with heavy metal intensified diaminobenzidine after tracer application to the dorsal roots, were flat-embedded in Epon. The five types of labelled terminal arbors occurring in lamina IIi (Cruz et al., '87: J. Comp. Neurol. 261:221-236) were drawn and relocated in 5-microns sections cut serially from the thick sections. Ultrathin sections were then cut from the 5-microns sections so that the terminal fibers and swellings observed in the light microscope could be traced in the electron microscope. The flame-shaped arbors arose from fine myelinated stem fibers. Terminal strands generated large oval central terminals of type II synaptic glomeruli (CII), which established frequent axoaxonal contacts. Similar terminals have been labelled in the cat after tracer injections into hair-follicle fibers (Réthelyi et al., '82: J. Comp. Neurol. 207:381-393). The other four plexuses arose from unmyelinated stem fibers. The swarms of ultrafine boutons consisted of extremely thin terminal fibers generating very small, round, or polygonal glomerular terminals containing tightly packed agranular synaptic vesicles of variable size and one mitochondrion at best. The terminal strands of the bouquet plexus bore long and scalloped central varicosities of type I synaptic glomeruli (CI) with pleomorphic agranular vesicles and a relative abundance of dendroaxonal contacts. These features, together with the location in dorsal lamina IIi, suggest their belonging to the fluoride resistant acid phosphatase (FRAP)-reactive population. The boutons of the undulating fibers and those of the lateral plexus were, like those of the bouquets, scalloped and elongated rostrocaudally (CI), but contained a few large granular vesicles. The occurrence of the swarm, undulating, and lateral plexuses in ventral lamina IIi, which seems to lack FRAP or peptidergic terminals, suggests an origin from other, still unidentified neurochemical populations of fine primary afferents. PMID:2033122

Cruz, F; Lima, D; Zieglgänsberger, W; Coimbra, A

1991-03-01

36

Cholinergic synaptic transmission in adult Drosophila Kenyon cells in situ.  

PubMed

Behavioral and genetic studies in Drosophila have contributed to our understanding of molecular mechanisms that underlie the complex processes of learning and memory. Use of this model organism for exploration of the cellular mechanisms of memory formation requires the ability to monitor synaptic activity in the underlying neural networks, a challenging task in the tiny adult fly. Here, we describe an isolated whole-brain preparation in which it is possible to obtain in situ whole-cell recordings from adult Kenyon cells, key members of a neural circuit essential for olfactory associative learning in Drosophila. The presence of sodium action potential (AP)-dependent synaptic potentials and synaptic currents in >50% of the Kenyon cells shows that these neurons are members of a spontaneously active neural circuit in the isolated brain. The majority of sodium AP-dependent synaptic transmission is blocked by curare and by alpha-bungarotoxin (alpha-BTX). This demonstrates that nicotinic acetylcholine receptors (nAChRs) are responsible for most of the spontaneous excitatory drive in this circuit in the absence of normal sensory input. Furthermore, analysis of sodium AP-independent synaptic currents provides the first direct demonstration that alpha-BTX-sensitive nAChRs mediate fast excitatory synaptic transmission in Kenyon cells in the adult Drosophila brain. This new preparation, in which whole-cell recordings and pharmacology can be combined with genetic approaches, will be critical in understanding the contribution of nAChR-mediated fast synaptic transmission to cellular plasticity in the neural circuits underlying olfactory associative learning. PMID:16399696

Gu, Huaiyu; O'Dowd, Diane K

2006-01-01

37

Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants  

PubMed Central

Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo) mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR) ? subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho) mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch-once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch-once’ mutants, including beo and sho, and report the identification of a new ?2 subunit that revises the phylogeny of zebrafish GlyRs.

Hirata, Hiromi; Carta, Eloisa; Yamanaka, Iori; Harvey, Robert J.; Kuwada, John Y.

2009-01-01

38

Progesterone Regulation of Synaptic Transmission and Plasticity in Rodent Hippocampus  

ERIC Educational Resources Information Center

Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the…

Foy, Michael R.; Akopian, Garnik; Thompson, Richard F.

2008-01-01

39

Cholinergic modulation of primary afferent glutamatergic transmission in rat medullary dorsal horn neurons.  

PubMed

Although muscarinic acetylcholine (mACh) receptors are expressed in trigeminal ganglia, it is still unknown whether mACh receptors modulate glutamatergic transmission from primary afferents onto medullary dorsal horn neurons. In this study, we have addressed the cholinergic modulation of primary afferent glutamatergic transmission using a conventional whole cell patch clamp technique. Glutamatergic excitatory postsynaptic currents (EPSCs) were evoked from primary afferents by electrical stimulation of trigeminal tract and monosynaptic EPSCs were recorded from medullary dorsal horn neurons of rat horizontal brain stem slices. Muscarine and ACh reversibly and concentration-dependently decreased the amplitude of glutamatergic EPSCs and increased the paired-pulse ratio. In addition, muscarine reduced the frequency of miniature EPSCs without affecting the current amplitude, suggesting that muscarine acts presynaptically to decrease the probability of glutamate release onto medullary dorsal horn neurons. The muscarine-induced decrease of glutamatergic EPSCs was significantly occluded by methoctramine or AF-DX116, M2 receptor antagonists, but not pirenzepine, J104129 and MT-3, selective M1, M3 and M4 receptor antagonists. The muscarine-induced decrease of glutamatergic EPSCs was highly dependent on the extracellular Ca2+ concentration. Physostigmine and clinically available acetylcholinesterase inhibitors, such as rivastigmine and donepezil, significantly shifted the concentration-inhibition relationship of ACh for glutamatergic EPSCs. These results suggest that muscarine acts on presynaptic M2 receptors to inhibit glutamatergic transmission by reducing the Ca2+ influx into primary afferent terminals, and that M2 receptor agonists and acetylcholinesterase inhibitors could be, at least, potential targets to reduce nociceptive transmission from orofacial tissues. PMID:23954675

Jeong, Seok-Gwon; Choi, In-Sun; Cho, Jin-Hwa; Jang, Il-Sung

2013-12-01

40

Effect of Synaptic Transmission on Viral Fitness in HIV Infection  

PubMed Central

HIV can spread through its target cell population either via cell-free transmission, or by cell-to-cell transmission, presumably through virological synapses. Synaptic transmission entails the transfer of tens to hundreds of viruses per synapse, a fraction of which successfully integrate into the target cell genome. It is currently not understood how synaptic transmission affects viral fitness. Using a mathematical model, we investigate how different synaptic transmission strategies, defined by the number of viruses passed per synapse, influence the basic reproductive ratio of the virus, R0, and virus load. In the most basic scenario, the model suggests that R0 is maximized if a single virus particle is transferred per synapse. R0 decreases and the infection eventually cannot be maintained for larger numbers of transferred viruses, because multiple infection of the same cell wastes viruses that could otherwise enter uninfected cells. To explain the relatively large number of HIV copies transferred per synapse, we consider additional biological assumptions under which an intermediate number of viruses transferred per synapse could maximize R0. These include an increased burst size in multiply infected cells, the saturation of anti-viral factors upon infection of cells, and rate limiting steps during the process of synapse formation.

Komarova, Natalia L.; Levy, David N.; Wodarz, Dominik

2012-01-01

41

Brain-derived neurotrophic factor and nerve growth factor potentiate excitatory synaptic transmission in the rat visual cortex.  

PubMed Central

1. The effect of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) on excitatory synaptic transmission in the developing visual cortex was studied by whole-cell patch-clamp recordings from rat brain slices. 2. Both neurotrophins induced a rapid increase in the amplitude of impulse-evoked excitatory postsynaptic currents (EPSCs). BDNF also increased the frequency of spontaneous EPSCs. 3. Analysis of the currents revealed that alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated components contributing to the EPSC peak amplitude were equally potentiated by the neurotrophins. 4. When synaptic transmission was studied by minimal stimulation of intracortical afferents, neurotrophins induced a decrease in the occurrence of release failures. 5. A number of neurones were insensitive to the effects of the neurotrophins, possibly related to the considerable heterogeneity of neuronal types and to the uneven distribution of neurotrophin receptors in the visual cortex. 6. The probability of neurotransmitter release represents a rapidly modifiable synaptic feature by which neurotrophins can potentiate the efficacy of excitatory synaptic transmission in the visual cortex.

Carmignoto, G; Pizzorusso, T; Tia, S; Vicini, S

1997-01-01

42

proBDNF Negatively Regulates Neuronal Remodeling, Synaptic Transmission, and Synaptic Plasticity in Hippocampus.  

PubMed

Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75(NTR). In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75(NTR). Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission, and plasticity, effects that are distinct from those of mature BDNF. PMID:24746813

Yang, Jianmin; Harte-Hargrove, Lauren C; Siao, Chia-Jen; Marinic, Tina; Clarke, Roshelle; Ma, Qian; Jing, Deqiang; Lafrancois, John J; Bath, Kevin G; Mark, Willie; Ballon, Douglas; Lee, Francis S; Scharfman, Helen E; Hempstead, Barbara L

2014-05-01

43

MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity  

SciTech Connect

Parkinson's disease (PD)-like symptoms including learning deficits are inducible by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Therefore, it is possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)- and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within 7 days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes pair-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs) only at the 30 ms inter-pulse interval. In addition, the induction of long-term potentiation (LTP) is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about 23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of D1/D5 and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed 7 days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity. - Highlights: > I.p. MPTP-injection mediates death of dopaminergic neurons. > I.p. MPTP-injection depletes DA and DOPAC in striatum and hippocampus. > I.p. MPTP-injection does not alter basal synaptic transmission. > Reduction of LTP and enhancement of LTD after i.p. MPTP-injection. > Attenuation of NMDA-receptors mediated fEPSPs after i.p. MPTP-injection.

Zhu Guoqi; Chen Ying; Huang Yuying [Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); Li Qinglin [Key laboratory of XinAn Medicine, Anhui University of Traditional Chinese Medicine, Hefei 230038 (China); Behnisch, Thomas, E-mail: behnish@fudan.edu.cn [Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China); State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032 (China)

2011-08-01

44

Homeostasis of Synaptic Transmission in Drosophila with Genetically Altered Nerve Terminal Morphology  

Microsoft Academic Search

We present a new test of the hypothesis that synaptic strength is directly related to nerve terminal morphology through analy- sis of synaptic transmission at Drosophila neuromuscular junc- tions with a genetically reduced number of nerve terminal var- icosities. Synaptic transmission would decrease in target cells with fewer varicosities if there is a relationship between the number of varicosities and

Bryan A. Stewart; Christoph M. Schuster; Corey S. Goodman; Harold L. Atwood

1996-01-01

45

How do astrocytes shape synaptic transmission? Insights from electrophysiology  

PubMed Central

A major breakthrough in neuroscience has been the realization in the last decades that the dogmatic view of astroglial cells as being merely fostering and buffering elements of the nervous system is simplistic. A wealth of investigations now shows that astrocytes actually participate in the control of synaptic transmission in an active manner. This was first hinted by the intimate contacts glial processes make with neurons, particularly at the synaptic level, and evidenced using electrophysiological and calcium imaging techniques. Calcium imaging has provided critical evidence demonstrating that astrocytic regulation of synaptic efficacy is not a passive phenomenon. However, given that cellular activation is not only represented by calcium signaling, it is also crucial to assess concomitant mechanisms. We and others have used electrophysiological techniques to simultaneously record neuronal and astrocytic activity, thus enabling the study of multiple ionic currents and in depth investigation of neuro-glial dialogues. In the current review, we focus on the input such approach has provided in the understanding of astrocyte-neuron interactions underlying control of synaptic efficacy.

Dallerac, Glenn; Chever, Oana; Rouach, Nathalie

2013-01-01

46

From Synaptic Transmission to Cognition: An Intermediary Role for Dendritic Spines  

ERIC Educational Resources Information Center

Dendritic spines are cytoplasmic protrusions that develop directly or indirectly from the filopodia of neurons. Dendritic spines mediate excitatory neurotransmission and they can isolate the electrical activity generated by synaptic impulses, enabling them to translate excitatory afferent information via several types of plastic changes, including…

Gonzalez-Burgos, Ignacio

2012-01-01

47

Quercetin Targets Cysteine String Protein (CSP?) and Impairs Synaptic Transmission  

PubMed Central

Background Cysteine string protein (CSP?) is a synaptic vesicle protein that displays unique anti-neurodegenerative properties. CSP? is a member of the conserved J protein family, also called the Hsp40 (heat shock protein of 40 kDa) protein family, whose importance in protein folding has been recognized for many years. Deletion of the CSP? in mice results in knockout mice that are normal for the first 2–3 weeks of life followed by an unexplained presynaptic neurodegeneration and premature death. How CSP? prevents neurodegeneration is currently not known. As a neuroprotective synaptic vesicle protein, CSP? represents a promising therapeutic target for the prevention of neurodegenerative disorders. Methodology/Principal Findings Here, we demonstrate that the flavonoid quercetin promotes formation of stable CSP?-CSP? dimers and that quercetin-induced dimerization is dependent on the unique cysteine string region. Furthermore, in primary cultures of Lymnaea neurons, quercetin induction of CSP? dimers correlates with an inhibition of synapse formation and synaptic transmission suggesting that quercetin interfers with CSP? function. Quercetin's action on CSP? is concentration dependent and does not promote dimerization of other synaptic proteins or other J protein family members and reduces the assembly of CSP?:Hsc70 units (70kDa heat shock cognate protein). Conclusions/Significance Quercetin is a plant derived flavonoid and popular nutritional supplement proposed to prevent memory loss and altitude sickness among other ailments, although its precise mechanism(s) of action has been unclear. In view of the therapeutic promise of upregulation of CSP? and the undesired consequences of CSP? dysfunction, our data establish an essential proof of principle that pharmaceutical agents can selectively target the neuroprotective J protein CSP?.

Xu, Fenglian; Proft, Juliane; Gibbs, Sarah; Winkfein, Bob; Johnson, Jadah N.; Syed, Naweed; Braun, Janice E. A.

2010-01-01

48

Statistical analysis of synaptic transmission: model discrimination and confidence limits.  

PubMed Central

Procedures for discriminating between competing statistical models of synaptic transmission, and for providing confidence limits on the parameters of these models, have been developed. These procedures were tested against simulated data and were used to analyze the fluctuations in synaptic currents evoked in hippocampal neurones. All models were fitted to data using the Expectation-Maximization algorithm and a maximum likelihood criterion. Competing models were evaluated using the log-likelihood ratio (Wilks statistic). When the competing models were not nested, Monte Carlo sampling of the model used as the null hypothesis (H0) provided density functions against which H0 and the alternate model (H1) were tested. The statistic for the log-likelihood ratio was determined from the fit of H0 and H1 to these probability densities. This statistic was used to determine the significance level at which H0 could be rejected for the original data. When the competing models were nested, log-likelihood ratios and the chi 2 statistic were used to determine the confidence level for rejection. Once the model that provided the best statistical fit to the data was identified, many estimates for the model parameters were calculated by resampling the original data. Bootstrap techniques were then used to obtain the confidence limits of these parameters.

Stricker, C; Redman, S; Daley, D

1994-01-01

49

Demonstrating the Temperature Sensitivity of Synaptic Transmission in a Drosophila Mutant  

NSDL National Science Digital Library

This article describes an exercise that illustrates the temperature sensitivity of synaptic transmission. The temperature dependence of synaptic transmission is demonstrated by cooling the larval Drosophila melanogaster preparation and recording excitatory junction potentials. Vesicle recycling is explored by utilizing a mutation of the shibire gene.

Jacob L. Krans, Patricia K. Rivlin, and Ronald R. Hoy (Cornell University;)

2005-09-27

50

? 9Tetrahydrocannabinol antagonizes endocannabinoid modulation of synaptic transmission between hippocampal neurons in culture  

Microsoft Academic Search

Cannabinoids inhibit excitatory synaptic transmission between hippocampal neurons in culture. ?9-tetrahydrocannabinol (THC), the principal psychoactive component in marijuana, acts as a partial agonist at these synapses. Thus, THC inhibited but did not block synaptic transmission when applied alone and, when applied in combination with WIN552212-2, it partially reversed the effects of this full agonist. Here, we address the question of

Brooke G. Kelley; Stanley A. Thayer

2004-01-01

51

Regulation of Synaptic Transmission by Ambient Extracellular Glutamate  

PubMed Central

Many neuroscientists assume that ambient extracellular glutamate concentrations in the nervous system are biologically negligible under nonpathological conditions. This assumption is false. Hundreds of studies over several decades suggest that ambient extracellular glutamate levels in the intact mammalian brain are ~0.5 to ~5 ?M. This has important implications. Glutamate receptors are desensitized by glutamate concentrations significantly lower than needed for receptor activation; 0.5 to 5 ?M of glutamate is high enough to cause constitutive desensitization of most glutamate receptors. Therefore, most glutamate receptors in vivo may be constitutively desensitized, and ambient extracellular glutamate and receptor desensitization may be potent but generally unrecognized regulators of synaptic transmission. Unfortunately, the mechanisms regulating ambient extracellular glutamate and glutamate receptor desensitization remain poorly understood and understudied.

FEATHERSTONE, DAVID E.; SHIPPY, SCOTT A.

2008-01-01

52

Fidelity of complex spike mediated synaptic transmission between inhibitory interneurons  

PubMed Central

Complex spikes are high-frequency bursts of Na+ spikes, often riding on a slower Ca2+-dependent waveform. Although complex spikes may propagate into axons, given their unusual shape it is not clear how reliably these bursts reach nerve terminals, whether their spikes are efficiently transmitted as a cluster of postsynaptic responses, or what function is served by such a concentrated postsynaptic signal. We examined these questions by recording from synaptically coupled pairs of cartwheel cells, neurons which fire complex spikes and form an inhibitory network in the dorsal cochlear nucleus. Complex spikes in the presynaptic soma were reliably propagated to nerve terminals and elicited powerful, temporally precise postsynaptic responses. Single presynaptic neurons could prevent their postsynaptic partner from firing complex, but not simple, spikes, dramatically reducing dendritic Ca2+ signals in the postsynaptic neuron. We suggest that rapid transmission of complex spikes may control the susceptibility of neighboring neurons to Ca2+-dependent plasticity.

Roberts, Michael T.; Bender, Kevin J.; Trussell, Laurence O.

2008-01-01

53

Contribution of NR2B Subunits to Synaptic Transmission in Amygdaloid Interneurons  

Microsoft Academic Search

Synaptic responses of interneurons in the rat lateral amygdala (LA) to electrical microstimulation of putative cortical and thalamic afferents were studied in slice preparations in situ. The EPSPs at both thalamic and cortical inputs were composed of two major compo- nents that were sensitive to 6,7-dinitroxaline-2,3-dione and DL-2-amino-5-phosphonovaleric acid (APV), indicating mediation through AMPA and NMDA receptors. NMDA receptor activation

Csaba Szinyei; Oliver Stork; Hans-Christian Pape

2003-01-01

54

The cell-autonomous role of excitatory synaptic transmission in the regulation of neuronal structure and function  

PubMed Central

The cell-autonomous role of synaptic transmission in the regulation of neuronal structural and electrical properties is unclear. We have now employed a genetic approach to eliminate glutamatergic synaptic transmission onto individual CA1 pyramidal neurons in a mosaic fashion in vivo. Surprisingly, while electrical properties are profoundly affected in these neurons, as well as inhibitory synaptic transmission, we found little perturbation of neuronal morphology, demonstrating a functional segregation of excitatory synaptic transmission from neuronal morphological development.

Lu, Wei; Bushong, Eric A.; Shih, Tiffany P.; Ellisman, Mark H.; Nicoll, Roger A.

2013-01-01

55

Effects of kainic acid on synaptic transmission in skate electroreceptors (ampullae of Lorenzini)  

Microsoft Academic Search

The effects of kainic acid on synaptic transmission in electroreceptors were investigated in the skate using techniques of uninterrupted superfusion of the synaptic area with a solution containing this substance and then recording the spike activity of single nerve fibers of the ampullae of Lorenzini. Kainic acid at threshold concentrations of the order of 10-9 M effectively changed spontaneous and

G. N. Akoev; Yu. N. Andrianov; N. O. Sherman

1986-01-01

56

Postnatal aniracetam treatment improves prenatal ethanol induced attenuation of AMPA receptor-mediated synaptic transmission  

Microsoft Academic Search

Aniracetam is a nootropic compound and an allosteric modulator of AMPA receptors (AMPARs) which mediate synaptic mechanisms of learning and memory. Here we analyzed impairments in AMPAR-mediated synaptic transmission caused by moderate prenatal ethanol exposure and investigated the effects of postnatal aniracetam treatment on these abnormalities. Pregnant Sprague–Dawley rats were gavaged with ethanol or isocaloric sucrose throughout pregnancy, and subsequently

Nayana Wijayawardhane; Brian C. Shonesy; Julia Vaglenova; Thirumalini Vaithianathan; Mark Carpenter; Charles R. Breese; Alexander Dityatev; Vishnu Suppiramaniam

2007-01-01

57

Extracellular ATP Hydrolysis Inhibits Synaptic Transmission by Increasing pH Buffering in the Synaptic Cleft  

PubMed Central

Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (??200 ms), highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca2+ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form of synaptic modulation may be a widespread phenomenon.

Vroman, Rozan; Klaassen, Lauw J.; Howlett, Marcus H.C.; Cenedese, Valentina; Klooster, Jan; Sjoerdsma, Trijntje; Kamermans, Maarten

2014-01-01

58

Endocannabinoids blunt the augmentation of synaptic transmission by serotonin 2A receptors in the nucleus tractus solitarii (nTS).  

PubMed

Serotonin (5-Hydroxytryptamine, 5-HT) and the 5-HT2 receptor modulate cardiovascular and autonomic function in part through actions in the nTS, the primary termination and integration point for cardiorespiratory afferents in the brainstem. In other brain regions, 5-HT2 receptors (5-HT2R) modify synaptic transmission directly, as well as through 5-HT2AR-induced endocannabinoid release. This study examined the role of 5-HT2AR as well as their interaction with endocannabinoids on neurotransmission in the nucleus tractus solitarii (nTS). Excitatory postsynaptic currents (EPSCs) in monosynaptic nTS neurons were recorded in the horizontal brainstem slice during activation and blockade of 5-HT2ARs. 5-HT2AR activation augmented solitary tract (TS) evoked EPSC amplitude whereas 5-HT2AR blockade depressed TS-EPSC amplitude at low and high TS stimulation rates. The 5-HT2AR-induced increase in neurotransmission was reduced by endocannabinoid receptor block and increased endogenous endocannabinoids in the synaptic cleft during high frequency, but not low, TS stimulation. Endocannabinoids did not tonically modify EPSCs. These data suggest 5-HT acting through the 5-HT2AR is an excitatory neuromodulator in the nTS and its effects are modulated by the endocannabinoid system. PMID:24041777

Austgen, James R; Kline, David D

2013-11-01

59

Synapsin-dependent reserve pool of synaptic vesicles supports replenishment of the readily releasable pool under intense synaptic transmission.  

PubMed

Synapsins are abundant synaptic vesicle (SV)-associated proteins thought to mediate synaptic vesicle mobility and clustering at most synapses. We used synapsin triple knock-out (TKO) mice to examine the morphological and functional consequences of deleting all synapsin isoforms at the calyx of Held, a giant glutamatergic synapse located in the auditory brain stem. Quantitative three-dimensional (3D) immunohistochemistry of entire calyces showed lower amounts of the synaptic vesicle protein vGluT1 while the level of the active zone marker bassoon was unchanged in TKO terminals. Examination of brain lysates by ELISA revealed a strong reduction in abundance of several synaptic vesicle proteins, while proteins of the active zone cytomatrix or postsynaptic density were unaffected. Serial section scanning electron microscopy of large 3D-reconstructed segments confirmed a decrease in the number of SVs to approximately 50% in TKO calyces. Short-term depression tested at stimulus frequencies ranging from 10 to 300 Hz was accelerated only at frequencies above 100 Hz and the time course of recovery from depression was slowed in calyces lacking synapsins. These results reveal that in wild-type synapses, the synapsin-dependent reserve pool contributes to the replenishment of the readily releasable pool (RRP), although accounting only for a small fraction of the SVs that enter the RRP. In conclusion, our results suggest that synapsins may be required for normal synaptic vesicle biogenesis, trafficking and immobilization of synaptic vesicles, yet they are not essential for sustained high-frequency synaptic transmission at the calyx terminal. PMID:22805168

Vasileva, Mariya; Horstmann, Heinz; Geumann, Constanze; Gitler, Daniel; Kuner, Thomas

2012-10-01

60

Myosin VI contributes to synaptic transmission and development at the Drosophila neuromuscular junction  

PubMed Central

Background Myosin VI, encoded by jaguar (jar) in Drosophila melanogaster, is a unique member of the myosin superfamily of actin-based motor proteins. Myosin VI is the only myosin known to move towards the minus or pointed ends of actin filaments. Although Myosin VI has been implicated in numerous cellular processes as both an anchor and a transporter, little is known about the role of Myosin VI in the nervous system. We previously recovered jar in a screen for genes that modify neuromuscular junction (NMJ) development and here we report on the genetic analysis of Myosin VI in synaptic development and function using loss of function jar alleles. Results Our experiments on Drosophila third instar larvae revealed decreased locomotor activity, a decrease in NMJ length, a reduction in synaptic bouton number, and altered synaptic vesicle localization in jar mutants. Furthermore, our studies of synaptic transmission revealed alterations in both basal synaptic transmission and short-term plasticity at the jar mutant neuromuscular synapse. Conclusions Altogether these findings indicate that Myosin VI is important for proper synaptic function and morphology. Myosin VI may be functioning as an anchor to tether vesicles to the bouton periphery and, thereby, participating in the regulation of synaptic vesicle mobilization during synaptic transmission.

2011-01-01

61

Spinal use-dependent plasticity of synaptic transmission in humans after a single cycling session  

PubMed Central

The spinal cord is able to express use-dependent plasticity, as demonstrated in spinalized cats following treadmill training. In humans, spinal use-dependent plasticity is inferred from modifications in the size of H reflex, which are often more prominent after skilled motor training. Plasticity can develop at synaptic connections between afferent fibres and/or descending tracts and motoneurones or interneurones interposed in the spinal pathways. Here we explore whether skilled training induces a change in synaptic efficacy at the synapse between Ia afferents and soleus (Sol) motoneurones. Synaptic efficacy can be modulated presynaptically through changes of the probability of transmitter release (homosynaptic depression, HD). The frequency-related depression of the Sol H reflex, thought to reflect HD, was tested at rest, before and after one single skilled (14 subjects) or non-skilled (9 subjects) cycling training session. Performance improved in both groups but to a larger extent with skilled training, while HD increased immediately after and the day following skilled training in the absence of changes with non-skilled training. These results support the view that spinal cord function is able to encode a local motor memory.

Meunier, Sabine; Kwon, Jeongyi; Russmann, Heike; Ravindran, Shashi; Mazzocchio, Riccardo; Cohen, Leonardo

2007-01-01

62

Achieving high-frequency optical control of synaptic transmission.  

PubMed

The optogenetic tool channelrhodopsin-2 (ChR2) is widely used to excite neurons to study neural circuits. Previous optogenetic studies of synapses suggest that light-evoked synaptic responses often exhibit artificial synaptic depression, which has been attributed to either the inability of ChR2 to reliably fire presynaptic axons or to ChR2 elevating the probability of release by depolarizing presynaptic boutons. Here, we compare light-evoked and electrically evoked synaptic responses for high-frequency stimulation at three synapses in the mouse brain. At synapses from Purkinje cells to deep cerebellar nuclei neurons (PC?DCN), light- and electrically evoked synaptic currents were remarkably similar for ChR2 expressed transgenically or with adeno-associated virus (AAV) expression vectors. For hippocampal CA3?CA1 synapses, AAV expression vectors of serotype 1, 5, and 8 led to light-evoked synaptic currents that depressed much more than electrically evoked currents, even though ChR2 could fire axons reliably at up to 50 Hz. The disparity between optical and electrical stimulation was eliminated when ChR2 was expressed transgenically or with AAV9. For cerebellar granule cell to stellate cell (grc?SC) synapses, AAV1 also led to artificial synaptic depression and AAV9 provided superior performance. Artificial synaptic depression also occurred when stimulating over presynaptic boutons, rather than axons, at CA3?CA1 synapses, but not at PC?DCN synapses. These findings indicate that ChR2 expression methods and light stimulation techniques influence synaptic responses in a neuron-specific manner. They also identify pitfalls associated with using ChR2 to study synapses and suggest an approach that allows optogenetics to be applied in a manner that helps to avoid potential complications. PMID:24872574

Jackman, Skyler L; Beneduce, Brandon M; Drew, Iain R; Regehr, Wade G

2014-05-28

63

Adenosine A 2A receptor facilitation of hippocampal synaptic transmission is dependent on tonic A 1 receptor inhibition  

Microsoft Academic Search

Adenosine tonically inhibits synaptic transmission through actions at A1 receptors. It also facilitates synaptic transmission, but it is unclear if this facilitation results from pre- and\\/or postsynaptic A2A receptor activation or from indirect control of inhibitory GABAergic transmission. The A2A receptor agonist, CGS 21680 (10 nM), facilitated synaptic transmission in the CA1 area of rat hippocampal slices (by 14%), independent

L. V. Lopes; R. A. Cunha; B. Kull; B. B. FREDHOLMc; J. A. RIBEIROa

2002-01-01

64

Homeostatic regulation of spontaneous and evoked synaptic transmission in two steps  

PubMed Central

Background During development both Hebbian and homeostatic mechanisms regulate synaptic efficacy, usually working in opposite directions in response to neuronal activity. Homeostatic plasticity has often been investigated by assaying changes in spontaneous synaptic transmission resulting from chronic circuit inactivation. However, effects of inactivation on evoked transmission have been less frequently reported. Importantly, contributions from the effects of circuit inactivation and reactivation on synaptic efficacy have not been individuated. Results Here we show for developing hippocampal neurons in primary culture that chronic inactivation with TTX results in increased mean amplitude of miniature synaptic currents (mEPSCs), but not evoked synaptic currents (eEPSCs). However, changes in quantal properties of transmission, partially reflected in mEPSCs, accurately predicted higher-order statistical properties of eEPSCs. The classical prediction of homeostasis – increased strength of evoked transmission – was realized after explicit circuit reactivation, in the form of cells’ pairwise connection probability. In contrast, distributions of eEPSC amplitudes for control and inactivated-then-reactivated groups matched throughout. Conclusions Homeostatic up-regulation of evoked synaptic transmission in developing hippocampal neurons in primary culture requires both the inactivation and reactivation stages, leading to a net increase in functional circuit connectivity.

2013-01-01

65

Differential roles of postsynaptic density-93 isoforms in regulating synaptic transmission.  

PubMed

In the postsynaptic density of glutamatergic synapses, the discs large (DLG)-membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins coordinates a multiplicity of signaling pathways to maintain and regulate synaptic transmission. Postsynaptic density-93 (PSD-93) is the most variable paralog in this family; it exists in six different N-terminal isoforms. Probably because of the structural and functional variability of these isoforms, the synaptic role of PSD-93 remains controversial. To accurately characterize the synaptic role of PSD-93, we quantified the expression of all six isoforms in the mouse hippocampus and examined them individually in hippocampal synapses. Using molecular manipulations, including overexpression, gene knockdown, PSD-93 knock-out mice combined with biochemical assays, and slice electrophysiology both in rat and mice, we demonstrate that PSD-93 is required at different developmental synaptic states to maintain the strength of excitatory synaptic transmission. This strength is differentially regulated by the six isoforms of PSD-93, including regulations of ?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-active and inactive synapses, and activity-dependent modulations. Collectively, these results demonstrate that alternative combinations of N-terminal PSD-93 isoforms and DLG-MAGUK paralogs can fine-tune signaling scaffolds to adjust synaptic needs to regulate synaptic transmission. PMID:24068818

Krüger, Juliane M; Favaro, Plinio D; Liu, Mingna; Kitlinska, Agata; Huang, Xiaojie; Raabe, Monika; Akad, Derya S; Liu, Yanling; Urlaub, Henning; Dong, Yan; Xu, Weifeng; Schlüter, Oliver M

2013-09-25

66

Differential Roles of Postsynaptic Density-93 Isoforms in Regulating Synaptic Transmission  

PubMed Central

In the postsynaptic density of glutamatergic synapses, the discs large (DLG)-membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins coordinates a multiplicity of signaling pathways to maintain and regulate synaptic transmission. Postsynaptic density-93 (PSD-93) is the most variable paralog in this family; it exists in six different N-terminal isoforms. Probably because of the structural and functional variability of these isoforms, the synaptic role of PSD-93 remains controversial. To accurately characterize the synaptic role of PSD-93, we quantified the expression of all six isoforms in the mouse hippocampus and examined them individually in hippocampal synapses. Using molecular manipulations, including overexpression, gene knockdown, PSD-93 knock-out mice combined with biochemical assays, and slice electrophysiology both in rat and mice, we demonstrate that PSD-93 is required at different developmental synaptic states to maintain the strength of excitatory synaptic transmission. This strength is differentially regulated by the six isoforms of PSD-93, including regulations of ?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-active and inactive synapses, and activity-dependent modulations. Collectively, these results demonstrate that alternative combinations of N-terminal PSD-93 isoforms and DLG-MAGUK paralogs can fine-tune signaling scaffolds to adjust synaptic needs to regulate synaptic transmission.

Kruger, Juliane M.; Favaro, Plinio D.; Liu, Mingna; Kitlinska, Agata; Huang, Xiaojie; Raabe, Monika; Akad, Derya S.; Liu, Yanling; Urlaub, Henning; Dong, Yan; Xu, Weifeng

2013-01-01

67

Rab11 as a modulator of synaptic transmission  

PubMed Central

Many neurodegenerative disorders are characterized by synaptic dysfunction preceding general neuronal loss and subsequent cognitive or behavioral anomalies. Much recent research has been aimed at understanding the early underlying processes leading to dysfunction at the synapse, as this knowledge would likely inform interventions that could potentially slow progression and delay onset of disease. We have recently reported that synaptic dysfunction in a Drosophila melanogaster model of Huntington’s disease (HD) can be prevented by enhanced neuronal expression of Rab11, a Rab family GTPase involved in endosomal recycling, which complements studies that have found disrupted Rab11 activity in several models of this disorder. Indeed, inhibition of Rab11 function in fibroblasts of HD patients has been observed to perturb vesicle formation from recycling endosomes. Therefore, our study investigated a potential role of Rab11 in synaptic dysfunction prior to the onset of HD symptoms, with the aim of finding a possible early intervention to disease progression. We found that Rab11 ameliorates synaptic dysfunction due to expression of mutant huntingtin—the causative protein in HD—by normalizing synaptic vesicle size, which consequently ameliorates locomotor deficits in Drosophila larvae. Here we further consider these results and the implications this work has on potential therapeutic intervention in HD and other neurodegenerative disorders.

Giorgini, Flaviano; Steinert, Joern R

2013-01-01

68

Decreased pain threshold and enhanced synaptic transmission in the anterior cingulate cortex of experimental hypothyroidism mice  

PubMed Central

Background Thyroid hormones are essential for the maturation and functions of the central nervous system. Pain sensitivity is related to the thyroid status. However, information on how thyroid hormones affect pain processing and synaptic transmission in the anterior cingulate cortex (ACC) is limited. Nociceptive threshold and synaptic transmission in the ACC were detected in the experimental hypothyroidism (HT) mice. Results HT was induced by methimazole and potassium perchlorate in distilled drinking water for 4 weeks. The threshold of pain perception to hot insults, but not mechanical ones, decreased in hypothyroid mice. After treatment with tri-iodothyronine (T3) or thyroxine (T4) for 2 weeks, thermal pain threshold recovered. Electrophysiological recordings revealed enhanced glutamatergic synaptic transmission and reduced GABAergic synaptic transmission in the ACC. Supplementation with T3 or T4 significantly rescued this synaptic transmission imbalance. In the same model, HT caused the up-regulation of the GluR1 subunit of the ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and NR2B-containing N-methyl-D-aspartate receptors, but it down-regulated ?-aminobutyric acid A receptors in the ACC. Supplementation with T3 or T4 notably recovered the levels of above proteins. Conclusions These results suggest that HT promotes hypersensitivity to noxious thermal, and that supplementation with T3 or T4 rescues the imbalance between excitatory and inhibitory transmission in the ACC.

2014-01-01

69

Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels.  

PubMed

Presynaptic activation of adenylyl cyclase and subsequent generation of cAMP represent an important mechanism in the modulation of synaptic transmission. In many cases, short- to medium-term modulation of synaptic strength by cAMP is due to activation of protein kinase A and subsequent covalent modification of presynaptic ion channels or synaptic proteins. Here we show that presynaptic cAMP generation via serotonin receptor activation directly modulated hyperpolarization-activated cation channels (Ih channels) in axons. This modulation of Ih produced an increase in synaptic strength that could not be explained solely by depolarization of the presynaptic membrane. These studies identify a mechanism by which cAMP and Ih regulate synaptic plasticity. PMID:10649568

Beaumont, V; Zucker, R S

2000-02-01

70

Self-administration enhances excitatory synaptic transmission in the bed nucleus of the stria terminalis  

PubMed Central

Understanding the neurobiology of motivation might help in reducing compulsive behaviors such as drug addiction or eating disorders. This study shows that excitatory synaptic transmission was enhanced in the bed nucleus of the stria terminalis of rats that performed an operant task to obtain cocaine or palatable food. There was no effect when cocaine or food was delivered passively, suggesting that synaptic plasticity in this area is involved in reward-seeking behaviors.

Dumont, Eric C; Mark, Gregory P; Mader, Sarah; Williams, John T

2014-01-01

71

GABAAR-dependent synaptic transmission sculpts dendritic arbor structure in Xenopus tadpoles in vivo  

PubMed Central

The emergence of dendritic arbor structure in vivo depends on synaptic inputs. We tested whether inhibitory GABAergic synaptic transmission regulates Xenopus optic tectal cell dendritic arbor development in vivo by expressing a peptide corresponding to an intracellular loop (ICL) of the ?2 subunit of GABAAR which is required to anchor GABAA receptors to the postsynaptic scaffold. GFP-tagged ICL (EGFP-ICL) was distributed in a punctate pattern at putative inhibitory synapses, identified by VGAT-immunoreactive puncta. ICL expression completely blocked GABAAR - mediated transmission in 36% of transfected neurons and significantly reduced GABAAR - mediated synaptic currents relative to AMPAR-mediated synaptic currents in the remaining transfected neurons without altering release probability or neuronal excitability. Further analysis of ICL-expressing neurons with residual GABAAR- mediated inputs showed that the capacity of benzodiazepine to enhance GABAergic synaptic responses was reduced in ICL-expressing neurons, indicating that they were likely depleted of ?2 subunit-containing GABAAR. Neurons expressing a mutant form of ICL were comparable to controls. In vivo time-lapse images showed that ICL-expressing neurons have more sparsely branched dendritic arbors which expand over larger neuropil areas than EGFP-expressing control neurons. Analysis of branch dynamics indicated that ICL expression affected arbor growth by reducing rates of branch addition. Furthermore, we found that decreasing GABAergic synaptic transmission with ICL expression blocked visual experience dependent dendritic arbor structural plasticity. Our findings establish an essential role for inhibitory GABAergic synaptic transmission in the regulation of dendritic structural plasticity in Xenopus in vivo.

Shen, Wanhua; Da Silva, Jorge Santos; He, Haiyan; Cline, Hollis T.

2009-01-01

72

Antibody-mediated Impairment and Homeostatic Plasticity of Autonomic Ganglionic Synaptic Transmission  

PubMed Central

Antibodies against ganglionic acetylcholine receptors (AChR) are implicated as the cause of autoimmune autonomic ganglionopathy (AAG). To characterize ganglionic neurotransmission in an animal model of AAG, evoked and spontaneous excitatory post-synaptic potentials (EPSP) were recorded from neurons in isolated mouse superior cervical ganglia (SCG). In vitro exposure of ganglia to IgG from AAG patients progressively inhibited synaptic transmission. After passive transfer of antibody to mice, evoked EPSP amplitude decreased, and some neurons showed no synaptic responses. EPSP amplitude recovered by day seven despite persistence of ganglionic AChR antibody in the mouse serum. There was a more persistent (at least 14 day) reduction in miniature EPSP amplitude consistent with antibody-mediated reduction in post-synaptic AChR. Although the quantal size was reduced, a progressive increase in the frequency of spontaneous synaptic events occurred, suggesting a compensatory increase in presynaptic efficacy. The quantal size returned to baseline by 21 days while the frequency remained increased for at least four weeks. Ganglionic AChR antibodies cause an impairment of autonomic ganglionic synaptic transmission. Homeostatic plasticity in autonomic neurotransmission could help explain the spontaneous clinical recovery seen in some AAG patients and may also play an important role in regulating normal autonomic reflexes.

Wang, Zhengbei; Low, Phillip A.; Vernino, Steven

2010-01-01

73

Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism.  

PubMed

The biological mechanisms of autism spectrum disorders (ASDs) are largely unknown in spite of extensive research. ASD is characterized by altered function of multiple brain areas including the temporal cortex and by an increased synaptic excitation:inhibition ratio. While numerous studies searched for evidence of increased excitation in ASD, fewer have investigated the possibility of reduced inhibition. We characterized the cortical ?-amino butyric acid (GABA)ergic system in the rat temporal cortex of an ASD model [offspring of mothers prenatally injected with valproic acid (VPA)], by monitoring inhibitory post-synaptic currents (IPSCs) with patch-clamp. We found that numerous features of inhibition were severely altered in VPA animals compared to controls. Among them were the frequency of miniature IPSCs, the rise time and decay time of electrically-evoked IPSCs, the slope and saturation of their input/output curves, as well as their modulation by adrenergic and muscarinic agonists and by the synaptic GABAA receptor allosteric modulator zolpidem (but not by the extra-synaptic modulator gaboxadol). Our data suggest that both pre- and post-synaptic, but not extra-synaptic, inhibitory transmission is impaired in the offspring of VPA-injected mothers. We speculate that impairment in the GABAergic system critically contributes to an increase in the ratio between synaptic excitation and inhibition, which in genetically predisposed individuals may alter cortical circuits responsible for emotional, communication and social impairments at the core of ASD. PMID:23228615

Banerjee, Anwesha; García-Oscos, Francisco; Roychowdhury, Swagata; Galindo, Luis C; Hall, Shawn; Kilgard, Michael P; Atzori, Marco

2013-07-01

74

Computational quest for understanding the role of astrocyte signaling in synaptic transmission and plasticity  

PubMed Central

The complexity of the signaling network that underlies astrocyte-synapse interactions may seem discouraging when tackled from a theoretical perspective. Computational modeling is challenged by the fact that many details remain hitherto unknown and conventional approaches to describe synaptic function are unsuitable to explain experimental observations when astrocytic signaling is taken into account. Supported by experimental evidence is the possibility that astrocytes perform genuine information processing by means of their calcium signaling and are players in the physiological setting of the basal tone of synaptic transmission. Here we consider the plausibility of this scenario from a theoretical perspective, focusing on the modulation of synaptic release probability by the astrocyte and its implications on synaptic plasticity. The analysis of the signaling pathways underlying such modulation refines our notion of tripartite synapse and has profound implications on our understanding of brain function.

De Pitta, Maurizio; Volman, Vladislav; Berry, Hugues; Parpura, Vladimir; Volterra, Andrea; Ben-Jacob, Eshel

2012-01-01

75

Restless AMPA receptors: implications for synaptic transmission and plasticity  

PubMed Central

A central assumption in neurobiology holds that changes in the strength of individual synapses underlie changes in behavior. This concept is widely accepted in the case of learning and memory where LTP and LTD are the most compelling cellular models. It is therefore of great interest to understand, on a molecular level, how the brain regulates the strength of neuronal connections. We review a large body of evidence in support of the very straightforward regulation of synaptic strength by changing the number of postsynaptic receptors, and discuss the molecular machinery required for insertion and removal of AMPA receptors.

Luscher, Christian; Frerking, Matthew

2010-01-01

76

Na+/K(+)-ATPase as an effector of synaptic transmission.  

PubMed

Evidence is presented in support of the hypothesis that transmitter monoamines can exert their post-synaptic effects by stimulation or inhibition of Na+/K(+)-ATPase in neuronal or glial cell plasma membranes. Stimulation of electrogenic sodium pumping, causing a hyperpolarization with an increase in membrane resistance, could account for the depression of neuronal spontaneous firing and the signal/noise enhancing actions of these amines. Conversely, inhibition of an electrogenic sodium pump in neuronal plasma membranes would lead to depolarization and enhanced excitability. PMID:1363911

Phillis, J W

1992-01-01

77

Ovarian Hormone Loss Impairs Excitatory Synaptic Transmission at Hippocampal CA3-CA1 Synapses  

PubMed Central

Premature and long-term ovarian hormone loss following ovariectomy (OVX) is associated with cognitive impairment. This condition is prevented by estradiol (E2) therapy when initiated shortly following OVX but not after substantial delay. To determine whether these clinical findings are correlated with changes in synaptic functions, we used adult OVX rats to evaluate the consequences of short-term (7–10 d, OVXControl) and long-term (?5 months, OVXLT) ovarian hormone loss, as well as subsequent in vivo E2 treatment, on excitatory synaptic transmission at the hippocampal CA3–CA1 synapses important for learning and memory. The results show that ovarian hormone loss was associated with a marked decrease in synaptic strength. E2 treatment increased synaptic strength in OVXControl but not OVXLT rats, demonstrating a change in the efficacy for E2 5 months following OVX. E2 also had a more rapid effect: within minutes of bath application, E2 acutely increased synaptic strength in all groups except OVXLT rats that did not receive in vivo E2 treatment. E2's acute effect was mediated postsynaptically, and required Ca2+ influx through the voltage-gated Ca2+ channels. Despite E2's acute effect, synaptic strength of OVXLT rats remained significantly lower than that of OVXControl rats. Thus, changes in CA3–CA1 synaptic transmission associated with ovarian hormone loss cannot be fully reversed with delayed E2 treatment. Given that synaptic strength at CA3–CA1 synapses is related to the ability to learn hippocampus-dependent tasks, these findings provide additional insights for understanding cognitive impairment-associated long-term ovarian hormone loss and ineffectiveness for delayed E2 treatment to maintain cognitive functions.

Bryant, Damani N.; Dorsa, Daniel M.; Adelman, John P.; Maylie, James

2013-01-01

78

Ovarian hormone loss impairs excitatory synaptic transmission at hippocampal CA3-CA1 synapses.  

PubMed

Premature and long-term ovarian hormone loss following ovariectomy (OVX) is associated with cognitive impairment. This condition is prevented by estradiol (E2) therapy when initiated shortly following OVX but not after substantial delay. To determine whether these clinical findings are correlated with changes in synaptic functions, we used adult OVX rats to evaluate the consequences of short-term (7-10 d, OVXControl) and long-term (?5 months, OVXLT) ovarian hormone loss, as well as subsequent in vivo E2 treatment, on excitatory synaptic transmission at the hippocampal CA3-CA1 synapses important for learning and memory. The results show that ovarian hormone loss was associated with a marked decrease in synaptic strength. E2 treatment increased synaptic strength in OVXControl but not OVXLT rats, demonstrating a change in the efficacy for E2 5 months following OVX. E2 also had a more rapid effect: within minutes of bath application, E2 acutely increased synaptic strength in all groups except OVXLT rats that did not receive in vivo E2 treatment. E2's acute effect was mediated postsynaptically, and required Ca(2+) influx through the voltage-gated Ca(2+) channels. Despite E2's acute effect, synaptic strength of OVXLT rats remained significantly lower than that of OVXControl rats. Thus, changes in CA3-CA1 synaptic transmission associated with ovarian hormone loss cannot be fully reversed with delayed E2 treatment. Given that synaptic strength at CA3-CA1 synapses is related to the ability to learn hippocampus-dependent tasks, these findings provide additional insights for understanding cognitive impairment-associated long-term ovarian hormone loss and ineffectiveness for delayed E2 treatment to maintain cognitive functions. PMID:24107948

Wu, Wendy W; Bryant, Damani N; Dorsa, Daniel M; Adelman, John P; Maylie, James

2013-10-01

79

Regulation of Synaptic Transmission and Plasticity by Neuronal Nicotinic Acetylcholine Receptors  

PubMed Central

Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system and participate in a variety of physiological functions. Recent advances have revealed roles of nAChRs in the regulation of synaptic transmission and synaptic plasticity, particularly in the hippocampus and midbrain dopamine centers. In general, activation of nAChRs causes membrane depolarization and directly and indirectly increases the intracellular calcium concentration. Thus, when nAChRs are expressed on presynaptic membranes their activation generally increases the probability of neurotransmitter release. When expressed on postsynaptic membranes, nAChR-initiated calcium signals and depolarization activate intracellular signaling mechanisms and gene transcription. Together, the presynaptic and postsynaptic effects of nAChRs generate and facilitate the induction of long-term changes in synaptic transmission. The direction of hippocampal nAChR-mediated synaptic plasticity –either potentiation or depression – depends on the timing of nAChR activation relative to coincident presynaptic and postsynaptic electrical activity, and also depends on the location of cholinergic stimulation within the local network. Therapeutic activation of nAChRs may prove efficacious in the treatment of neuropathologies where synaptic transmission is compromised, as in Alzheimer’s or Parkinson’s disease.

McKay, Bruce E.; Placzek, Andon N.; Dani, John A.

2007-01-01

80

Variable timing of synaptic transmission in cerebellar unipolar brush cells  

PubMed Central

The cerebellum ensures the smooth execution of movements, a task that requires accurate neural signaling on multiple time scales. Computational models of cerebellar timing mechanisms have suggested that temporal information in cerebellum-dependent behavioral tasks is in part computed locally in the cerebellar cortex. These models rely on the local generation of delayed signals spanning hundreds of milliseconds, yet the underlying neural mechanism remains elusive. Here we show that a granular layer interneuron, called the unipolar brush cell, is well suited to represent time intervals in a robust way in the cerebellar cortex. Unipolar brush cells exhibited delayed increases in excitatory synaptic input in response to presynaptic stimulation in mouse cerebellar slices. Depending on the frequency of stimulation, delays extended from zero up to hundreds of milliseconds. Such controllable protraction of delayed currents was the result of an unusual mode of synaptic integration, which was well described by a model of steady-state AMPA receptor activation. This functionality extends the capabilities of the cerebellum for adaptive control of behavior by facilitating appropriate output in a broad temporal window.

van Dorp, Stijn; De Zeeuw, Chris I.

2014-01-01

81

Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.  

PubMed

Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (?-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders. PMID:24870235

Karayannis, T; Au, E; Patel, C; Kruglikov, I; Markx, S; Delorme, R; Héron, D; Salomon, D; Glessner, J; Restituito, S; Gordon, A; Rodriguez-Murillo, L; Roy, N C; Gogos, J A; Rudy, B; Rice, M E; Karayiorgou, M; Hakonarson, H; Keren, B; Huguet, G; Bourgeron, T; Hoeffer, C; Tsien, R W; Peles, E; Fishell, G

2014-07-10

82

Purines released from astrocytes inhibit excitatory synaptic transmission in the ventral horn of the spinal cord  

PubMed Central

Spinal neuronal networks are essential for motor function. They are involved in the integration of sensory inputs and the generation of rhythmic motor outputs. They continuously adapt their activity to the internal state of the organism and to the environment. This plasticity can be provided by different neuromodulators. These substances are usually thought of being released by dedicated neurons. However, in other networks from the central nervous system synaptic transmission is also modulated by transmitters released from astrocytes. The star-shaped glial cell responds to neurotransmitters by releasing gliotransmitters, which in turn modulate synaptic transmission. Here we investigated if astrocytes present in the ventral horn of the spinal cord modulate synaptic transmission. We evoked synaptic inputs in ventral horn neurons recorded in a slice preparation from the spinal cord of neonatal mice. Neurons responded to electrical stimulation by monosynaptic EPSCs (excitatory monosynaptic postsynaptic currents). We used mice expressing the enhanced green fluorescent protein under the promoter of the glial fibrillary acidic protein to identify astrocytes. Chelating calcium with BAPTA in a single neighboring astrocyte increased the amplitude of synaptic currents. In contrast, when we selectively stimulated astrocytes by activating PAR-1 receptors with the peptide TFLLR, the amplitude of EPSCs evoked by a paired stimulation protocol was reduced. The paired-pulse ratio was increased, suggesting an inhibition occurring at the presynaptic side of synapses. In the presence of blockers for extracellular ectonucleotidases, TFLLR did not induce presynaptic inhibition. Puffing adenosine reproduced the effect of TFLLR and blocking adenosine A1 receptors with 8-Cyclopentyl-1,3-dipropylxanthine prevented it. Altogether our results show that ventral horn astrocytes are responsible for a tonic and a phasic inhibition of excitatory synaptic transmission by releasing ATP, which gets converted into adenosine that binds to inhibitory presynaptic A1 receptors.

Carlsen, Eva Meier; Perrier, Jean-Francois

2014-01-01

83

A Model of Graded Synaptic Transmission for Use in Dynamic Network Simulations  

Microsoft Academic Search

1. The heartbeat central pattern-generating network of the me- dicinal leech contains elemental neural oscillators, comprising re- ciprocally inhibitory pairs of segmental heart interneurons, that use graded as well as spike-mediated synaptic transmission. We are in the process of developing a general computer model of this pattern generator. Our modeling goal is to explore the interaction of membrane currents and

ERIK DE SCHUTTER; JAMES D. ANGSTADT; RONALD L. CALABRESE

1993-01-01

84

Effects of glutamic acid diethylester on synaptic transmission in the skate ampullae of Lorenzini  

Microsoft Academic Search

The effects on synaptic transmission of glutamic acid diethylester (GDEE), a glutamate receptor blocker, were investigated by recording spike activity from single nerve fibers in the electroreceptor cells of the skate (Raja clavata) ampullae of Lorenzini. It was found that adding GDEE to the bathing medium led to a concentration-dependent reduction in or complete blockade of background and evoked receptor

G. N. Akoev; Yu. N. Andrianov; N. O. Sherman

1987-01-01

85

In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA  

Microsoft Academic Search

Maternal exposure to cocaine may perturb fetal development and affect synaptic maturation in the offspring. However, the molecular mechanism underlying such changes remains elusive. We focused on the postnatal maturation of glutamatergic transmission onto ventral tegmental area dopamine neurons in the mouse. We found that, during the first postnatal week, transmission was dominated by calcium-permeable AMPA receptors and GluN2B-containing NMDA

Manuel Mameli; Camilla Bellone; Christian Lüscher

2011-01-01

86

DHA supplementation enhances high-frequency, stimulation-induced synaptic transmission in mouse hippocampus.  

PubMed

While some studies on dietary supplementation with docosahexaenoic acid (DHA, 22:6n-3) have reported a beneficial effect on memory as a function of age, others have failed to find any effect. To clarify this issue, we sought to determine whether supplementing mice with a DHA-enriched diet could alter the ability of synapses to undergo activity-dependent changes in the hippocampus, a brain structure involved in forming new spatial memories. We found that DHA was increased by 29% ± 5% (mean ± SE) in the hippocampus for the supplemented (DHA+) versus nonsupplemented (control) group (n = 5 mice per group; p < 0.05). Such DHA elevation was associated with enhanced synaptic transmission (p < 0.05) as assessed by application of a high-frequency electrical stimulation protocol (100 Hz stimulation, which induced transient (<2 h) increases in synaptic strength) to slices from DHA+ (n = 4 mice) hippocampi when compared with controls (n = 4 mice). Increased synaptic responses were evident 60 min poststimulation. These results suggest that dietary DHA supplementation facilitates synaptic plasticity following brief high-frequency stimulation. This increase in synaptic transmission might provide a physiological correlation for the improved spatial learning and memory observed following DHA supplementation. PMID:22716290

Connor, Steve; Tenorio, Gustavo; Clandinin, Michael Tom; Sauvé, Yves

2012-10-01

87

Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex  

PubMed Central

Dopamine (DA) is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homolog of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell recordings revealed no obvious effects of DA on membrane potential or input resistance in the majority of Dp neurons. Electrical stimulation of the olfactory tracts produced a complex sequence of synaptic currents in Dp neurons. DA selectively decreased inhibitory currents with little or no effect on excitatory components. Multiphoton calcium imaging showed that population responses of Dp neurons to olfactory tract stimulation or odor application were enhanced by DA, consistent with its effect on inhibitory synaptic transmission. These effects of DA were blocked by an antagonist of D2-like receptors. DA therefore disinhibits and reorganizes sensory responses in Dp. This modulation may affect sensory perception and could be involved in the experience-dependent modification of odor representations.

Scharer, Yan-Ping Zhang; Shum, Jennifer; Moressis, Anastasios; Friedrich, Rainer W.

2012-01-01

88

ALLN rescues an in vitro excitatory synaptic transmission deficit in Lis1 mutant mice.  

PubMed

LIS1 gene mutations lead to a rare neurological disorder, classical lissencephaly, characterized by brain malformations, mental retardation, seizures, and premature death. Mice heterozygous for Lis1 (Lis1(+/-)) exhibit cortical malformations, defects in neuronal migration, increased glutamate-mediated synaptic transmission, and spontaneous electrographic seizures. Recent work demonstrated that in utero treatment of Lis1(+/-) mutant dams with ALLN, a calpain inhibitor, partially rescues neuronal migration defects in the offspring. Given the challenges of in utero drug administration, we examined the therapeutic potential of ALLN on postnatal lissencephalic cells. Voltage- and current-clamp studies were performed with acute hippocampal slices obtained from Lis1 mutant mice and age-matched littermate control mice. Specifically, we determined whether postnatal ALLN treatment can reverse excitatory synaptic transmission deficits, namely, an increase in spontaneous and miniature excitatory postsynaptic current (EPSC) frequency, on CA1 pyramidal neurons observed in tissue slices from Lis1(+/-) mice. We found that acute application of ALLN restored spontaneous and miniature EPSC frequencies to wild-type levels without affecting inhibitory postsynaptic synaptic current. Furthermore, Western blot analysis of protein expression, including proteins involved in excitatory synaptic transmission, demonstrated that ALLN blocks the cleavage of the calpain substrate ?II-spectrin but does not rescue Lis1 protein levels in Lis1(+/-) mutants. PMID:23100132

Sebe, Joy Y; Bershteyn, Marina; Hirotsune, Shinji; Wynshaw-Boris, Anthony; Baraban, Scott C

2013-01-01

89

Corticosterone targets distinct steps of synaptic transmission via concentration specific activation of mineralocorticoid and glucocorticoid receptors.  

PubMed

Hippocampal neurons are affected by chronic stress and have a high density of cytoplasmic mineralocorticoid and glucocorticoid receptors (MR and GR). Detailed studies on the genomic effects of the stress hormone corticosterone at physiologically relevant concentrations on different steps in synaptic transmission are limited. In this study, we tried to delineate how activation of MR and GR by different concentrations of corticosterone affects synaptic transmission at various levels. The effect of 3-h corticosterone (25, 50, and 100 nM) treatment on depolarization-mediated calcium influx, vesicular release and properties of miniature excitatory post-synaptic currents (mEPSCs) were studied in cultured hippocampal neurons. Activation of MR with 25 nM corticosterone treatment resulted in enhanced depolarization-mediated calcium influx via a transcription-dependent process and increased frequency of mEPSCs with larger amplitude. On the other hand, activation of GR upon 100 nM corticosterone treatment resulted in increase in the rate of vesicular release via the genomic actions of GR. Furthermore, GR activation led to significant increase in the frequency of mEPSCs with larger amplitude and faster decay. Our studies indicate that differential activation of the dual receptor system of MR and GR by corticosterone targets the steps in synaptic transmission differently. PMID:24117520

Chatterjee, Sreejata; Sikdar, Sujit K

2014-02-01

90

Synaptic Transmission Deficits in Caenorhabditis elegans Synaptobrevin Mutants  

Microsoft Academic Search

Synaptobrevins are vesicle-associated proteins implicated in neurotransmitter release by both biochemical studies and per- turbation experiments that use botulinum toxins. To test these models in vivo, we have isolated and characterized the first synaptobrevin mutants in metazoans and show that neuro- transmission is severely disrupted in mutant animals. Mutants lacking snb-1 die just after completing embryogenesis. The dying animals retain

Michael L. Nonet; Owais Saifee; Hongjuan Zhao; James B. Rand; Liping Wei

1998-01-01

91

Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats  

PubMed Central

Alterations in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA-R) receptor and N-methyl-D-aspartate receptor (NMDA-R) have been documented in aged animals and may contribute to changes in hippocampal-dependent memory. Growth Hormone (GH) regulates AMPA-R and NMDA-R-dependent excitatory transmission and decreases with age. Chronic GH treatment mitigates age-related cognitive decline. An in vitro CA1 hippocampal slice preparation was used to compare hippocampal excitatory transmission and plasticity in old animals treated for 6–8 months with either saline or GH. Our findings indicate that GH treatment restores NMDA-R dependent basal synaptic transmission in old rats to young adult levels and enhances both AMPA-R-dependent basal synaptic transmission and long-term potentiation. These alterations in synaptic function occurred in the absence of changes in presynaptic function, as measured by paired-pulse ratios, the total protein levels of AMPA-R and NMDA-R subunits or in plasma or hippocampal levels of insulin-like growth factor-I. These data suggest a direct role for GH in altering age-related changes in excitatory transmission and provide a possible cellular mechanism through which GH changes the course of cognitive decline.

Molina, Doris P.; Ariwodola, Olusegun J.; Linville, Constance; Sonntag, William E.; Weiner, Jeff L.; Brunso-Bechtold, Judy K.; Adams, Michelle M.

2011-01-01

92

Long-term actions of BDNF on inhibitory synaptic transmission in identified neurons of the rat substantia gelatinosa.  

PubMed

Peripheral nerve injury promotes the release of brain-derived neurotrophic factor (BDNF) from spinal microglial cells and primary afferent terminals. This induces an increase in dorsal horn excitability that contributes to "central sensitization" and to the onset of neuropathic pain. Although it is accepted that impairment of GABAergic and/or glycinergic inhibition contributes to this process, certain lines of evidence suggest that GABA release in the dorsal horn may increase after nerve injury. To resolve these contradictory findings, we exposed rat spinal cord neurons in defined-medium organotypic culture to 200 ng/ml BDNF for 6 days to mimic the change in spinal BDNF levels that accompanies peripheral nerve injury. Morphological and electrophysiological criteria and glutamic acid decarboxylase (GAD) immunohistochemistry were used to distinguish putative inhibitory tonic-islet-central neurons from putative excitatory delay-radial neurons. Whole cell recording in the presence of 1 ?M tetrodotoxin showed that BDNF increased the amplitude of GABAergic and glycinergic miniature inhibitory postsynaptic currents (mIPSCs) in both cell types. It also increased the amplitude and frequency of spontaneous, action potential-dependent IPSCs (sIPSCs) in putative excitatory neurons. By contrast, BDNF reduced sIPSC amplitude in inhibitory neurons but frequency was unchanged. This increase in inhibitory drive to excitatory neurons and decreased inhibitory drive to inhibitory neurons seems inconsistent with the observation that BDNF increases overall dorsal horn excitability. One of several explanations for this discrepancy is that the action of BDNF in the substantia gelatinosa is dominated by previously documented increases in excitatory synaptic transmission rather than by impediment of inhibitory transmission. PMID:22496528

Lu, Van B; Colmers, William F; Smith, Peter A

2012-07-01

93

CNQX and AMPA inhibit electrical synaptic transmission: a potential interaction between electrical and glutamatergic synapses  

PubMed Central

Electrical synapses play an important role in signaling between neurons and the synaptic connections between many neurons possess both electrical and chemical components. Although modulation of electrical synapses is frequently observed, the cellular processes that mediate such changes have not been studied as thoroughly as plasticity in chemical synapses. In the leech (Hirudo sp), the competitive AMPA receptor antagonist CNQX inhibited transmission at the rectifying electrical synapse of a mixed glutamatergic/electrical synaptic connection. This CNQX-mediated inhibition of the electrical synapse was blocked by concanavalin A (Con A) and dynamin inhibitory peptide (DIP), both of which are known to inhibit endocytosis of neurotransmitter receptors. CNQX-mediated inhibition was also blocked by pep2-SVKI (SVKI), a synthetic peptide that prevents internalization of AMPA-type glutamate receptor. AMPA itself also inhibited electrical synaptic transmission and this AMPA-mediated inhibition was partially blocked by Con A, DIP and SVKI. Low frequency stimulation induced long-term depression (LTD) in both the electrical and chemical components of these synapses and this LTD was blocked by SVKI. GYKI 52466, a selective non-competitive antagonist of AMPA receptors, did not affect the electrical EPSP, although it did block the chemical component of these synapses. CNQX did not affect non-rectifying electrical synapses in two different pairs of neurons. These results suggest an interaction between AMPA-type glutamate receptors and the gap junction proteins that mediate electrical synaptic transmission. This putative interaction between glutamate receptors and gap junction proteins represents a novel mechanism for regulating the strength of synaptic transmission.

Li, Qin; Burrell, Brian D.

2008-01-01

94

Effect of VGLUT inhibitors on glutamatergic synaptic transmission in the rodent hippocampus and prefrontal cortex.  

PubMed

Vesicular glutamate transporters (VGLUTs) are known to be important in the uptake of glutamate into vesicles in the presynaptic terminal; thereby playing a role in synaptic function. VGLUT dysfunction has also been suggested in neurological and psychiatric disorders such as epilepsy and schizophrenia. A number of compounds have been identified as VGLUT inhibitors; however, little is known as to how these compounds affect synaptic transmission. We therefore investigated the effects of structurally unrelated VGLUT inhibitors on synaptic transmission in the rodent hippocampus and prefrontal cortex. In the CA1 and dentate gyrus regions of the in vitro slice preparation of mouse hippocampus, AMPA receptor-mediated field excitatory postsynaptic potentials (fEPSPs) were evoked in response to Schaffer collateral/commissural pathway stimulation. Application of the VGLUT inhibitors Rose Bengal (RB), Congo Red (CR) or Chicago Sky Blue 6B (CB) resulted in a concentration-related reduction of fEPSP amplitudes. RB (30?M) or CB (300?M) also depressed NMDA receptor-mediated responses in the CA1 region. The naturally occurring kynurenine Xanthurenic Acid (XA) is reported to be a VGLUT inhibitor. We found XA attenuated both AMPA and NMDA receptor-mediated synaptic transmission. The potency order of the VGLUT inhibitors was consistent with literature Ki values for VGLUT inhibition. Impaired glutamatergic neurotransmission is believed to contribute to schizophrenia, and VGLUTs have also been implicated in this disease. We therefore investigated the effect of VGLUT inhibition in the prefrontal cortex. Application of the VGLUT inhibitors RB or CB resulted in a concentration-dependent reduction in the amplitude of glutamate receptor-mediated fEPSPs recorded in layer V/VI in response to stimulation in the forceps minor. We conclude that VGLUT inhibitors can modulate glutamatergic synaptic transmission in the PFC and hippocampus. This could be important in the pathophysiology of nervous system disorders and might represent a target for developing novel pharmacological therapies. PMID:24121008

Neale, S A; Copeland, C S; Salt, T E

2014-07-01

95

Specific functions of synaptically localized potassium channels in synaptic transmission at the neocortical GABAergic fast-spiking cell synapse.  

PubMed

Potassium (K+) channel subunits of the Kv3 subfamily (Kv3.1-Kv3.4) display a positively shifted voltage dependence of activation and fast activation/deactivation kinetics when compared with other voltage-gated K+ channels, features that confer on Kv3 channels the ability to accelerate the repolarization of the action potential (AP) efficiently and specifically. In the cortex, the Kv3.1 and Kv3.2 proteins are expressed prominently in a subset of GABAergic interneurons known as fast-spiking (FS) cells and in fact are a significant determinant of the fast-spiking discharge pattern. However, in addition to expression at FS cell somata, Kv3.1 and Kv3.2 proteins also are expressed prominently at FS cell terminals, suggesting roles for Kv3 channels in neurotransmitter release. We investigated the effect of 1.0 mM tetraethylammonium (TEA; which blocks Kv3 channels) on inhibitory synaptic currents recorded in layer II/III neocortical pyramidal cells. Spike-evoked GABA release by FS cells was enhanced nearly twofold by 1.0 mM TEA, with a decrease in the paired pulse ratio (PPR), effects not reproduced by blockade of the non-Kv3 subfamily K+ channels also blocked by low concentrations of TEA. Moreover, in Kv3.1/Kv3.2 double knock-out (DKO) mice, the large effects of TEA were absent, spike-evoked GABA release was larger, and the PPR was lower than in wild-type mice. Together, these results suggest specific roles for Kv3 channels at FS cell terminals that are distinct from those of Kv1 and large-conductance Ca2+-activated K+ channels (also present at the FS cell synapse). We propose that at FS cell terminals synaptically localized Kv3 channels keep APs brief, limiting Ca2+ influx and hence release probability, thereby influencing synaptic depression at a synapse designed for sustained high-frequency synaptic transmission. PMID:15917463

Goldberg, Ethan M; Watanabe, Shigeo; Chang, Su Ying; Joho, Rolf H; Huang, Z Josh; Leonard, Christopher S; Rudy, Bernardo

2005-05-25

96

[Neuromuscular synaptic transmission at different stages of postnatal development in rats].  

PubMed

On the nerve-muscle preparation of rats diaphragm muscle on different stages of postnatal development, the comparison of morphological features and functions of synaptic apparatus, including induced secretion time parameters was carried out. It was found that, along with the reduced, compared to the adult animals, area of nerve endings in the newborn the speed of the motor nerve excitation was slower, intensity of spontaneous and induced secretion of quantum fluctuations was reduced and real synaptic delays in the end plate were intense. Severe degree of acetylcholine quanta asynchronous secretion with longer open state of the ion channel in newborns synapses can compensate reduction in reliability of synaptic transmission due to a decrease of the quantal content of the postsynaptic response. PMID:23461198

Khuzakhmetova, B F; Samigullin, D V; Nurullin, L F; Nikol'ski?, E E; Bukhareva, É A

2012-12-01

97

Heterogeneity in synaptic transmission along a Drosophila larval motor axon  

PubMed Central

Summary At the Drosophila larval neuromuscular junction (NMJ), a motor neuron releases glutamate from 30-100 boutons onto the muscle it innervates. How transmission strength is distributed among the boutons of the NMJ is unknown. To address this, we created SynapCam, a version of the Ca2+ reporter Cameleon. SynapCam localizes to the postsynapse and selectively reveals Ca2+ influx through glutamate receptors (GluRs) with single-impulse and single-bouton resolution. GluR-based Ca2+ signals were uniform within a given connection (i.e., bouton and postsynapse pair), but differed considerably among connections of an NMJ. A steep gradient of transmission strength was observed along axonal branches, from weak proximal connections to strong distal ones. Presynaptic imaging revealed a matching axonal gradient, with higher Ca2+ influx and exocytosis at distal boutons. The results suggest that transmission strength is mainly determined presynaptically at the level of individual boutons, possibly by one or more factors existing in a gradient.

Guerrero, Giovanna; Agarwal, Gautam; Reiff, Dierk F.; Ball, Robin W.; Borst, Alexander; Goodman, Corey S.

2005-01-01

98

[Relationship between a state of sleep and wakefulness and transmission of an afferent signal through the posterior ventral nucleus of the thalamus].  

PubMed

Chronic experiments were carried out on nonanesthetized cats. A study was made of peculiarities attending the transmission of the afferent signals and the following inhibitory processes in the posterior ventral nucleus of the thalamus, depending on the state of sleep and wakefulness. Transmission of the signals decreases during the dreaming condition and the slow-wave sleep, and increases during the active states of alert cats. In paradoxical sleep the signal transmission is at the same level as such at resting wakeful condition. A marked transmission fluctuation is seen during the dreaming state and in the course of the first phase of sleep. The level of signal transmission is the most stable during the active states. The degree of the trance inhibitory process after the afferent signal transmission depends on the level of anesthesia, wakefulness and natural sleep. Processes following the afferent signal transmission in the posterior ventral nucleus of the thalamus show a radical difference in the barbituiate-anesthetized in comparison with nonanesthetized animals. The trace inhibition, so characteristic of anesthesia, was expressed in the dreaming state of the animal but insignificantly; in the wakeful condition it is not manifested at all. PMID:192390

Lang, E; Durinian, R A

1977-04-01

99

Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease.  

PubMed

Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in >30% of these patients. While postmortem pathology studies and in vivo magnetic resonance imaging demonstrate that the hippocampus is targeted in MS, the neuropathology underlying hippocampal dysfunction remains unknown. Furthermore, there are no treatments available to date to effectively prevent neurodegeneration and associated cognitive dysfunction in MS. We have recently demonstrated that the hippocampus is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. The objective of this study was to assess whether a candidate treatment (testosterone) could prevent hippocampal synaptic dysfunction and underlying pathology when administered in either a preventative or a therapeutic (postdisease induction) manner. Electrophysiological studies revealed impairments in basal excitatory synaptic transmission that involved both AMPA receptor-mediated changes in synaptic currents, and faster decay rates of NMDA receptor-mediated currents in mice with EAE. Neuropathology revealed atrophy of the pyramidal and dendritic layers of hippocampal CA1, decreased presynaptic (Synapsin-1) and postsynaptic (postsynaptic density 95; PSD-95) staining, diffuse demyelination, and microglial activation. Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as presynaptic and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in EPSPs are significantly correlated to changes in postsynaptic protein levels and suggest that PSD-95 is a neuropathological substrate to impaired synaptic transmission in the hippocampus during EAE. This is the first report demonstrating that testosterone is a viable therapeutic treatment option that can restore both hippocampal function and disease-associated pathology that occur during autoimmune disease. PMID:22956822

Ziehn, Marina O; Avedisian, Andrea A; Dervin, Shannon M; Umeda, Elizabeth A; O'Dell, Thomas J; Voskuhl, Rhonda R

2012-09-01

100

Controlling the first-spike latency response of a single neuron via unreliable synaptic transmission  

NASA Astrophysics Data System (ADS)

Previous experimental and theoretical studies suggest that first-spike latency is an efficient information carrier and may contain more amounts of neural information than those of other spikes. Therefore, the biophysical mechanisms underlying the first-spike response latency are of considerable interest. Here we present a systematical investigation on the response latency dynamics of a single Hodgkin-Huxley neuron subject to both a suprathreshold periodic forcing and background activity. In contrast to most earlier works, we consider a biophysically realistic noise model which allows us to relate the synaptic background activity to unreliable synapses and latency. Our results show that first-spike latency of a neuron can be regulated via unreliable synapses. An intermediate level of successful synaptic transmission probability significantly increases both the latency and its jitter, indicating that the unreliable synaptic transmission constrains the signal detection ability of neurons. Furthermore, we demonstrate that the destructive influence of synaptic unreliability can be controlled by the input regime and by the excitatory coupling strength. Better tuning of these two factors could help the H-H neuron encode information more accurately in terms of the first-spike latency.

Uzuntarla, M.; Ozer, M.; Guo, D. Q.

2012-08-01

101

Action-potential-independent GABAergic tone mediated by nicotinic stimulation of immature striatal miniature synaptic transmission.  

PubMed

Stimulation of presynaptic nicotinic acetylcholine receptors (nAChRs) increases the frequency of miniature excitatory synaptic activity (mEPSCs) to a point where they can promote cell firing in hippocampal CA3 neurons. We have evaluated whether nicotine regulation of miniature synaptic activity can be extended to inhibitory transmission onto striatal medium spiny projection neurons (MSNs) in acute brain slices. Bath application of micromolar nicotine typically induced 12-fold increases in the frequency of miniature inhibitory synaptic currents (mIPSCs). Little effect was observed on the amplitude of mIPSCs or mEPSCs under these conditions. Nicotine stimulation of mIPSCs was dependent on entry of extracellular calcium because removal of calcium from perfusate was able to block its action. To assess the potential physiological significance of the nicotine-stimulated increase in mIPSC frequency, we also examined the nicotine effect on evoked IPSCs (eIPSCs). eIPSCs were markedly attenuated by nicotine. This effect could be attributed to two potential mechanisms: transmitter depletion due to extremely high mIPSC rates and/or a reduction in presynaptic excitability associated with nicotinic depolarization. Treatment with low concentrations of K(+) was able to in part mimic nicotine's stimulatory effect on mIPSCs and inhibitory effect on eIPSCs. Current-clamp recordings confirmed a direct depolarizing action of nicotine that could dampen eIPSC activity leading to a switch to striatal inhibitory synaptic transmission mediated by tonic mIPSCs. PMID:17553945

Liu, Zhi; Otsu, Yo; Vasuta, Cristina; Nawa, Hiroyuki; Murphy, Timothy H

2007-08-01

102

Possible involvement of Rap1 and Ras in glutamatergic synaptic transmission.  

PubMed

Rap1A, first identified as a suppressor of transformed phenotype induced by an activated ras oncogene, is abundantly expressed in the brain. Its neurophysiological function, however, is poorly understood. When an activated Rap1A mutant (Rap1-12V) or a dominant negative H-Ras mutant (Ras-17N) was expressed in CA1 neurons in cultured hippocampal slices using the sindbis virus-mediated gene transfer technique, NMDA receptor current in response to Schaffer collateral stimulation was suppressed. Expression of activated H-Ras mutant (Ras-12V) resulted in the elevation of both NMDA receptor current and AMPA receptor current. These results implicate counteracting functions of Ras and Rap1 in the regulation of NMDA receptor-mediated synaptic transmission and a positive regulatory role of Ras in AMPA receptor-mediated synaptic transmission. PMID:12824760

Imamura, Y; Matsumoto, N; Kondo, S; Kitayama, H; Noda, M

2003-07-01

103

Modulation of Glutamatergic Synaptic Transmission in the Bed Nucleus of the Stria Terminalis  

PubMed Central

Glutamate, catecholamine and neuropeptide signaling within the bed nucleus of the stria terminalis (BNST) have all been identified as key participants in anxiety-like behaviors and behaviors related to withdrawal from exposure to substances of abuse. The BNST is thought to serve as a key relay between limbic cognitive centers and reward, stress and anxiety nuclei. Human studies and animal models have demonstrated that stressors and drugs of abuse can result in long term behavioral modifications that can culminate in psychological diseases such as addiction and post-traumatic stress disorder. The ability of catecholamines and neuropeptides to influence synaptic glutamatergic transmission (stemming from cognitive centers) within the BNST may have profound consequences over these behaviors. In this review we highlight studies examining synaptic plasticity and modulation of excitatory transmission within the BNST, emphasizing how such modulation may result in alterations in anxiety and reward related behavior.

McElligott, Zoe Anastasia; Winder, Danny G.

2009-01-01

104

PICK1 is required for the control of synaptic transmission by the metabotropic glutamate receptor 7.  

PubMed

Both postsynaptic density and presynaptic active zone are structural matrix containing scaffolding proteins that are involved in the organization of the synapse. Little is known about the functional role of these proteins in the signaling of presynaptic receptors. Here we show that the interaction of the presynaptic metabotropic glutamate (mGlu) receptor subtype, mGlu7a, with the postsynaptic density-95 disc-large zona occludens 1 (PDZ) domain-containing protein, PICK1, is required for specific inhibition of P/Q-type Ca(2+) channels, in cultured cerebellar granule neurons. Furthermore, we show that activation of the presynaptic mGlu7a receptor inhibits synaptic transmission and this effect also requires the presence of PICK1. These results indicate that the scaffolding protein, PICK1, plays an essential role in the control of synaptic transmission by the mGlu7a receptor complex. PMID:12065412

Perroy, J; El Far, O; Bertaso, F; Pin, J P; Betz, H; Bockaert, J; Fagni, L

2002-06-17

105

Snx14 Regulates Neuronal Excitability, Promotes Synaptic Transmission, and Is Imprinted in the Brain of Mice  

PubMed Central

Genomic imprinting describes an epigenetic process through which genes can be expressed in a parent-of-origin-specific manner. The monoallelic expression of imprinted genes renders them particularly susceptible to disease causing mutations. A large proportion of imprinted genes are expressed in the brain, but little is known about their functions. Indeed, it has proven difficult to identify cell type-specific imprinted genes due to the heterogeneity of cell types within the brain. Here we used laser capture microdissection of visual cortical neurons and found evidence that sorting nexin 14 (Snx14) is a neuronally imprinted gene in mice. SNX14 protein levels are high in the brain and progressively increase during neuronal development and maturation. Snx14 knockdown reduces intrinsic excitability and severely impairs both excitatory and inhibitory synaptic transmission. These data reveal a role for monoallelic Snx14 expression in maintaining normal neuronal excitability and synaptic transmission.

Huang, Hsien-Sung; Yoon, Bong-June; Brooks, Sherian; Bakal, Robert; Berrios, Janet; Larsen, Rylan S.; Wallace, Michael L.; Han, Ji Eun; Chung, Eui Hwan; Zylka, Mark J.; Philpot, Benjamin D.

2014-01-01

106

Recording long-term potentiation of synaptic transmission by three-dimensional multi-electrode arrays  

Microsoft Academic Search

BACKGROUND: Multi-electrode arrays (MEAs) have become popular tools for recording spontaneous and evoked electrical activity of excitable tissues. The majority of previous studies of synaptic transmission in brain slices employed MEAs with planar electrodes that had limited ability to detect signals coming from deeper, healthier layers of the slice. To overcome this limitation, we used three-dimensional (3D) MEAs with tip-shaped

Maksym V Kopanitsa; Nurudeen O Afinowi; Seth GN Grant

2006-01-01

107

Synaptic transmission changes in fear memory circuits underlie key features of an animal model of schizophrenia  

Microsoft Academic Search

Non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) such as phencyclidine (PCP) elicit schizophrenia-like symptoms in healthy individuals. Similarly, PCP dosing in rats produces typical behavioral phenotypes that mimic human schizophrenia symptoms. Although schizophrenic behavioral phenotypes of the PCP model have been extensively studied, the underlying alterations of intrinsic neuronal properties and synaptic transmission in relevant limbic brain microcircuits remain elusive.

Marie Pollard; Christophe Varin; Brian Hrupka; Darrel J. Pemberton; Thomas Steckler; Hamdy Shaban

108

Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation.  

PubMed

Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of ?-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposure to a-syn oligomers drives the increase of glutamatergic synaptic transmission, preventing further potentiation by physiological stimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies. PMID:22915117

Diógenes, Maria José; Dias, Raquel B; Rombo, Diogo M; Vicente Miranda, Hugo; Maiolino, Francesca; Guerreiro, Patrícia; Näsström, Thomas; Franquelim, Henri G; Oliveira, Luís M A; Castanho, Miguel A R B; Lannfelt, Lars; Bergström, Joakim; Ingelsson, Martin; Quintas, Alexandre; Sebastião, Ana M; Lopes, Luísa V; Outeiro, Tiago Fleming

2012-08-22

109

"Self" versus "non-self" connectivity dictates properties of synaptic transmission and plasticity.  

PubMed

Autapses are connections between a neuron and itself. These connections are morphologically similar to "normal" synapses between two different neurons, and thus were long thought to have similar properties of synaptic transmission. However, this has not been directly tested. Here, using a micro-island culture assay in which we can define the number of interconnected cells, we directly compared synaptic transmission in excitatory autapses and in two-neuron micronetworks consisting of two excitatory neurons, in which a neuron is connected to one other neuron and to itself. We discovered that autaptic synapses are optimized for maximal transmission, and exhibited enhanced EPSC amplitude, charge, and RRP size compared to interneuronal synapses. However, autapses are deficient in several aspects of synaptic plasticity. Short-term potentiation only became apparent when a neuron was connected to another neuron. This acquisition of plasticity only required reciprocal innervation with one other neuron; micronetworks consisting of just two interconnected neurons exhibited enhanced short-term plasticity in terms of paired pulse ratio (PPR) and release probability (Pr), compared to autapses. Interestingly, when a neuron was connected to another neuron, not only interneuronal synapses, but also the autaptic synapses on itself exhibited a trend toward enhanced short-term plasticity in terms of PPR and Pr. Thus neurons can distinguish whether they are connected via "self" or "non-self" synapses and have the ability to adjust their plasticity parameters when connected to other neurons. PMID:23658626

Liu, Huisheng; Chapman, Edwin R; Dean, Camin

2013-01-01

110

The ALS gene FUS regulates synaptic transmission at the Drosophila neuromuscular junction.  

PubMed

Mutations in the RNA binding protein Fused in sarcoma (FUS) are estimated to account for 5-10% of all inherited cases of amyotrophic lateral sclerosis (ALS), but the function of FUS in motor neurons is poorly understood. Here, we investigate the early functional consequences of overexpressing wild-type or ALS-associated mutant FUS proteins in Drosophila motor neurons, and compare them to phenotypes arising from loss of the Drosophila homolog of FUS, Cabeza (Caz). We find that lethality and locomotor phenotypes correlate with levels of FUS transgene expression, indicating that toxicity in developing motor neurons is largely independent of ALS-linked mutations. At the neuromuscular junction (NMJ), overexpression of either wild-type or mutant FUS results in decreased number of presynaptic active zones and altered postsynaptic glutamate receptor subunit composition, coinciding with a reduction in synaptic transmission as a result of both reduced quantal size and quantal content. Interestingly, expression of human FUS downregulates endogenous Caz levels, demonstrating that FUS autoregulation occurs in motor neurons in vivo. However, loss of Caz from motor neurons increases synaptic transmission as a result of increased quantal size, suggesting that the loss of Caz in animals expressing FUS does not contribute to motor deficits. These data demonstrate that FUS/Caz regulates NMJ development and plays an evolutionarily conserved role in modulating the strength of synaptic transmission in motor neurons. PMID:24569165

Machamer, James B; Collins, Sarah E; Lloyd, Thomas E

2014-07-15

111

Excitatory synaptic transmission and network activity are depressed following mechanical injury in cortical neurons.  

PubMed

In vitro and in vivo traumatic brain injury (TBI) alter the function and expression of glutamate receptors, yet the combined effect of these alterations on cortical excitatory synaptic transmission is unclear. We examined the effect of in vitro mechanical injury on excitatory synaptic function in cultured cortical neurons by assaying synaptically driven intracellular free calcium ([Ca(2+)](i)) oscillations in small neuronal networks as well as spontaneous and miniature excitatory postsynaptic currents (mEPSCs). We show that injury decreased the incidence and frequency of spontaneous neuronal [Ca(2+)](i) oscillations for at least 2 days post-injury. The amplitude of the oscillations was reduced immediately and 2 days post-injury, although a transient rebound at 4 h post-injury was observed due to increased activity of N-methyl-d-aspartate (NMDARs) and calcium-permeable ?-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (CP-AMPARs). Increased CP-AMPAR function was abolished by the inhibition of protein synthesis. In parallel, mEPSC amplitude decreased immediately, 4 h, and 2 days post-injury, with a transient increase in the contribution of synaptic CP-AMPARs observed at 4 h post-injury. Decreased mEPSC amplitude was evident after injury, even if NMDARs and CP-AMPARs were blocked pharmacologically, suggesting the decrease reflected alterations in synaptic Glur2-containing, calcium-impermeable AMPARs. Despite the transient increase in CP-AMPAR activity that we observed, the overriding effect of mechanical injury was long-term depression of excitatory neurotransmission that would be expected to contribute to the cognitive deficits of TBI. PMID:21346214

Goforth, Paulette B; Ren, Jianhua; Schwartz, Benjamin S; Satin, Leslie S

2011-05-01

112

Developmental Exposure to Perchlorate Alters Synaptic Transmission in Hippocampus of the Adult Rat  

PubMed Central

Background Perchlorate is an environmental contaminant that blocks iodine uptake into the thyroid gland and reduces thyroid hormones. This action of perchlorate raises significant concern over its effects on brain development. Objectives The purpose of this study was to evaluate neurologic function in rats after developmental exposure to perchlorate. Methods Pregnant rats were exposed to 0, 30, 300, or 1,000 ppm perchlorate in drinking water from gestational day 6 until weaning. Adult male offspring were evaluated on a series of behavioral tasks and neurophysiologic measures of synaptic function in the hippocampus. Results At the highest perchlorate dose, triiodothyronine (T3) and thyroxine (T4) were reduced in pups on postnatal day 21. T4 in dams was reduced relative to controls by 16%, 28%, and 60% in the 30-, 300-, and 1,000-ppm dose groups, respectively. Reductions in T4 were associated with increases in thyroid-stimulating hormone in the high-dose group. No changes were seen in serum T3. Perchlorate did not impair motor activity, spatial learning, or fear conditioning. However, significant reductions in baseline synaptic transmission were observed in hippocampal field potentials at all dose levels. Reductions in inhibitory function were evident at 300 and 1,000 ppm, and augmentations in long-term potentiation were observed in the population spike measure at the highest dose. Conclusions Dose-dependent deficits in hippocampal synaptic function were detectable with relatively minor perturbations of the thyroid axis, indicative of an irreversible impairment in synaptic transmission in response to developmental exposure to perchlorate.

Gilbert, Mary E.; Sui, Li

2008-01-01

113

Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures.  

PubMed

Nitrous oxide (N2O; laughing gas) has been a widely used anesthetic/analgesic since the 19th century, although its cellular mechanism of action is not understood. Here we characterize the effects of N2O on excitatory and inhibitory synaptic transmission in microcultures of rat hippocampal neurons, a preparation in which anesthetic effects on monosynaptic communication can be examined in a setting free of polysynaptic network variables. Eighty percent N2O occludes peak NMDA receptor-mediated (NMDAR) excitatory autaptic currents (EACs) with no effect on the NMDAR EAC decay time course. N2O also mildly depresses AMPA receptor-mediated (AMPAR) EACs. We find that N2O inhibits both NMDA and non-NMDA receptor-mediated responses to exogenous agonist. The postsynaptic blockade of NMDA receptors exhibits slight apparent voltage dependence, whereas the blockade of AMPA receptors is not voltage dependent. Although the degree of ketamine and Mg2+ blockade of NMDA-induced responses is dependent on permeant ion concentration, the degree of N2O blockade is not. We also observe a slight and variable prolongation of GABAA receptor-mediated (GABAR) postsynaptic currents likely caused by previously reported effects of N2O on GABAA receptors. Despite the effects of N2O on both NMDA and non-NMDA ionotropic receptors, glial glutamate transporter currents and metabotropic glutamate receptor-mediated synaptic depression are not affected. Paired-pulse depression, the frequency of spontaneous miniature excitatory synaptic currents, and high-voltage-activated calcium currents are not affected by N2O. Our results suggest that the effects of N2O on synaptic transmission are confined to postsynaptic targets. PMID:9822732

Mennerick, S; Jevtovic-Todorovic, V; Todorovic, S M; Shen, W; Olney, J W; Zorumski, C F

1998-12-01

114

Endocannabinoids mediate the glucocorticoid-induced inhibition of excitatory synaptic transmission to dorsal raphe serotonin neurons  

PubMed Central

Glucocorticoids play a critical role in the modulation of stress responses by controlling the function of the serotonin (5-HT) system. However, the precise effects of glucocorticoids on the excitability of dorsal raphe (DR) 5-HT neurons remain unknown. In this study, we investigated the effects of glucocorticoids on excitatory synaptic transmission to putative DR 5-HT neurons. We found that corticosterone or the synthetic glucocorticoid agonist dexamethasone rapidly suppressed glutamatergic synaptic transmission to DR 5-HT neurons by inhibiting glutamate release in the DR. This inhibitory effect was mimicked by membrane-impermeable glucocorticoids, indicating the involvement of membrane-located corticosteroid receptors. The glucocorticoid-induced inhibition of glutamatergic transmission was mediated by the activation of postsynaptic G-protein-coupled receptors and signalled by retrograde endocannabinoid (eCB) messengers. Examination of the downstream mechanisms revealed that glucocorticoids enhance eCB signalling via an inhibition of cyclooxygenase-2. Together, these findings unravel a novel mechanism by which glucocorticoids control the excitability of DR 5-HT neurons and provide new insight into the rapid effects of stress hormones on the function of the 5-HT system.

Wang, Jue; Shen, Roh-Yu; Haj-Dahmane, Samir

2012-01-01

115

Modulation of Hippocampal Synaptic Transmission by the Kynurenine Pathway Member Xanthurenic Acid and Other VGLUT Inhibitors  

PubMed Central

Xanthurenic acid (XA), an endogenous kynurenine, is a known vesicular glutamate transport (VGLUT) inhibitor and has also been proposed as an mGlu2/3 receptor agonist. Changes in these systems have been implicated in the pathophysiology of schizophrenia and other psychiatric disorders; however, little is known of how XA affects synaptic transmission. We therefore investigated the effects of XA on synaptic transmission at two hippocampal glutamatergic pathways and evaluated the ability of XA to bind to mGlu2/3 receptors. Field excitatory postsynaptic potentials (fEPSPs) were recorded from either the dentate gyrus (DG) or CA1 region of mouse hippocampal slices in vitro. Addition of XA to the bathing medium (1–10?mM) resulted in a dose-related reduction of fEPSP amplitudes (up to 52% reduction) in both hippocampal regions. In the DG, the VGLUT inhibitors Congo Red and Rose Bengal, and the mGlu2/3 agonist LY354740, also reduced fEPSPs (up to 80% reduction). The mGlu2/3 antagonist LY341495 reversed the LY354740 effect, but not the XA effect. LY354740, but not XA, also reduced DG paired-pulse depression. XA had no effect on specific binding of 1?nM [3H]LY341495 to membranes with human mGlu2 receptors. We conclude that XA can modulate synaptic transmission via a mechanism that may involve VGLUT inhibition rather than activation of mGlu2/3 receptors. This could be important in the pathophysiology of nervous system disorders including schizophrenia and might represent a target for developing novel pharmacological therapies.

Neale, S A; Copeland, C S; Uebele, V N; Thomson, F J; Salt, T E

2013-01-01

116

Impaired Photoreceptor Protein Transport and Synaptic Transmission in a Mouse Model of Bardet-Biedl Syndrome  

PubMed Central

Bardet-Biedl Syndrome (BBS) is an oligogenic syndrome whose manifestations include retinal degeneration, renal abnormalities, obesity and polydactylia. Evidence suggests that the main etiopathophysiology of this syndrome is impaired Intraflagellar Transport (IFT). In this study, we study the Bbs4-null mouse and investigate photoreceptor structure and function after loss of this gene. We find that Bbs4-null mice have defects in the transport of phototransduction proteins from the inner segments to the outer segments, before signs of cell death. Additionally, we show defects in synaptic transmission from the photoreceptors to secondary neurons of the visual system, demonstrating multiple functions for BBS4 in photoreceptors.

Abd-El-Barr, Muhammad M.; Sykoudis, Kristen; Andrabi, Sara; Eichers, Erica R.; Pennesi, Mark E.; Tan, Perciliz L.; Wilson, John H.; Katsanis, Nicholas; Lupski, James R.; Wu, Samuel M.

2009-01-01

117

Enhancement of synaptic transmission induced by BDNF in cultured cortical neurons  

NASA Astrophysics Data System (ADS)

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, BDNF has been reported to exert an acute potentiation of synaptic activity and are critically involved in long-term potentiation (LTP). We found that BDNF rapidly induced potentiation of synaptic activity and an increase in the intracellular Ca2+ concentration in cultured cortical neurons. Within minutes of BDNF application to cultured cortical neurons, spontaneous firing rate was dramatically increased as were the frequency and amplitude of excitatory spontaneous postsynaptic currents (EPSCs). Fura-2 recordings showed that BDNF acutely elicited an increase in intracellular calcium concentration ([Ca2+]c). This effect was partially dependent on [Ca2+]o; The BDNF-induced increase in [Ca2+]c can not be completely blocked by Ca2+-free solution. It was completely blocked by K252a and partially blocked by Cd2+ and TTX. The results demonstrate that BDNF can enhances synaptic transmission and that this effect is accompanied by a rise in [Ca2+]c that requires two route: the release of Ca2+ from intracellular calcium stores and influx of extracellular Ca2+ through voltage-dependent Ca2+ channels in cultured cortical neurons.

He, Jun; Gong, Hui; Zeng, Shaoqun; Li, Yanling; Luo, Qingming

2005-03-01

118

Cytoskeletal Changes Underlie Estrogen's Acute Effects on Synaptic Transmission and Plasticity  

PubMed Central

Estrogen, in addition to its genomic effects in brain, causes rapid and reversible changes to synaptic operations. We report here that these acute actions are due to selective activation of an actin-signaling cascade normally used in the production of long-term potentiation (LTP). Estrogen, or a selective agonist of the steroid’s beta-receptor, caused a modest increase in fast glutamatergic transmission and a pronounced facilitation of LTP in adult hippocampal slices; both effects were completely eliminated by latrunculin, a toxin that prevents actin filament assembly. Estrogen also increased spine concentrations of filamentous actin and strongly enhanced its polymerization in association with LTP. A search for the origins of these effects showed that estrogen activates the small GTPase RhoA and phosphorylates (inactivates) the actin severing protein cofilin, a downstream target of RhoA. Moreover, an antagonist of RhoA kinase (ROCK) blocked estrogen’s synaptic effects. Estrogen thus emerges as a positive modulator of a RhoA>ROCK>LIM kinase>cofilin pathway that regulates the sub-synaptic cytoskeleton. It does not, however, strongly affect a second LTP-related pathway, involving the GTPases Rac and Cdc42 and their effector p21-activated kinase, which may explain why its acute effects are reversible. Finally, ovariectomy depressed RhoA activity, spine cytoskeletal plasticity, and LTP whereas brief infusions of estrogen rescued plasticity, suggesting that the deficits in plasticity arise from acute, as well as genomic, consequences of hormone loss.

Kramar, Eniko A.; Chen, Lulu Y.; Brandon, Nicholas J.; Christopher, S. Rex; Liu, Feng; Gall, Christine M.; Lynch, Gary

2009-01-01

119

miR-153 Regulates SNAP-25, Synaptic Transmission, and Neuronal Development  

PubMed Central

SNAP-25 is a core component of the trimeric SNARE complex mediating vesicle exocytosis during membrane addition for neuronal growth, neuropeptide/growth factor secretion, and neurotransmitter release during synaptic transmission. Here, we report a novel microRNA mechanism of SNAP-25 regulation controlling motor neuron development, neurosecretion, synaptic activity, and movement in zebrafish. Loss of miR-153 causes overexpression of SNAP-25 and consequent hyperactive movement in early zebrafish embryos. Conversely, overexpression of miR-153 causes SNAP-25 down regulation resulting in near complete paralysis, mimicking the effects of treatment with Botulinum neurotoxin. miR-153-dependent changes in synaptic activity at the neuromuscular junction are consistent with the observed movement defects. Underlying the movement defects, perturbation of miR-153 function causes dramatic developmental changes in motor neuron patterning and branching. Together, our results indicate that precise control of SNAP-25 expression by miR-153 is critically important for proper neuronal patterning as well as neurotransmission.

Olena, Abigail F.; Cha, Diana J.; Perdigoto, Ana L.; Marshall, Andrew F.; Carter, Bruce D.; Broadie, Kendal; Patton, James G.

2013-01-01

120

Roles of N-Type and Q-Type Ca2+ Channels in Supporting Hippocampal Synaptic Transmission  

NASA Astrophysics Data System (ADS)

Several types of calcium channels found in the central nervous system are possible participants in triggering neurotransmitter release. Synaptic transmission between hippocampal CA3 and CA1 neurons was mediated by N-type calcium channels, together with calcium channels whose pharmacology differs from that of L- and P-type channels but resembles that of the Q-type channel encoded by the ?1A subunit gene. Blockade of either population of channels strongly increased enhancement of synaptic transmission with repetitive stimuli. Even after complete blockade of N-type channels, transmission was strongly modulated by stimulation of neurotransmitter receptors or protein kinase C. These findings suggest a role for ?1A subunits in synaptic transmission and support the idea that neurotransmitter release may depend on multiple types of calcium channels under physiological conditions.

Wheeler, David B.; Randall, Andrew; Tsien, Richard W.

1994-04-01

121

D9Tetrahydrocannabinol Acts as a Partial Agonist to Modulate Glutamatergic Synaptic Transmission between Rat Hippocampal Neurons in Culture  

Microsoft Academic Search

D9-Tetrahydrocannabinol (D9-THC) is the principal psychoac- tive ingredient in marijuana. We examined the effects of D9- THC on glutamatergic synaptic transmission. Reducing the extracellular Mg11 concentration bathing rat hippocampal neu- rons in culture to 0.1 mM elicited a repetitive pattern of gluta- matergic synaptic activity that produced intracellular Ca11 concentration spikes that were measured by indo-1-based mi- crofluorimetry. D9-THC produced

MAOXING SHEN; STANLEY A. THAYER

122

A genetic screen for synaptic transmission mutants mapping to the right arm of chromosome 3 in Drosophila.  

PubMed Central

Neuronal function depends upon the proper formation of synaptic connections and rapid communication at these sites, primarily through the regulated exocytosis of chemical neurotransmitters. Recent biochemical and genomic studies have identified a large number of candidate molecules that may function in these processes. To complement these studies, we are pursuing a genetic approach to identify genes affecting synaptic transmission in the Drosophila visual system. Our screening approach involves a recently described genetic method allowing efficient production of mosaic flies whose eyes are entirely homozygous for a mutagenized chromosome arm. From a screen of 42,500 mutagenized flies, 32 mutations on chromosome 3R that confer synaptic transmission defects in the visual system were recovered. These mutations represent 14 complementation groups, of which at least 9 also appear to perform functional roles outside of the eye. Three of these complementation groups disrupt photoreceptor axonal projection, whereas the remaining complementation groups confer presynaptic defects in synaptic transmission without detectably altering photoreceptor structure. Mapping and complementation testing with candidate mutations revealed new alleles of the neuronal fate determinant svp and the synaptic vesicle trafficking component lap among the collection of mutants recovered in this screen. Given the tools available for investigation of synaptic function in Drosophila, these mutants represent a valuable resource for future analysis of synapse development and function.

Babcock, Michael C; Stowers, R Steven; Leither, Jennifer; Goodman, Corey S; Pallanck, Leo J

2003-01-01

123

Presynaptic alpha-7 nicotinic acetylcholine receptors modulate excitatory synaptic transmission in hippocampal neurons.  

PubMed

The effects of presynaptic nicotinic acetylcholine receptors (nAChRs) on excitatory synaptic transmission in CA1 pyramidal neurons of the rat hippocampus were examined by blind whole-cell patch clamp recording from hippocampal slice preparations. Local application of the nAChRs agonist dimethylphenyl-piperazinium iodide (DMPP) did not induce a postsynaptic current response in CA1 pyramidal cells. However, DMPP enhanced the frequency and amplitude of spontaneous excitatory postsynaptic current (sEPSC) in these cells in a dose-dependent manner. This enhancement was blocked by the selective nicotinic alpha-7 receptor antagonist alpha-bungarotoxin, but not by the antagonist mecamylamine, hexamethonium or dihydro-beta-erythroidine. The frequency of miniature excitatory postsynaptic current (mEPSC) in CA1 pyramidal neurons was also increased by application of DMPP, indicating a presynaptic site of action of the agonist. Taken together, these results suggest that activation of presynaptic nAChRs in CA1 pyramidal neurons, which contain alpha-7 subunits, potentiates presynaptic glutamate release and consequently modulate excitatory synaptic transmission in the hippocampus. PMID:14695493

Liu, Zhen-Wei; Yang, Sheng; Zhang, Yong-Xiang; Liu, Chuan-Hui

2003-12-25

124

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice  

PubMed Central

Itch, also known as pruritus, is a common, intractable symptom of several skin diseases, such as atopic dermatitis and xerosis. TLRs mediate innate immunity and regulate neuropathic pain, but their roles in pruritus are elusive. Here, we report that scratching behaviors induced by histamine-dependent and -independent pruritogens are markedly reduced in mice lacking the Tlr3 gene. TLR3 is expressed mainly by small-sized primary sensory neurons in dorsal root ganglions (DRGs) that coexpress the itch signaling pathway components transient receptor potential subtype V1 and gastrin-releasing peptide. Notably, we found that treatment with a TLR3 agonist induces inward currents and action potentials in DRG neurons and elicited scratching in WT mice but not Tlr3–/– mice. Furthermore, excitatory synaptic transmission in spinal cord slices and long-term potentiation in the intact spinal cord were impaired in Tlr3–/– mice but not Tlr7–/– mice. Consequently, central sensitization–driven pain hypersensitivity, but not acute pain, was impaired in Tlr3–/– mice. In addition, TLR3 knockdown in DRGs also attenuated pruritus in WT mice. Finally, chronic itch in a dry skin condition was substantially reduced in Tlr3–/– mice. Our findings demonstrate a critical role of TLR3 in regulating sensory neuronal excitability, spinal cord synaptic transmission, and central sensitization. TLR3 may serve as a new target for developing anti-itch treatment.

Liu, Tong; Berta, Temugin; Xu, Zhen-Zhong; Park, Chul-Kyu; Zhang, Ling; Lu, Ning; Liu, Qin; Liu, Yang; Gao, Yong-Jing; Liu, Yen-Chin; Ma, Qiufu; Dong, Xinzhong; Ji, Ru-Rong

2012-01-01

125

Toluene decreases Purkinje cell output by enhancing inhibitory synaptic transmission in the cerebellar cortex.  

PubMed

Toluene belongs to a class of psychoactive drugs known as inhalants. Found in common household products such as adhesives, paint products, and aerosols, toluene is inhaled for its intoxicating and euphoric properties. Additionally, exposure to toluene disrupts motor behaviors in a manner consistent with impairments to cerebellar function. Previous work has suggested a role of GABA in mediating toluene's neurobehavioral effects, but how this manifests in the cerebellar cortex is not yet understood. In the present study, we examined the effects of toluene on cerebellar Purkinje cell action potential output and inhibitory synaptic transmission onto Purkinje cells using patch clamp electrophysiology in acute rat cerebellar slices. Toluene (1mM) reduced the frequency of Purkinje cell action potential output without affecting input resistance. Furthermore, toluene dose-dependently enhanced inhibitory synaptic transmission onto Purkinje cells, increasing the amplitude and frequency of inhibitory postsynaptic currents; no change in the frequency of action potentials from molecular layer interneurons was noted. The observed decreases in Purkinje cell action potential output could contribute to toluene-evoked impairments in cerebellar and motor functions. PMID:24345417

Gmaz, Jimmie M; McKay, Bruce E

2014-02-01

126

A possible synaptic configuration underlying coeruleospinal inhibition of visceral nociceptive transmission in the rat.  

PubMed

A synaptic arrangement underlying descending inhibition from the locus coeruleus/subcoeruleus (LC/SC) on visceral nociceptive transmission in the spinal cord was investigated in the anesthetized rat. Extracellular recordings were made from the L(6)-S(2) segmental level using a carbon filament glass microelectrode (4-6 M?). Colorectal distention (CRD) was produced by inflating a balloon inside the descending colon and rectum. All neurons tested responded to both CRD and to cutaneous pinch (a force of 613 g/mm(2)), indicating that nociceptive signals from visceral organs and nociceptive signals from the cutaneous receptive field converge on a single neuron. These neurons were divided into two groups based on their response to CRD: short latency-abrupt and short latency-sustained neurons. Electrical stimulation of the LC/SC (30 or 50 ?A, 100 Hz, 0.1 ms pulses) inhibited both CRD-evoked and cutaneous pinch-evoked responses in short latency-abrupt and short latency-sustained neurons. When graded CRD (20, 40, 60, and 80 mmHg) was delivered, LC/SC stimulation produced a reduction in slope of the linear CRD intensity-response magnitude curve without a change in the response threshold in both short latency-abrupt (n = 42) and short latency-sustained neurons (n = 11). This result suggests that coeruleospinal inhibition of visceral nociceptive transmission is due to a synaptic configuration in which inhibitory and excitatory terminals are in close spatial proximity, including presynaptic inhibition. PMID:21845475

Hayashi, Bunsho; Tsuruoka, Masayoshi; Maeda, Masako; Tamaki, Junichiro; Inoue, Tomio

2012-04-01

127

Synchronous and asynchronous modes of synaptic transmission utilize different calcium sources  

PubMed Central

Asynchronous transmission plays a prominent role at certain synapses but lacks the mechanistic insights of its synchronous counterpart. The current view posits that triggering of asynchronous release during repetitive stimulation involves expansion of the same calcium domains underlying synchronous transmission. In this study, live imaging and paired patch clamp recording at the zebrafish neuromuscular synapse reveal contributions by spatially distinct calcium sources. Synchronous release is tied to calcium entry into synaptic boutons via P/Q type calcium channels, whereas asynchronous release is boosted by a propagating intracellular calcium source initiated at off-synaptic locations in the axon and axonal branch points. This secondary calcium source fully accounts for the persistence following termination of the stimulus and sensitivity to slow calcium buffers reported for asynchronous release. The neuromuscular junction and CNS neurons share these features, raising the possibility that secondary calcium sources are common among synapses with prominent asynchronous release. DOI: http://dx.doi.org/10.7554/eLife.01206.001

Wen, Hua; Hubbard, Jeffrey M; Rakela, Benjamin; Linhoff, Michael W; Mandel, Gail; Brehm, Paul

2013-01-01

128

Estradiol acutely potentiates hippocampal excitatory synaptic transmission through a presynaptic mechanism  

PubMed Central

While recent evidence suggests that the hippocampus is a source of 17?-estradiol (E2), the physiological role of this neurosteroid E2, as distinct from ovarian E2, is unknown. One likely function of neurosteroid E2 is to acutely potentiate excitatory synaptic transmission, but the mechanism of this effect is not well understood. Using whole-cell voltage-clamp recording of synaptically evoked EPSCs in adult rat hippocampal slices, we show that, in contrast to the conclusions of earlier studies, E2 potentiates excitatory transmission through a presynaptic mechanism. We find that E2 acutely potentiates EPSCs by increasing the probability of glutamate release specifically at inputs with low initial release probability. This effect is mediated by estrogen receptor (ER)? acting as a monomer, whereas ER? is not required. We further show that the E2-induced increase in glutamate release is due primarily to increased individual vesicle release probability and is associated with higher average cleft glutamate concentration. These two findings together argue strongly that E2 promotes multivesicular release, which has not been shown before in the adult hippocampus. The rapid time course of acute EPSC potentiation and its concentration dependence suggest that locally-synthesized neurosteroid E2 may activate this effect in vivo.

Smejkalova, Tereza; Woolley, Catherine S.

2010-01-01

129

HCN channel activity-dependent modulation of inhibitory synaptic transmission in the rat basolateral amygdala.  

PubMed

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed in the central nervous system and play a regulatory role in neuronal excitability. In the present study, we examined a physiological role of HCN channels in the rat basolateral amygdala (BLA). In vitro electrophysiological studies showed that ZD7288 decreased spontaneous inhibitory postsynaptic current (sIPSC) without changing miniature IPSC (mIPSC). HCN channel blockade also attenuated feedback inhibitions in BLA principal neurons. However, blockade of HCN channel had little effects on spontaneous excitatory postsynaptic current (sEPSC) and mEPSC. Therefore, HCN channel appeared to decrease BLA excitability by increasing the action potential-dependent inhibitory control over the BLA principal neurons. Anxiety is reported to be influenced by neuronal excitability in the BLA and inhibitory synaptic transmission is thought to play a pivotal role in regulating overall excitability of the amygdala. As expected, blockade of HCN channels by targeted injection of ZD7288 to the BLA increased anxiety-like behavior under elevated plus maze test. Our results suggest that HCN channel activity can modulate the GABAergic synaptic transmission in the BLA, which in turn control the amygdala-related emotional behaviors such as anxiety. PMID:21185265

Park, Kyungjoon; Yi, Jee Hyun; Kim, Hyejin; Choi, Kyuhyun; Kang, Shin Jung; Shin, Ki Soon

2011-01-28

130

Ca-channel blockers and the electrophysiology of synaptic transmission of the guinea-pig olfactory cortex.  

PubMed

Slices of guinea-pig olfactory cortex have been used to compare the potency of various Ca-blockers on the electrophysiology of synaptic transmission. Listed in the order of potency, the divalent cations Cd2+, Ni2+, Mn2+, Co2+, La3+ and Mg2+ depressed synaptic transmission. The organic Ca-blockers, nifedipine or nimodipine or verapamil and diltiazem were ineffective up to 0.01 mmol/l. Verapamil, D600 or diltiazem (0.1-0.3 mmol/l) depressed both synaptic transmission and the sodium-mediated presynaptic action potential. These results reaffirm the idea that 'organic Ca-antagonist' do not block all Ca-channels in brain and the high Cd2+ sensitivity suggests the Ca-channels in post- and presynaptic membranes have dissimilar pharmacological profiles. PMID:3025004

Kuan, Y F; Scholfield, C N

1986-11-01

131

Emerging Pharmacological Properties of Cholinergic Synaptic Transmission: Comparison between Mammalian and Insect Synaptic and Extrasynaptic Nicotinic Receptors  

PubMed Central

Acetylcholine (ACh) is probably the oldest signalling neurotransmitter which appeared in evolution before the nervous system. It is present in bacteria, algae, protozoa and plants. In insects and mammals it is involved in cell-to-cell communications in various neuronal and non-neuronal tissues. The discovery of nicotinic acetylcholine receptors (nAChRs) as the main receptors involved in rapid cholinergic neurotransmission has helped to understand the role of ACh at synaptic level. Recently, several lines of evidence have indicated that extrasynaptically expressed nAChRs display distinct pharmacological properties from the ones expressed at synaptic level. The role of both nAChRs at insect extrasynaptic and/or synaptic levels has been underestimated due to the lack of pharmacological tools to identify different nicotinic receptor subtypes. In the present review, we summarize recent electrophysiological and pharmacological studies on the extrasynaptic and synaptic differences between insect and mammalian nAChR subtypes and we discuss on the pharmacological impact of several drugs such as neonicotinoid insecticides targeting these receptors. In fact, nAChRs are involved in a wide range of pathophysiological processes such as epilepsy, pain and a wide range of neurodegenerative and psychiatric disorders. In addition, they are the target sites of neonicotinoid insecticides which are known to act as nicotinic agonists causing severe poisoning in insects and mammals.

Thany, Steeve H; Tricoire-Leignel, Helene

2011-01-01

132

ben Functions with Scamp during Synaptic Transmission and Long-Term Memory Formation in Drosophila  

PubMed Central

Genetic screens for Drosophila mutants defective in pavlovian olfactory memory have provided unique insight into the molecular basis of memory storage. Occasionally, these singular genetic lesions have been assembled into meaningful molecular pathways and neural circuitries. For the most part, however, these genes and their expression patterns in the CNS remain fragmented, demanding new clues from continued mutant screens. From a behavioral screen for long-term memory (LTM) mutants, we have identified ben (CG32594), which encodes a novel protein. Mutations of ben specifically disrupt LTM, leaving earlier memory phases intact. The role of ben appears physiological rather than developmental, because acutely induced expression of a ben+ transgene in adults rescues the mutant’s LTM defect. More interestingly, induced expression of ben+ specifically in mushroom bodies (MBs), but not in the ellipsoid body of the central complex, is sufficient to rescue the mutant LTM defect. This suggests a role for ben in the MB during olfactory memory formation. We also provide evidence that BEN interacts genetically in both synaptic transmission and LTM formation with SCAMP, a synaptic protein known to be involved in vesicle recycling.

Zhao, Hong; Zheng, Xingguo; Yuan, Xiaojing; Wang, Lei; Wang, Xin; Zhong, Yi; Xie, Zuoping; Tully, Tim

2011-01-01

133

[Major mechanisms involved in the synaptic transmission of the neuromuscular apparatus].  

PubMed

Neuromuscular transmission results from a double signal transduction from electric impulses to chemical messengers, taking place at a highly differentiated region, the neuromuscular junction (NMJ). A nerve cell responds to a specific stimulus by modifications of its plasmic membrane properties, generating an action potential (AP). This electric signal is transmitted along the axon to the NMJ, where it induces the voltage-gated calcium channels to open. Intracellular calcium entry leads to acetylcholine release in the synaptic space at the active zones but all scientists do not consider it the major release factor. Acetylcholine binding with its receptor at the muscle membrane generates an endplate potential when the induced depolarization is greater than the sodium voltage channel opening threshold. Muscle AP causes a muscle contraction involving the three phases. This paper will successively review the electrophysiological and molecular mechanisms involved at the pre-, inter- and postsynaptic levels. The last part of the article will discuss electromechanical considerations directly affecting the mechanical properties of the muscle fiber, most particularly the factors influencing the predetermined involvement of motor units, motor neuron electrical properties determining responses to synaptic inputs and finally the impact of recruited motor neurons and their electrical impulse rates on muscle contraction strength and velocity. PMID:19230941

Rigoard, S; Wager, M; Buffenoir, K; Bauche, S; Giot, J-P; Maixent, J-M; Rigoard, P

2009-03-01

134

A 'long-term-potentiation-like' facilitation of hippocampal synaptic transmission induced by the nootropic nefiracetam.  

PubMed

Nefiracetam, a nootropic agent, enhanced the slope of field excitatory postsynaptic potentials in the CA1 region of rat hippocampal slices to about 170% of basal levels, being evident still at 4-h washing-out of the drug. A similar sustained enhancement (>/=16 h after i.m. injection with nefiracetam) was observed in the population spikes recorded from the granular cell layer of the intact mouse hippocampus. Saturation of the enhancement in the synaptic strength occluded potentiation obtained with long-term potentiation (LTP) induced by high-frequency (tetanic) stimulation, and vice versa. Interestingly, the facilitatory action of nefiracetam was blocked by either the nicotinic acetylcholine (ACh) receptor antagonists, alpha-bungarotoxin and mecamylamine, or the selective protein kinase C (PKC) inhibitor, GF109203X, but in contrast, it was not affected by D-2-amino-5-phosphonovaleric acid (APV), a selective N-methyl-D-aspartate (NMDA) receptor antagonist. The results of the present study suggest that nefiracetam, whereas the action is independent of NMDA receptors, induces an 'LTP-like' facilitation of hippocampal synaptic transmission as a consequence of modulation of nicotinic ACh receptors and PKC. This may represent a likely mechanism underlying the cognition-enhancing actions of nefiracetam. PMID:10224305

Nishizaki, T; Matsuoka, T; Nomura, T; Matsuyama, S; Watabe, S; Shiotani, T; Yoshii, M

1999-05-01

135

Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.  

PubMed Central

1. The effects of excitatory amino acids and some antagonists applied by ionophoresis to stratum radiatum in the CA1 region of rat hippocampal slices were examined on the locally recorded field e.p.s.p. evoked by stimulation of the Schaffer collateral-commissural projection. 2. L-glutamate, L-aspartate and the more potent and selective excitatory amino acids quisqualate, kainate and N-methyl-DL-aspartate (NMA) depressed the e.p.s.p., presumably through depolarization and/or a change in membrane conductance. 3. The depression induced by kainate considerably outlasted the period of ejection whereas NMA depressions were rapidly reversible and were often followed by a potentiation of the e.p.s.p. In higher doses NMA also depressed the presynaptic fibre volley. The possible involvement of these effects in neurotoxicity and synaptic plasticity is raised. 4. The selective NMA antagonist, DL-2-amino-5-phosphonovalerate (APV) applied in doses which abolished responses to NMA, had no effect on the e.p.s.p. but prevented long term potentiation (l.t.p.) of synaptic transmission evoked by high frequency stimulation of the Schaffer collateral-commissural pathway. Other antagonists which had little or no effect on normal synaptic transmission included D-alpha-aminoadipate (DAA), the optical isomers of 2-amino-4-phosphonobutyrate (APB) and L-glutamate diethylester (GDEE). 5. In contrast, gamma-D-glutamylglycine (DGG), applied in amounts which affected quisqualate and kainate actions as well as those of NMA, was an effective synaptic antagonist whilst having no effect on the presynaptic fibre volley. 6. These results indicate that the synaptic receptor in the Schaffer collateral-commissural pathway may be of the kainate or quisqualate type. Although NMA receptors do not appear to be involved in normal synaptic transmission in this pathway they may play a role in synaptic plasticity. The interaction of L-glutamate and L-aspartate with these receptors is discussed.

Collingridge, G L; Kehl, S J; McLennan, H

1983-01-01

136

Direct synaptic connections between superior colliculus afferents and thalamo-insular projection neurons in the feline suprageniculate nucleus: a double-labeling study with WGA-HRP and kainic acid.  

PubMed

The suprageniculate nucleus (Sg) of the feline thalamus, which subserves largely unimodal sensory and orientation behavior, receives input from the deep layers of the superior colliculus (SC), and projects to the suprasylvian cortical areas, such as the anterior ectosylvian visual area and the insular visual area (IVA), which contain visually responsive neurons. Through a double tract-tracing procedure involving the injection of wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP) into the IVA and the injection of kainic acid into the SC, this study sought to determine the nature of the synaptic relationship between the SC afferents and the thalamo-cortical projection neurons. WGA-HRP injections labeled numerous neurons in the Sg, while kainic acid injections destroyed many tectothalamic terminals in the Sg. The distributions of the WGA-HRP-labeled neurons and the degenerated axon terminals overlapped in the dorsal part of the Sg. Electron microscopic observations demonstrated that the degenerated axon terminals made synaptic contacts with the dendrites of the WGA-HRP-labeled neurons in this overlapping region of the Sg. These results provide the first anatomical evidence that the Sg may play a role in the key relay of visual information from the SC to the IVA, within an identified extrageniculo-cortical pathway. PMID:19755134

Hoshino, Kaeko; Horie, Masao; Nagy, Attila; Berényi, Antal; Benedek, György; Norita, Masao

2010-01-01

137

Energy demand of synaptic transmission at the hippocampal Schaffer-collateral synapse  

PubMed Central

Neuroenergetic models of synaptic transmission predicted that energy demand is highest for action potentials (APs) and postsynaptic ion fluxes, whereas the presynaptic contribution is rather small. Here, we addressed the question of energy consumption at Schaffer-collateral synapses. We monitored stimulus-induced changes in extracellular potassium, sodium, and calcium concentration while recording partial oxygen pressure (pO2) and NAD(P)H fluorescence. Blockade of postsynaptic receptors reduced ion fluxes as well as pO2 and NAD(P)H transients by ?50%. Additional blockade of transmitter release further reduced Na+, K+, and pO2 transients by ?30% without altering presynaptic APs, indicating considerable contribution of Ca2+-removal, transmitter and vesicle turnover to energy consumption.

Liotta, Agustin; Rosner, Jorg; Huchzermeyer, Christine; Wojtowicz, Anna; Kann, Oliver; Schmitz, Dietmar; Heinemann, Uwe; Kovacs, Richard

2012-01-01

138

Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission  

NASA Astrophysics Data System (ADS)

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 ?3-containing GABAA receptors into synapses with no discernible effect on resident ?1-containing receptors. Since mROS promotes the emergence of postsynaptic events with unique kinetic properties, we conclude that newly recruited ?3-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.

Accardi, Michael V.; Daniels, Bryan A.; Brown, Patricia M. G. E.; Fritschy, Jean-Marc; Tyagarajan, Shiva K.; Bowie, Derek

2014-01-01

139

Enhancement of synaptic transmission by HPC-1 antibody in the cultured hippocampal neuron.  

PubMed

To clarify the function of HPC-1/syntaxin 1A in the mammalian central synapse, the effects of intracellularly applied antibody on the synaptic transmission were examined at the autapse of the cultured rat hippocampal neuron. Intracellularly applied antibody against HPC-1/syntaxin 1A (IgG, 0.3 mg ml(-1)) during whole-cell recording enhanced the autaptic excitatory postsynaptic current (EPSC). Pre-immune IgG (0.3 mg ml(-1)) showed no effect. The amplitude-distribution of an asynchronous EPSC was not affected by administration of this antibody, indicating that the increase in the amplitude of the evoked EPSC was attributable to an increase in transmitter release from the presynaptic terminal HPC-1/syntaxin 1A could be involved in suppressing as well as facilitating process of the exocytosis at the mammalian central synapse. PMID:9427341

Yamaguchi, K; Takada, M; Fujimori, K; Tsuchimoto, Y; Kushima, Y; Sanada, M; Fujiwara, T; Akagawa, K

1997-11-10

140

Propagation of epileptiform activity can be independent of synaptic transmission, gap junctions, or diffusion and is consistent with electrical field transmission.  

PubMed

The propagation of activity in neural tissue is generally associated with synaptic transmission, but epileptiform activity in the hippocampus can propagate with or without synaptic transmission at a speed of ?0.1 m/s. This suggests an underlying common nonsynaptic mechanism for propagation. To study this mechanism, we developed a novel unfolded hippocampus preparation, from CD1 mice of either sex, which preserves the transverse and longitudinal connections and recorded activity with a penetrating microelectrode array. Experiments using synaptic transmission and gap junction blockers indicated that longitudinal propagation is independent of chemical or electrical synaptic transmission. Propagation speeds of 0.1 m/s are not compatible with ionic diffusion or pure axonal conduction. The only other means of communication between neurons is through electric fields. Computer simulations revealed that activity can indeed propagate from cell to cell solely through field effects. These results point to an unexpected propagation mechanism for neural activity in the hippocampus involving endogenous field effect transmission. PMID:24453330

Zhang, Mingming; Ladas, Thomas P; Qiu, Chen; Shivacharan, Rajat S; Gonzalez-Reyes, Luis E; Durand, Dominique M

2014-01-22

141

Neuronal Nogo-A negatively regulates dendritic morphology and synaptic transmission in the cerebellum  

PubMed Central

Neuronal signal integration as well as synaptic transmission and plasticity highly depend on the morphology of dendrites and their spines. Nogo-A is a membrane protein enriched in the adult central nervous system (CNS) myelin, where it restricts the capacity of axons to grow and regenerate after injury. Nogo-A is also expressed by certain neurons, in particular during development, but its physiological function in this cell type is less well understood. We addressed this question in the cerebellum, where Nogo-A is transitorily highly expressed in the Purkinje cells (PCs) during early postnatal development. We used general genetic ablation (KO) as well as selective overexpression of Nogo-A in PCs to analyze its effect on dendritogenesis and on the formation of their main input synapses from parallel (PFs) and climbing fibers (CFs). PC dendritic trees were larger and more complex in Nogo-A KO mice and smaller than in wild-type in Nogo-A overexpressing PCs. Nogo-A KO resulted in premature soma-to-dendrite translocation of CFs and an enlargement of the CF territory in the molecular layer during development. Although spine density was not influenced by Nogo-A, the size of postsynaptic densities of PF–PC synapses was negatively correlated with the Nogo-A expression level. Electrophysiological studies revealed that Nogo-A negatively regulates the strength of synaptic transmission at the PF–PC synapse. Thus, Nogo-A appears as a negative regulator of PC input synapses, which orchestrates cerebellar connectivity through regulation of synapse morphology and the size of the PC dendritic tree.

Petrinovic, Marija M.; Hourez, Raphael; Aloy, Elisabeth M.; Dewarrat, Gregoire; Gall, David; Weinmann, Oliver; Gaudias, Julien; Bachmann, Lukas C.; Schiffmann, Serge N.; Vogt, Kaspar E.; Schwab, Martin E.

2013-01-01

142

Actions of 5-HT1 ligands on excitatory synaptic transmission in the hippocampus of alert rats.  

PubMed Central

1. The effects of 5-hydroxytryptamine1 (5-HT1) ligands on excitatory synaptic transmission were examined in the stratum radiatum of the CA1 region of the dorsal hippocampus of alert, gently restrained, rats. 2. 5-HT produced a dose-dependent reduction in the amplitude of the electrically evoked population excitatory postsynaptic potential (e.p.s.p.) when injected directly into the hippocampus via a cannula (dose producing 50% maximum inhibition, ED50 = 0.46 microgram). 3. Direct intrahippocampal (i.h.) application of buspirone (ED50 = 0.29 microgram), gepirone (1 microgram), ipsapirone (1 microgram), BMY 7378 (0.1 microgram) and 5-carboxamidotryptamine (5-CT, 0.02 microgram) mimicked the inhibitory effect of 5-HT. 4. Systemic injection of buspirone (ED50 = 0.88 mg kg-1, i.p.), BMY 7378 (0.01 mg kg-1, i.p.) and RU 24969 (1 mg kg-1, s.c.) also had an inhibitory effect on the amplitude of the e.p.s.p. 5. Injection of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 2 micrograms) and spiroxatrine (1 microgram) i.h. alone had no effect on the e.p.s.p. amplitude but prevented the inhibitory effect of 5-HT. 6. Systemic injection (i.p.) of methysergide (5 mg kg-1) and spiroxatrine (1 mg kg-1) antagonized the inhibitory effect of buspirone whereas pretreatment with ketanserin (1 mg kg-1), trifluoperazine (1 mg kg-1) and idazoxan (1 mg kg-1) had no effect on the response to buspirone. 7. It is concluded that hippocampal synaptic transmission is highly sensitive to the agonist and antagonist properties of 5-HT1 ligands in the alert rat.

O'Connor, J. J.; Rowan, M. J.; Anwyl, R.

1990-01-01

143

Plasticity of synaptic connections in sensory-motor pathways of the adult locust flight system.  

PubMed

We investigated possible roles of retrograde signals and competitive interactions in the lesion-induced reorganization of synaptic contacts in the locust CNS. Neuronal plasticity is elicited in the adult flight system by removal of afferents from the tegula, a mechanoreceptor organ at the base of the wing. We severed one hindwing organ and studied the resulting rearrangement of synaptic contacts between flight interneurons and afferent neurons from the remaining three tegulae (2 forewing, 1 hindwing). This was done by electric stimulation of afferents and intracellular recording from interneurons (and occasionally motoneurons). Two to three weeks after unilateral tegula lesion, connections between tegula afferents and flight interneurons were altered in the following way. 1) Axons from the forewing tegula on the operated side had established new synaptic contacts with metathoracic elevator interneurons. In addition, the amplitude of compound excitatory postsynaptic potentials elicited by electric stimulation was increased, indicating that a larger number of afferents connected to any given interneuron. 2) On the side contralateral to the lesion, connectivity between axons from the forewing tegula and elevator interneurons was decreased. 3) The efficacy of the (remaining) hindwing afferents appeared to be increased with regard to both synaptic transmission to interneurons and impact on flight motor pattern. 4) Flight motoneurons, which are normally restricted to the ipsilateral hemiganglion, sprouted across the ganglion midline after unilateral tegula removal and apparently established new synaptic contacts with tegula afferents on that side. The changes on the operated side are interpreted as occupation of synaptic space vacated on the interneurons by the severed hindwing afferents. On the contralateral side, the changes in synaptic contact must be elicited by retrograde signals from bilaterally arborizing flight interneurons, because tegula projections remain strictly ipsilateral. The pattern of changes suggests competitive interactions between forewing and hindwing afferents. The present investigation thus presents evidence that the CNS of the mature locust is capable of extensive synaptic rearrangement in response to injury and indicates for the first time the action of retrograde signals from interneurons. PMID:9310419

Wolf, H; Büschges, A

1997-09-01

144

Opposing effects by pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide on hippocampal synaptic transmission  

Microsoft Academic Search

Pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), and their receptors have been localized within the hippocampus but their physiological function on synaptic transmission is still unclear. We investigated the effects of PACAP and VIP on evoked excitatory postsynaptic currents (EPSCs) recorded with patch clamp from CA1 pyramidal neurons in rat hippocampal slices. Bath application of PACAP reversibly reduced

Lucia Ciranna; Sebastiano Cavallaro

2003-01-01

145

Relative contribution of free-virus and synaptic transmission to the spread of HIV-1 through target cell populations  

PubMed Central

Human immunodeficiency virus can spread through target cells by transmission of cell-free virus or directly from cell-to-cell via formation of virological synapses. Although cell-to-cell transmission has been described as much more efficient than cell-free infection, the relative contribution of the two transmission pathways to virus growth during multiple rounds of replication remains poorly defined. Here, we fit a mathematical model to previously published and newly generated in vitro data, and determine that free-virus and synaptic transmission contribute approximately equally to the growth of the virus population.

Komarova, Natalia L.; Anghelina, Daniela; Voznesensky, Igor; Trinite, Benjamin; Levy, David N.; Wodarz, Dominik

2013-01-01

146

Indirect modulation of neuronal excitability and synaptic transmission in the hippocampus by activation of proteinase-activated receptor-2  

PubMed Central

BACKGROUND AND PURPOSE Proteinase-activated receptor-2 (PAR2) is widely expressed in the CNS under normal physiological conditions. However, its potential role in modulating neuronal excitability and synaptic transmission remains to be determined. Here, we have investigated whether PAR2 activation modulates synaptic activity in the hippocampus. EXPERIMENTAL APPROACH PAR2 activation and its effect on the hippocampus were examined in rat primary cultures and acute slices using whole cell patch clamp and standard extracellular recordings, respectively. KEY RESULTS PAR2 activation leads to a depolarization of hippocampal neurones and a paradoxical reduction in the occurrence of synaptically driven spontaneous action potentials (APs). PAR2-induced neuronal depolarization was abolished following either the inhibition of astrocytic function or antagonism of ionotropic glutamate receptors whilst the PAR2-induced decrease in AP frequency was also reduced when astrocytic function was inhibited. Furthermore, when examined in acute hippocampal slices, PAR2 activation induced a profound long-term depression of synaptic transmission that was dependent on NMDA receptor activation and was sensitive to disruption of astrocytic function. CONCLUSIONS AND IMPLICATIONS These novel findings show that PAR2 activation indirectly inhibits hippocampal synaptic activity and indicate that these receptors may play an active role in modulating normal physiological CNS function, in addition to their role in pathophysiological disorders.

Gan, J; Greenwood, SM; Cobb, SR; Bushell, TJ

2011-01-01

147

Chemical synaptic transmission onto superficial stellate cells of the mouse dorsal cochlear nucleus.  

PubMed

The dorsal cochlear nucleus (DCN) is a cerebellum-like auditory brain stem region whose functions include sound localization and multisensory integration. Although previous in vivo studies have shown that glycinergic and GABAergic inhibition regulate the activity of several DCN cell types in response to sensory stimuli, data regarding the synaptic inputs onto DCN inhibitory interneurons remain limited. Using acute DCN slices from mice, we examined the properties of excitatory and inhibitory synapses onto the superficial stellate cell, a poorly understood cell type that provides inhibition to DCN output neurons (fusiform cells) as well as to local inhibitory interneurons (cartwheel cells). Excitatory synapses onto stellate cells activated both NMDA receptors and fast-gating, Ca(2+)-permeable AMPA receptors. Inhibition onto superficial stellate cells was mediated by glycine and GABAA receptors with different temporal kinetics. Paired recordings revealed that superficial stellate cells make reciprocal synapses and autapses, with a connection probability of ? 18-20%. Unexpectedly, superficial stellate cells co-released both glycine and GABA, suggesting that co-transmission may play a role in fine-tuning the duration of inhibitory transmission. PMID:24523517

Apostolides, Pierre F; Trussell, Laurence O

2014-05-01

148

Impairment of synaptic transmission by transient hypoxia in hippocampal slices: Improved recovery in glutathione peroxidase transgenic mice  

PubMed Central

There is increasing evidence that oxygen free radicals contribute to ischemic brain injury. It is unclear, however, to what extent specific antioxidant enzymes can prevent or reverse the impairment of synaptic function caused by transient hypoxia. In this study, we investigated in transgenic (Tg) mice whether a moderate increase in glutathione peroxidase-1 (GPx1) may improve the capacity of CA1 pyramidal cells to recover synaptic transmission after a short period of hypoxia in vitro. In control hippocampal slices, transient hypoxia (7–9 min) produced irreversible loss of excitatory postsynaptic potentials. Complete recovery of synaptic transmission was observed with homozygous Tg-MT-GPx-6 mice after reoxygenation, and, after repeated episodes of hypoxia, synaptic transmission was still viable in most Tg slices, in contrast to non-Tg slices. Moreover, hypoxic episodes abolished the capacity of hippocampal slices to generate long-term potentiation in area CA1 of control mice, whereas a significant extent of long-term potentiation expression was still preserved in Tg tissues. We also demonstrated that susceptibility to N-methyl-d-aspartate-mediated oxidative injury was reduced in Tg hippocampal slices. In conclusion, our results suggest that a moderate GPx increase can be sufficient to prevent irreversible functional damage produced by transient hypoxia in the hippocampus and to help maintain basic electrophysiological mechanisms involved in memory formation.

Furling, Denis; Ghribi, Othman; Lahsaini, Ahmed; Mirault, Marc-Edouard; Massicotte, Guy

2000-01-01

149

Impairment of synaptic transmission by transient hypoxia in hippocampal slices: improved recovery in glutathione peroxidase transgenic mice.  

PubMed

There is increasing evidence that oxygen free radicals contribute to ischemic brain injury. It is unclear, however, to what extent specific antioxidant enzymes can prevent or reverse the impairment of synaptic function caused by transient hypoxia. In this study, we investigated in transgenic (Tg) mice whether a moderate increase in glutathione peroxidase-1 (GPx1) may improve the capacity of CA1 pyramidal cells to recover synaptic transmission after a short period of hypoxia in vitro. In control hippocampal slices, transient hypoxia (7-9 min) produced irreversible loss of excitatory postsynaptic potentials. Complete recovery of synaptic transmission was observed with homozygous Tg-MT-GPx-6 mice after reoxygenation, and, after repeated episodes of hypoxia, synaptic transmission was still viable in most Tg slices, in contrast to non-Tg slices. Moreover, hypoxic episodes abolished the capacity of hippocampal slices to generate long-term potentiation in area CA1 of control mice, whereas a significant extent of long-term potentiation expression was still preserved in Tg tissues. We also demonstrated that susceptibility to N-methyl-d-aspartate-mediated oxidative injury was reduced in Tg hippocampal slices. In conclusion, our results suggest that a moderate GPx increase can be sufficient to prevent irreversible functional damage produced by transient hypoxia in the hippocampus and to help maintain basic electrophysiological mechanisms involved in memory formation. PMID:10759548

Furling, D; Ghribi, O; Lahsaini, A; Mirault, M E; Massicotte, G

2000-04-11

150

Presynaptic actions of propofol enhance inhibitory synaptic transmission in isolated solitary tract nucleus neurons.  

PubMed

General anesthetics variably enhance inhibitory synaptic transmission that relies on (-aminobutyric acid (GABA) and GABAA receptor function with distinct differences across brain regions. Activation of "extra-synaptic" GABAA receptors produces a tonic current considered the most sensitive target for general anesthetics, particularly in forebrain neurons. To evaluate the contribution of poor drug access to neurons in slices, we tested the intravenous anesthetic propofol in mechanically isolated neurons from the solitary tract nucleus (NTS). Setting chloride concentrations to ECl=-29 mV made GABA currents inward at holding potentials of -60 mV. Propofol triggered pronounced but slowly-developing tonic currents that reversed with 5 min washing. Effective concentrations in isolated cells were lower than in slices and propofol enhanced phasic IPSCs more potently than tonic currents (1 microM increased phasic decay-time constant vs. >3 microM tonic currents). Propofol increased IPSC frequency (>3 microM), a presynaptic action. Bicuculline blocked all propofol actions. Gabazine blocked only phasic IPSCs. IPSCs persisted in TTX and/or cadmium but these agents prevented propofol-induced increases in IPSC frequency. Furosemide (>1 mM) reversibly blocked propofol-evoked IPSC frequency changes without altering waveforms. We conclude that presynaptic actions of propofol depend on a depolarizing chloride gradient across presynaptic inhibitory terminals. Our results in isolated neurons indicate that propofol pharmacokinetics intrinsically trigger the tonic currents slowly and the time course is not related to slow permeation or delivery. Unlike forebrain, phasic NTS GABAA receptors are more sensitive to propofol than tonic receptors but that presynaptic GABAA receptor mechanisms regulate GABA release. PMID:19559683

Jin, Young-Ho; Zhang, Zhenxiong; Mendelowitz, David; Andresen, Michael C

2009-08-25

151

Synaptic Transmission from Horizontal Cells to Cones Is Impaired by Loss of Connexin Hemichannels  

PubMed Central

In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina.

Klaassen, Lauw J.; Sun, Ziyi; Steijaert, Marvin N.; Bolte, Petra; Fahrenfort, Iris; Sjoerdsma, Trijntje; Klooster, Jan; Claassen, Yvonne; Shields, Colleen R.; Ten Eikelder, Huub M. M.; Janssen-Bienhold, Ulrike; Zoidl, Georg; McMahon, Douglas G.; Kamermans, Maarten

2011-01-01

152

Vibrodissociation of neurons from rodent brain slices to study synaptic transmission and image presynaptic terminals.  

PubMed

Mechanical dissociation of neurons from the central nervous system has the advantage that presynaptic boutons remain attached to the isolated neuron of interest. This allows for examination of synaptic transmission under conditions where the extracellular and postsynaptic intracellular environments can be well controlled. A vibration-based technique without the use of proteases, known as vibrodissociation, is the most popular technique for mechanical isolation. A micropipette, with the tip fire-polished to the shape of a small ball, is placed into a brain slice made from a P1-P21 rodent. The micropipette is vibrated parallel to the slice surface and lowered through the slice thickness resulting in the liberation of isolated neurons. The isolated neurons are ready for study within a few minutes of vibrodissociation. This technique has advantages over the use of primary neuronal cultures, brain slices and enzymatically isolated neurons including: rapid production of viable, relatively mature neurons suitable for electrophysiological and imaging studies; superior control of the extracellular environment free from the influence of neighboring cells; suitability for well-controlled pharmacological experiments using rapid drug application and total cell superfusion; and improved space-clamp in whole-cell recordings relative to neurons in slice or cell culture preparations. This preparation can be used to examine synaptic physiology, pharmacology, modulation and plasticity. Real-time imaging of both pre- and postsynaptic elements in the living cells and boutons is also possible using vibrodissociated neurons. Characterization of the molecular constituents of pre- and postsynaptic elements can also be achieved with immunological and imaging-based approaches. PMID:21654624

Jun, Sang Beom; Cuzon Carlson, Verginia; Ikeda, Stephen; Lovinger, David

2011-01-01

153

VIP enhances synaptic transmission to hippocampal CA1 pyramidal cells through activation of both VPAC1 and VPAC2 receptors.  

PubMed

We previously described that vasoactive intestinal peptide (VIP) increases synaptic transmission to hippocampal CA1 pyramidal cells at concentrations known to activate VIP-selective receptors (VPAC1 and VPAC2) but not the PACAP-selective PAC1 receptor. We now investigated the involvement of VPAC1 and VPAC2 receptors in the effects elicited by VIP as well as the transduction pathways activated by VIP to cause enhancement of synaptic transmission. Blockade of either VPAC1 or VPAC2 receptors with PG 97-269 (100 nM) or PG 99-465 (100 nM) inhibited VIP-induced enhancement of synaptic transmission. Selective activation of VPAC1 receptors with [K15, R16, L27] VIP(1-7)/GRF(8-27) (10 nM) or of VPAC2 receptors with RO 25-1553 (10 nM) increased synaptic transmission to CA1 pyramidal cells, and this increase was larger when both agonists were applied together. Inhibition of either PKA with H-89 (1 microM) or PKC with GF109203X (1 microM) attenuated the effect of VIP (1 nM). GF109203X (1 microM) abolished the effect of the VPAC1 agonist [K15, R16, L27] VIP(1-7)/GRF(8-27) (10 nM) on hippocampal synaptic transmission but that effect was not changed by H-89 (1 microM). The effect of RO 25-1553 (100 nM) obtained in the presence of both the PAC1 and VPAC1 antagonists, M65 (30 nM) and PG 97-269 (100 nM), was strongly inhibited by H-89 (1 microM) but not GF109203X (1 microM). It is concluded that VIP enhances synaptic transmission to CA1 pyramidal cell dendrites through VPAC1 and VPAC2 receptor activation. VPAC1-mediated actions are dependent on PKC activity, and VPAC2-mediated actions are responsible for the PKA-dependent actions of VIP on CA1 hippocampal transmission. PMID:15935995

Cunha-Reis, Diana; Ribeiro, Joaquim Alexandre; Sebastião, Ana M

2005-07-01

154

Effects of 5-HT on thalamocortical synaptic transmission in the developing rat.  

PubMed

1. Recent immunocytochemical and receptor binding data have demonstrated a transient somatotopic patterning of serotonin (5-HT)-immunoreactive fibers in the primary somatosensory cortex of developing rats and a transient expression of 5-HT1B receptors on thalamocortical axons from the ventral posteromedial thalamic nucleus (VPM). 2. These results suggest that 5-HT should strongly modulate thalamocortical synaptic transmission for a limited time during postnatal development. This hypothesis was tested in intracellular recording experiments carried out in thalamocortical slice preparations that included VPM, the thalamic radiations, and the primary somatosensory cortex. Effects of 5-HT and analogues were monitored on membrane potentials and input resistances of cortical neurons and on the amplitude of the synaptic potentials evoked in them by stimulation of VPM. 3. Results obtained from cortical neurons in slices taken from rats during the first 2 wk of life indicated that 5-HT strongly inhibited the VPM-evoked excitatory postsynaptic potential (EPSP) recorded from cortical neurons in a dose-dependent manner. In contrast, 5-HT had no significant effects on membrane potential, input resistance, or depolarizations induced by direct application of glutamic acid to cortical cells. 4. The effects of 5-HT were mimicked by the 5-HT1B receptor agonists 1-[3-(trifluoromethyl)phenyl]-piperazine (TFMPP) and 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]-quinoxaline maleate and antagonized by the 5-HT1B receptor antagonist (-)-pindolol. The 5-HT1A agonist [(+/-)8-hydroxydipropylaminotetralin HBr] (8-OH-DPAT) had less effect on the VPM-elicited EPSP, and the effects of 5-HT upon this response were generally not antagonized by either 1-(2-methoxyphenyl)-4-[4-(2- phthalimmido)butyl]piperazine HBr (a 5-HT1A antagonist) or ketanserine (a 5-HT2 antagonist) or spiperone (a 5-HT1A and 2 antagonist). 5. The ability of 5-HT to inhibit the VPM-evoked EPSP in cortical neurons was significantly reduced in slices from animals > 2 wk of age. The effectiveness of TFMPP in such animals was even more attenuated than that of 5-HT, and the effectiveness of 8-OH-DPAT was unchanged with age. These results are consistent with the disappearance of 5-HT1B receptors from thalamocortical axons after the second postnatal week and the maintenance of 5-HT1A receptors on some neurons. 6. All of the results obtained in this study are consistent with the conclusion that 5-HT has a profound, but developmentally transient, presynaptic inhibitory effect upon thalamocortical transmission in the rat's somatosensory cortex. PMID:7884470

Rhoades, R W; Bennett-Clarke, C A; Shi, M Y; Mooney, R D

1994-11-01

155

Serotonin, dopamine and noradrenaline adjust actions of myelinated afferents via modulation of presynaptic inhibition in the mouse spinal cord.  

PubMed

Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD). PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT), dopamine (DA) and noradrenaline (NA) on afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs) or intracellular excitatory postsynaptic currents (EPSCs). The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs) recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75%) but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous afferent-evoked responses, supporting a global modulation of the multimodal afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated afferent-evoked DRPs and monosynaptic transmission in the dorsal horn are broadly reduced by descending monoamine transmitters. These actions likely integrate with modulatory actions elsewhere to reconfigure spinal circuits during motor behaviors. PMID:24587177

García-Ramírez, David L; Calvo, Jorge R; Hochman, Shawn; Quevedo, Jorge N

2014-01-01

156

Delayed reduction of hippocampal synaptic transmission and spines following exposure to repeated subclinical doses of organophosphorus pesticide in adult mice.  

PubMed

Agricultural and household organophosphorus (OP) pesticides inhibit acetylcholinesterase (AchE), resulting in increased acetylcholine (Ach) in the central nervous system. In adults, acute and prolonged exposure to high doses of AchE inhibitors causes severe, clinically apparent symptoms, followed by lasting memory impairments and cognitive dysfunction. The neurotoxicity of repeated environmental exposure to lower, subclinical doses of OP pesticides in adults is not as well studied. However, repeated exposure to acetylcholinesterase inhibitors, such as chlorpyrifos (CPF), pyridostigmine, and sarin nerve agent, has been epidemiologically linked to delayed onset symptoms in Gulf War Illness and may be relevant to environmental exposure in farm workers among others. We treated adult mice with a subclinical dose (5 mg/kg) of CPF for 5 consecutive days and investigated hippocampal synaptic transmission and spine density early (2-7 days) and late (3 months) after CPF administration. No signs of cholinergic toxicity were observed at any time during or after treatment. At 2-7 days after the last injection, we found increased synaptic transmission in the CA3-CA1 region of the hippocampus of CPF-treated mice compared with controls. In contrast, at 3 months after CPF administration, we observed a 50% reduction in synaptic transmission likely due to a corresponding 50% decrease in CA1 pyramidal neuron synaptic spine density. This study is the first to identify a biphasic progression of synaptic abnormalities following repeated OP exposure and suggests that even in the absence of acute cholinergic toxicity, repeated exposure to CPF causes delayed persistent damage to the adult brain in vivo. PMID:21948870

Speed, Haley E; Blaiss, Cory A; Kim, Ahleum; Haws, Michael E; Melvin, Neal R; Jennings, Michael; Eisch, Amelia J; Powell, Craig M

2012-01-01

157

STIM1 controls neuronal Ca²? signaling, mGluR1-dependent synaptic transmission, and cerebellar motor behavior.  

PubMed

In central mammalian neurons, activation of metabotropic glutamate receptor type1 (mGluR1) evokes a complex synaptic response consisting of IP3 receptor-dependent Ca(2+) release from internal Ca(2+) stores and a slow depolarizing potential involving TRPC3 channels. It is largely unclear how mGluR1 is linked to its downstream effectors. Here, we explored the role of stromal interaction molecule 1 (STIM1) in regulating neuronal Ca(2+) signaling and mGluR1-dependent synaptic transmission. By analyzing mouse cerebellar Purkinje neurons, we demonstrate that STIM1 is an essential regulator of the Ca(2+) level in neuronal endoplasmic reticulum Ca(2+) stores. Both mGluR1-dependent synaptic potentials and IP3 receptor-dependent Ca(2+) signals are strongly attenuated in the absence of STIM1. Furthermore, the Purkinje neuron-specific deletion of Stim1 causes impairments in cerebellar motor behavior. Together, our results demonstrate that in the mammalian nervous system STIM1 is a key regulator of intracellular Ca(2+) signaling, metabotropic glutamate receptor-dependent synaptic transmission, and motor coordination. PMID:24811382

Hartmann, Jana; Karl, Rosa M; Alexander, Ryan P D; Adelsberger, Helmuth; Brill, Monika S; Rühlmann, Charlotta; Ansel, Anna; Sakimura, Kenji; Baba, Yoshihiro; Kurosaki, Tomohiro; Misgeld, Thomas; Konnerth, Arthur

2014-05-01

158

Loss and gain of FUS function impair neuromuscular synaptic transmission in a genetic model of ALS.  

PubMed

Amyotrophic lateral sclerosis (ALS) presents clinically in adulthood and is characterized by the loss of motoneurons in the spinal cord and cerebral cortex. Animal models of the disease suggest that significant neuronal abnormalities exist during preclinical stages of the disease. Mutations in the gene fused in sarcoma (FUS) are associated with ALS and cause impairment in motor function in animal models. However, the mechanism of neuromuscular dysfunction underlying pathophysiological deficits causing impairment in locomotor function resulting from mutant FUS expression is unknown. To characterize the cellular pathophysiological defect, we expressed the wild-type human gene (wtFUS) or the ALS-associated mutation R521H (mutFUS) gene in zebrafish larvae and characterized their motor (swimming) activity and function of their neuromuscular junctions (NMJs). Additionally, we tested knockdown of zebrafish fus with an antisense morpholino oligonucleotide (fus AMO). Expression of either mutFUS or knockdown of fus resulted in impaired motor activity and reduced NMJ synaptic fidelity with reduced quantal transmission. Primary motoneurons expressing mutFUS were found to be more excitable. These impairments in neuronal function could be partially restored in fus AMO larvae also expressing wtFUS (fus AMO+wtFUS) but not mutFUS (fus AMO+mutFUS). These results show that both a loss and gain of FUS function result in defective presynaptic function at the NMJ. PMID:23771027

Armstrong, Gary A B; Drapeau, Pierre

2013-11-01

159

Genetic deletion of TNF receptor suppresses excitatory synaptic transmission via reducing AMPA receptor synaptic localization in cortical neurons.  

PubMed

The distribution of postsynaptic glutamate receptors has been shown to be regulated by proimmunocytokine tumor necrosis factor ? (TNF-?) signaling. The role of TNF-? receptor subtypes in mediating glutamate receptor expression, trafficking, and function still remains unclear. Here, we report that TNF receptor subtypes (TNFR1 and TNFR2) differentially modulate ?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) clustering and function in cultured cortical neurons. We find that genetic deletion of TNFR1 decreases surface expression and synaptic localization of the AMPAR GluA1 subunit, reduces the frequency of miniature excitatory postsynaptic current (mEPSC), and reduces AMPA-induced maximal whole-cell current. In addition, these results are not observed in TNFR2-deleted neurons. The decreased AMPAR expression and function in TNFR1-deleted cells are not significantly restored by short (2 h) or long (24 h) term exposure to TNF-?. In TNFR2-deleted cells, TNF-? promotes AMPAR trafficking to the synapse and increases mEPSC frequency. In the present study, we find no significant change in the GluN1 subunit of NMDAR clusters, location, and mEPSC. This includes applying or withholding the TNF-? treatment in both TNFR1- and TNFR2-deleted neurons. Our results indicate that TNF receptor subtype 1 but not 2 plays a critical role in modulating AMPAR clustering, suggesting that targeting TNFR1 gene might be a novel approach to preventing neuronal AMPAR-mediated excitotoxicity. PMID:21982949

He, Ping; Liu, Qiang; Wu, Jie; Shen, Yong

2012-01-01

160

Levetiracetam (ucb LO59) affects in vitro models of epilepsy in CA3 pyramidal neurons without altering normal synaptic transmission  

Microsoft Academic Search

Previous behavioural and electrophysiological studies have indicated that levetiracetam (ucb LO59) acts as an anticonvulsant\\u000a drug in vivo. The purpose of the present study was to investigate the effects of levetiracetam on normal synaptic transmission\\u000a and epileptiform activity in vitro. Intracellular recordings were obtained from the CA3 subfield of the rat hippocampal slice\\u000a preparation. Levetiracetam in a concentration of 10

Susanne Birnstiel; Ernst Wülfert; Sheryl G. Beck

1997-01-01

161

Effects of dieldrin (HEOD) and some of its metabolites on synaptic transmission in the frog motor end-plate  

Microsoft Academic Search

The effects of HEOD and some of its metabolites on synaptic transmission in the frog motor end-plate were studied by means of intracellular microelectrodes. HEOD itself and the metabolites 9-syn-hydroxy-HEOD and the aldrin-derived dicarboxilic acid had no significant effect on frequency and amplitude of miniature end-plate potentials, nor on end-plate membrane potential. In sharp contrast with this aldrin-transdiol (6,7-trans-dihydroxy-dihydro-aldrin) was

L. M. A. Akkermans; J. van den Bercken; J. M. van der Zalm; H. W. M. van Straaten

1974-01-01

162

Effects of some agonists of excitatory amino acids on synaptic transmission in the skate electroreceptors (ampullae of Lorenzini)  

Microsoft Academic Search

The effects on synaptic transmission of blockers of amino acids at postsynaptic receptors were investigated by means of external perfusion of the basal membrane of electroreceptor cells in ampullae of Lorenzini and by recording of spike activity from individual nerve fibers in the skateRajaclavata: glutamic acid diethyl ester (DEE-GLU), glutamic acid dimethyl ester (DME-GLU), D-?-aminoadipic acid (DAA), kynurenic acid (KYN),

G. N. Akoev; Yu. N. Andrianov; N. O. Sherman

1988-01-01

163

Characterization of age-related changes in synaptic transmission onto F344 rat basal forebrain cholinergic neurons using a reduced synaptic preparation.  

PubMed

Basal forebrain (BF) cholinergic neurons participate in a number of cognitive processes that become impaired during aging. We previously found that age-related enhancement of Ca(2+) buffering in rat cholinergic BF neurons was associated with impaired performance in the water maze spatial learning task (Murchison D, McDermott AN, Lasarge CL, Peebles KA, Bizon JL, and Griffith WH. J Neurophysiol 102: 2194-2207, 2009). One way that altered Ca(2+) buffering could contribute to cognitive impairment involves synaptic function. In this report we show that synaptic transmission in the BF is altered with age and cognitive status. We have examined the properties of spontaneous postsynaptic currents (sPSCs) in cholinergic BF neurons that have been mechanically dissociated without enzymes from behaviorally characterized F344 rats. These isolated neurons retain functional presynaptic terminals on their somata and proximal dendrites. Using whole cell patch-clamp recording, we show that sPSCs and miniature PSCs are predominately GABAergic (bicuculline sensitive) and in all ways closely resemble PSCs recorded in a BF in vitro slice preparation. Adult (4-7 mo) and aged (22-24 mo) male rats were cognitively assessed using the water maze. Neuronal phenotype was identified post hoc using single-cell RT-PCR. The frequency of sPSCs was reduced during aging, and this was most pronounced in cognitively impaired subjects. This is the same population that demonstrated increased intracellular Ca(2+) buffering. We also show that increasing Ca(2+) buffering in the synaptic terminals of young BF neurons can mimic the reduced frequency of sPSCs observed in aged BF neurons. PMID:24133226

Griffith, William H; Dubois, Dustin W; Fincher, Annette; Peebles, Kathryn A; Bizon, Jennifer L; Murchison, David

2014-01-01

164

Impaired neural transmission and synaptic plasticity in superior cervical ganglia from ?-amyloid rat model of Alzheimer's disease.  

PubMed

Basal synaptic transmission and activity-dependent synaptic plasticity were evaluated in superior cervical sympathetic ganglia (SCG) of amyloid-? rat model of Alzheimer's disease (A? rat) using electrophysiological and molecular techniques. Rats were administered A? peptides (a mixture of 1:1 A?1-40 and A?1-42) by chronic intracerebroventricular infusion via 14-day mini-osmotic pumps (300 pmol/day). Control rats received A?40-1 (inactive reverse peptide: 300 pmol/day). Ganglionic compound action potentials were recorded before (basal) and after repetitive stimulation. In isolated SCG, ganglionic long-term potentiation (gLTP) was generated by a brief train of stimuli (20Hz for 20s) and ganglionic long-term depression (gLTD) was produced with trains of paired pulses. The input/output (I/O) curves of ganglia from A? rats showed a marked downward shift along all stimulus intensities, compared to those of ganglia from control animals, indicating impaired basal synaptic transmission. In addition, repetitive stimulation induced robust gLTP and gLTD in ganglia isolated from control animals, but, the same protocols failed to induce gLTP or gLTD in ganglia from A? rats indicating impairment of activity-dependent synaptic plasticity in these animals. Western blotting of SCG homogenate from A? rats revealed reduction in the ratio of phosphorylated-/total-CaMKII and in calcineurin protein levels. Although other mechanisms could be involved, these changes in signaling molecules could represent an important molecular mechanism linked to the failure to express synaptic plasticity in A? rat ganglia. Results of the current study could explain some of the peripheral nervous system manifestations of Alzheimer's disease. PMID:21453246

Alzoubi, K H; Alhaider, I A; Tran, T T; Mosely, A; Alkadhi, K K

2011-06-01

165

Differential characteristics of endogenous serotonin-mediated synaptic transmission in the hippocampal CA1 and CA3 fields of anaesthetized rats  

Microsoft Academic Search

The characteristics of endogenous serotonin (5-HT)-mediated synaptic transmission were investigated in the hippocampal CA1 and CA3 fields of anaesthetized rats. Electrophysiological approaches were used to elucidate the effects of a selective 5-HT reuptake inhibitor, fluvoxamine, on synaptic transmission by determining the population spike amplitude (PSA). Fluvoxamine (10 or 30 mg\\/kg i.p.) increased the PSA in the CA1 and CA3 fields

Machiko Matsumoto; Taku Kojima; Hiroko Togashi; Kiyoshi Mori; Satoshi Ohashi; Ken-ichi Ueno; Mitsuhiro Yoshioka

2002-01-01

166

Implementing the cellular mechanisms of synaptic transmission in a neural mass model of the thalamo-cortical circuitry.  

PubMed

A novel direction to existing neural mass modeling technique is proposed where the commonly used "alpha function" for representing synaptic transmission is replaced by a kinetic framework of neurotransmitter and receptor dynamics. The aim is to underpin neuro-transmission dynamics associated with abnormal brain rhythms commonly observed in neurological and psychiatric disorders. An existing thalamocortical neural mass model is modified by using the kinetic framework for modeling synaptic transmission mediated by glutamatergic and GABA (gamma-aminobutyric-acid)-ergic receptors. The model output is compared qualitatively with existing literature on in vitro experimental studies of ferret thalamic slices, as well as on single-neuron-level model based studies of neuro-receptor and transmitter dynamics in the thalamocortical tissue. The results are consistent with these studies: the activation of ligand-gated GABA receptors is essential for generation of spindle waves in the model, while blocking this pathway leads to low-frequency synchronized oscillations such as observed in slow-wave sleep; the frequency of spindle oscillations increase with increased levels of post-synaptic membrane conductance for AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid) receptors, and blocking this pathway effects a quiescent model output. In terms of computational efficiency, the simulation time is improved by a factor of 10 compared to a similar neural mass model based on alpha functions. This implies a dramatic improvement in computational resources for large-scale network simulation using this model. Thus, the model provides a platform for correlating high-level brain oscillatory activity with low-level synaptic attributes, and makes a significant contribution toward advancements in current neural mass modeling paradigm as a potential computational tool to better the understanding of brain oscillations in sickness and in health. PMID:23847522

Bhattacharya, Basabdatta S

2013-01-01

167

Increased Gene Dosage of Ube3a Results in Autism Traits and Decreased Glutamate Synaptic Transmission in Mice  

PubMed Central

People with autism spectrum disorder are characterized by impaired social interaction, reduced communication, and increased repetitive behaviors. The disorder has a substantial genetic component, and recent studies have revealed frequent genome copy number variations (CNVs) in some individuals. A common CNV that occurs in 1 to 3% of those with autism—maternal 15q11-13 duplication (dup15) and triplication (isodicentric extranumerary chromosome, idic15)—affects several genes that have been suggested to underlie autism behavioral traits. To test this, we tripled the dosage of one of these genes, the ubiquitin protein ligase Ube3a, which is expressed solely from the maternal allele in mature neurons, and reconstituted the three core autism traits in mice: defective social interaction, impaired communication, and increased repetitive stereotypic behavior. The penetrance of these autism traits depended on Ube3a gene copy number. In animals with increased Ube3a gene dosage, glutamatergic, but not GABAergic, synaptic transmission was suppressed as a result of reduced presynaptic release probability, synaptic glutamate concentration, and postsynaptic action potential coupling. These results suggest that Ube3a gene dosage may contribute to the autism traits of individuals with maternal 15q11-13 duplication and support the idea that increased E3A ubiquitin ligase gene dosage results in reduced excitatory synaptic transmission.

Smith, Stephen E. P.; Zhou, Yu-Dong; Zhang, Guangping; Jin, Zhe; Stoppel, David C.; Anderson, Matthew P.

2012-01-01

168

Leptin inhibits 4-aminopyridine- and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents  

PubMed Central

Leptin is a hormone that reduces excitability in some hypothalamic neurons via leptin receptor activation of the JAK2 and PI3K intracellular signaling pathways. We hypothesized that leptin receptor activation in other neuronal subtypes would have anticonvulsant activity and that intranasal leptin delivery would be an effective route of administration. We tested leptin’s anticonvulsant action in 2 rodent seizure models by directly injecting it into the cortex or by administering it intranasally. Focal seizures in rats were induced by neocortical injections of 4-aminopyridine, an inhibitor of voltage-gated K+ channels. These seizures were briefer and less frequent upon coinjection of 4-aminopyridine and leptin. In mice, intranasal administration of leptin produced elevated brain and serum leptin levels and delayed the onset of chemical convulsant pentylenetetrazole-induced generalized convulsive seizures. Leptin also reduced neuronal spiking in an in vitro seizure model. Leptin inhibited ?-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor–mediated synaptic transmission in mouse hippocampal slices but failed to inhibit synaptic responses in slices from leptin receptor–deficient db/db mice. JAK2 and PI3K antagonists prevented leptin inhibition of AMPAergic synaptic transmission. We conclude that leptin receptor activation and JAK2/PI3K signaling may be novel targets for anticonvulsant treatments. Intranasal leptin administration may have potential as an acute abortive treatment for convulsive seizures in emergency situations.

Xu, Lin; Rensing, Nicholas; Yang, Xiao-Feng; Zhang, Hai Xia; Thio, Liu Lin; Rothman, Steven M.; Weisenfeld, Aryan E.; Wong, Michael; Yamada, Kelvin A.

2007-01-01

169

Short-term depression of external globus pallidus-subthalamic nucleus synaptic transmission and implications for patterning subthalamic activity  

PubMed Central

The frequency and pattern of activity in the reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN) are closely related to motor function. Although phasic, unitary GPe-STN inputs powerfully pattern STN activity ex vivo, correlated GPe-STN activity is not normally observed in vivo. To test the hypothesis that the GPe’s influence is constrained by short-term synaptic depression, unitary GPe-STN inputs were stimulated in rat and mouse brain slices at rates and in patterns that mimicked GPe activity in vivo. Together with connectivity estimates these data were then used to simulate GPe-STN transmission. Unitary GPe-STN synaptic connections initially generated large conductances and transmitted reliably. However, the amplitude and reliability of transmission declined rapidly (? = 0.6 ± 0.5 s) to <10% of their initial values when connections were stimulated at the mean rate of GPe activity in vivo (33 Hz). Recovery from depression (? = 17.3 ± 18.9 s) was also longer than pauses in tonic GPe activity in vivo. Depression was due to limited supply of release-ready vesicles and was in sharp contrast to Calyx of Held transmission, which exhibited 100% reliability. Injection of simulated GPe-STN conductances revealed that synaptic depression caused tonic, non-synchronized GPe-STN activity to disrupt rather than abolish autonomous STN activity. Furthermore, synchronous inhibition of tonically active GPe-STN neurons or phasic activity of GPe-STN neurons reliably patterned STN activity through disinhibition and inhibition, respectively. Together these data argue that the frequency and pattern of GPe activity profoundly influences its transmission to the STN.

Atherton, Jeremy F.; Menard, Ariane; Urbain, Nadia; Bevan, Mark D.

2013-01-01

170

Dynamics of synaptic transmission between fast-spiking interneurons and striatal projection neurons of the direct and indirect pathways.  

PubMed

The intrastriatal microcircuit is a predominantly inhibitory GABAergic network comprised of a majority of projection neurons [medium spiny neurons (MSNs)] and a minority of interneurons. The connectivity within this microcircuit is divided into two main categories: lateral connectivity between MSNs, and inhibition mediated by interneurons, in particular fast spiking (FS) cells. To understand the operation of striatum, it is essential to have a good description of the dynamic properties of these respective pathways and how they affect different types of striatal projection neurons. We recorded from neuronal pairs, triplets, and quadruplets in slices of rat and mouse striatum and analyzed the dynamics of synaptic transmission between MSNs and FS cells. Retrograde fluorescent labeling and transgenic EGFP (enhanced green fluorescent protein) mice were used to distinguish between MSNs of the direct (striatonigral) and indirect (striatopallidal) pathways. Presynaptic neurons were stimulated with trains of action potentials, and activity-dependent depression and facilitation of synaptic efficacy was recorded from postsynaptic neurons. We found that FS cells provide a strong and homogeneously depressing inhibition of both striatonigral and striatopallidal MSN types. Moreover, individual FS cells are connected to MSNs of both types. In contrast, both MSN types receive sparse and variable, depressing and facilitating synaptic transmission from nearby MSNs. The connection probability was higher for pairs with presynaptic striatopallidal MSNs; however, the variability in synaptic dynamics did not depend on the types of interconnected MSNs. The differences between the two inhibitory pathways were clear in both species and at different developmental stages. Our findings show that the two intrastriatal inhibitory pathways have fundamentally different dynamic properties that are, however, similarly applied to both direct and indirect striatal projections. PMID:20203210

Planert, Henrike; Szydlowski, Susanne N; Hjorth, J J Johannes; Grillner, Sten; Silberberg, Gilad

2010-03-01

171

Enhancement of synaptic transmission and nociceptive behaviour in HPC-1/syntaxin 1A knockout mice following peripheral nerve injury.  

PubMed

Our previous analysis of HPC-1/syntaxin 1A knockout (KO) mice indicated that HPC-1/syntaxin 1A plays an important role in the synaptic plasticity of the hippocampus in vitro and learning behaviour in vivo. In order to gain further insights into the physiological functions of HPC-1/syntaxin 1A, we studied the changes in the plasticity of synaptic transmission in the superficial dorsal horn of the spinal cord following a peripheral nerve injury in HPC-1/syntaxin 1A KO and wild-type (WT) mice. The von Frey filament test revealed that partial ligation of the sciatic nerve caused neuropathic pain in both WT and KO mice. However, KO mice showed significant enhancement of mechanical allodynia as compared with WT mice. Tight-seal whole-cell recordings were obtained from neurons in the superficial dorsal horn of the spinal cord slices. Electrical stimulus-evoked excitatory postsynaptic currents (EPSCs), asynchronous EPSCs (aEPSCs) in the presence of strontium, and spontaneously occurring miniature EPSCs (mEPSCs) were analysed. Prior to peripheral nerve ligation, no significant differences were observed in the properties of evoked EPSCs, aEPSCs and mEPSCs in KO and WT mice. Seven-14 days after partial ligation, the amplitude of evoked EPSCs and the frequency of aEPSCs and mEPSCs in KO mice were significantly greater than those in WT mice; however, the amplitude of aEPSCs and mEPSCs remained unchanged in both groups. Enhanced allodynia behaviour and significant enhancement of excitatory synaptic transmission following peripheral nerve ligation in KO mice suggest that HPC-1/syntaxin 1A might play a role in synaptic plasticity in the nociceptive pathway. PMID:17953616

Takasusuki, T; Fujiwara, T; Yamaguchi, S; Fukushima, T; Akagawa, K; Hori, Y

2007-10-01

172

Long-term enhancement of synaptic transmission between antennal lobe and mushroom body in cultured Drosophila brain.  

PubMed

In Drosophila, the mushroom body (MB) is a critical brain structure for olfactory associative learning. During aversive conditioning, the MBs are thought to associate odour signals, conveyed by projection neurons (PNs) from the antennal lobe (AL), with shock signals conveyed through ascending fibres of the ventral nerve cord (AFV). Although synaptic transmission between AL and MB might play a crucial role for olfactory associative learning, its physiological properties have not been examined directly. Using a cultured Drosophila brain expressing a Ca(2+) indicator in the MBs, we investigated synaptic transmission and plasticity at the AL-MB synapse. Following stimulation with a glass micro-electrode, AL-induced Ca(2+) responses in the MBs were mediated through Drosophila nicotinic acetylcholine receptors (dnAChRs), while AFV-induced Ca(2+) responses were mediated through Drosophila NMDA receptors (dNRs). AL-MB synaptic transmission was enhanced more than 2 h after the simultaneous 'associative-stimulation' of AL and AFV, and such long-term enhancement (LTE) was specifically formed at the AL-MB synapses but not at the AFV-MB synapses. AL-MB LTE was not induced by intense stimulation of the AL alone, and the LTE decays within 60 min after subsequent repetitive AL stimulation. These phenotypes of associativity, input specificity and persistence of AL-MB LTE are highly reminiscent of olfactory memory. Furthermore, similar to olfactory aversive memory, AL-MB LTE formation required activation of the Drosophila D1 dopamine receptor, DopR, along with dnAChR and dNR during associative stimulations. These physiological and genetic analogies indicate that AL-MB LTE might be a relevant cellular model for olfactory memory. PMID:23027817

Ueno, Kohei; Naganos, Shintaro; Hirano, Yukinori; Horiuchi, Junjiro; Saitoe, Minoru

2013-01-01

173

Effect of resiniferatoxin on glutamatergic spontaneous excitatory synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord.  

PubMed

The transient receptor potential (TRP) vanilloid type 1 (TRPV1) agonist, capsaicin, enhances glutamatergic spontaneous excitatory synaptic transmission in CNS neurons. Resiniferatoxin (RTX) has a much higher affinity for TRPV1 than capsaicin, but its ability to modulate excitatory transmission is unclear. We examined the effect of RTX on excitatory transmission using the whole-cell patch-clamp technique in substantia gelatinosa (SG) neurons of adult rat spinal cord slices. Bath-applied RTX dose-dependently increased the frequency, but not the amplitude, of spontaneous excitatory postsynaptic current (sEPSC), independent of its application time. In about a half of the neurons tested, this effect was accompanied by an inward current at -70 mV that was sensitive to glutamate-receptor antagonists. Repeated application of RTX did not affect excitatory transmission. RTX was more potent than capsaicin but showed similar efficacy. RTX activity could be blocked by capsazepine or SB-366791, a TRPV1 antagonist, but not tetrodotoxin, a Na(+)-channel blocker, and could be inhibited by pretreatment with capsaicin but not the TRPA1 agonist, allyl isothiocyanate. RTX enhances the spontaneous release of L-glutamate from nerve terminals with similar efficacy as capsaicin and produces a membrane depolarization by activating TRPV1 in the SG, with fast desensitization and slow recovery from desensitization. These results indicate a mechanism by which RTX can modulate excitatory transmission in SG neurons to regulate nociceptive transmission. PMID:19778582

Jiang, C-Y; Fujita, T; Yue, H-Y; Piao, L-H; Liu, T; Nakatsuka, T; Kumamoto, E

2009-12-29

174

Plasticity of GABA transporters: an unconventional route to shape inhibitory synaptic transmission  

PubMed Central

The brain relies on GABAergic neurons to control the ongoing activity of neuronal networks. GABAergic neurons control the firing pattern of excitatory cells, the temporal structure of membrane potential oscillations and the time window for integration of synaptic inputs. These actions require a fine control of the timing of GABA receptor activation which, in turn, depends on the precise timing of GABA release from pre-synaptic terminals and GABA clearance from the extracellular space. Extracellular GABA is not subject to enzymatic breakdown, and its clearance relies entirely on diffusion and uptake by specific transporters. In contrast to glutamate transporters, GABA transporters are abundantly expressed in neuronal pre-synaptic terminals. GABA transporters move laterally within the plasma membrane and are continuously trafficked to/from intracellular compartments. It is hypothesized that due to their proximity to GABA release sites, changes in the concentration and lateral mobility of GABA transporters may have a significant effect on the time course of the GABA concentration profile in and out of the synaptic cleft. To date, this hypothesis remains to be tested. Here we use 3D Monte Carlo reaction-diffusion simulations to analyze how changes in the density of expression and lateral mobility of GABA transporters in the cell membrane affect the extracellular GABA concentration profile and the activation of GABA receptors. Our results indicate that these manipulations mainly alter the GABA concentration profile away from the synaptic cleft. These findings provide novel insights into how the ability of GABA transporters to undergo plastic changes may alter the strength of GABAergic signals and the activity of neuronal networks in the brain.

Scimemi, Annalisa

2014-01-01

175

Long-lasting nicotinic modulation of GABAergic synaptic transmission in the rat nucleus accumbens associated with behavioural sensitization to amphetamine.  

PubMed

A robust increase in dopaminergic transmission in the nucleus accumbens (NAc) shell has been reported to be consistently associated with the long-term expression of behavioural sensitization to drugs of abuse. However, little is known about how this affects the neuronal network of the NAc. We made cellular recordings in NAc slices of saline- and amphetamine-pretreated adult rats and found that expression of behavioural sensitization was associated with long-lasting changes in the basal firing pattern of cholinergic interneurons up to 3 weeks after the last drug injection. Consequently, upon amphetamine sensitization, an inhibiting effect of the nicotinic receptor blocker mecamylamine on the amplitudes of spontaneous GABAergic synaptic currents as well as on the failure rate of electrically evoked GABAergic currents was found that was not present under control conditions. Thus, behavioural sensitization to amphetamine is associated with an up-regulation of the endogenous activation of nicotinic receptors that, in turn, stimulate the GABAergic synaptic transmission within the NAc shell. This is a new mechanism by which drugs of abuse may induce alterations in the processing and integration of NAc inputs involved in psychomotor sensitization. PMID:15147319

de Rover, Mischa; Mansvelder, Huibert D; Lodder, Johannes C; Wardeh, George; Schoffelmeer, Anton N M; Brussaard, Arjen B

2004-05-01

176

Exendin (5-39), an antagonist of GLP-1 receptor, modulates synaptic transmission via glutamate uptake in the dentate gyrus.  

PubMed

Extracellular concentrations of glutamate are mainly controlled by an astrocytic glutamate transporter, GLT-1. We previously reported that exendin (5-39) (Ex), an antagonist of the GLP-1 receptor, improved memory impairment in ?-amyloid protein-treated rats. In this study, we investigated effects of Ex on synaptic transmission through astrocytic GLT-1 in the hippocampus. Continuous intracerebroventricular (i.c.v.) administration of Ex for 1-week increased GLT-1 protein levels in the hippocampus of 4-week-old male Wistar rats. For electrophysiological studies, hippocampal slices were prepared from these Ex-treated rats or vehicle-treated rats. Ex decreased fEPSP decay time, and increased the input-output relation and decreased the paired-pulse ratio in the dentate gyrus (DG). Furthermore, Ex inhibited long-term depression but not long-term potentiation in the DG. These effects were prevented by DHK, a specific GLT-1 inhibitor. In addition, glutamate uptake was significantly increased by Ex-treatment in cultured astrocytes. These results suggest that Ex modulates synaptic transmission and plasticity through astrocytic glutamate uptake in the DG. PMID:23318256

Kobayashi, Kazuma; Iwai, Takashi; Sasaki-Hamada, Sachie; Kamanaka, Gaku; Oka, Jun-Ichiro

2013-04-10

177

The F-Box Protein MEC-15 (FBXW9) Promotes Synaptic Transmission in GABAergic Motor Neurons in C. elegans  

PubMed Central

Ubiquitination controls the activity of many proteins and has been implicated in almost every aspect of neuronal cell biology. Characterizing the precise function of ubiquitin ligases, the enzymes that catalyze ubiquitination of target proteins, is key to understanding distinct functions of ubiquitination. F-box proteins are the variable subunits of the large family of SCF ubiquitin ligases and are responsible for binding and recognizing specific ubiquitination targets. Here, we investigated the function of the F-box protein MEC-15 (FBXW9), one of a small number of F-box proteins evolutionarily conserved from C. elegans to mammals. mec-15 is widely expressed in the nervous system including GABAergic and cholinergic motor neurons. Electrophysiological and behavioral analyses indicate that GABAergic synaptic transmission is reduced in mec-15 mutants while cholinergic transmission appears normal. In the absence of MEC-15, the abundance of the synaptic vesicle protein SNB-1 (synaptobrevin) is reduced at synapses and increased in cell bodies of GABAergic motor neurons, suggesting that MEC-15 affects the trafficking of SNB-1 between cell bodies and synapses and may promote GABA release by regulating the abundance of SNB-1 at synapses.

Sun, Yu; Hu, Zhitao; Goeb, Yannick; Dreier, Lars

2013-01-01

178

Intracellular chloride ions regulate the time-course of GABA-mediated inhibitory synaptic transmission  

PubMed Central

The time-dependent integration of excitatory and inhibitory synaptic currents is an important process for shaping the input-output profiles of individual excitable cells, and therefore the activity of neuronal networks. Here, we show that the decay time-course of GABAergic inhibitory synaptic currents is considerably faster when recorded with physiological internal Cl? concentrations than with symmetrical Cl? solutions. This effect of intracellular Cl? is due to a direct modulation of the GABAA receptor that is independent of the net direction of current flow through the ion channel. As a consequence, the time window during which GABAergic inhibition can counteract coincident excitatory inputs is much shorter, under physiological conditions, compared to that previously measured using high internal Cl?. This is expected to have implications for neuronal network excitability and neurodevelopment, and for our understanding of pathological conditions, such as epilepsy and chronic pain, where intracellular Cl? concentrations can be altered.

Houston, Catriona M.; Bright, Damian P.; Sivilotti, Lucia G; Beato, Marco; Smart, Trevor G.

2009-01-01

179

Optogenetic silencing strategies differ in their effects on inhibitory synaptic transmission  

PubMed Central

Optogenetic silencing strategies using light-driven ion fluxes permit rapid and effective inhibition of neural activity. Using rodent hippocampal neurons we show that silencing activity with a chloride pump can increase the probability of synaptically-evoked spiking in the period following light-activation, whereas this is not the case for a proton pump. This effect can be accounted for by changes to the GABAA receptor reversal potential and demonstrates an important difference between silencing strategies.

Raimondo, Joseph V.; Kay, Louise; Ellender, Tommas J.; Akerman, Colin J.

2012-01-01

180

Synaptic Morphology and Differences in Sensitivity  

Microsoft Academic Search

A relation between synaptic morphology and physiology was observed in an in vitro preparation of a sense organ (the ampulla of Lorenzini), in which activity was monitored from the primary afferent neurons before electron microscopic examination of the afferent synapses. The depth of the postsynaptic trough decreased as prefixation sensitivity of the sense organ decreased. This relation and other ultrastructural

R. Douglas Fields; Mark H. Ellisman

1985-01-01

181

Postnatal Loss of P/Q-type Channels Confined to Rhombic Lip Derived Neurons Alters Synaptic Transmission at the Parallel Fiber to Purkinje Cell Synapse and Replicates Genomic Cacna1a Mutation Phenotype of Ataxia and Seizures in Mice  

PubMed Central

Ataxia, episodic dyskinesia and thalamocortical seizures are associated with an inherited loss of P/Q-type voltage-gated Ca2+ channel function. P/Q-type channels are widely expressed throughout the neuraxis, obscuring identification of the critical networks underlying these complex neurological disorders. We recently showed that the conditional postnatal loss of P/Q-type channels in cerebellar Purkinje cells (PCs) in mice (purky) leads to these aberrant phenotypes, suggesting that intrinsic alteration in PC output is a sufficient pathogenic factor for disease initiation. The question arises whether P/Q-type channel deletion confined to a single upstream cerebellar synapse might induce the pathophysiological abnormality of genomically inherited P/Q-type channel disorders. PCs integrate two excitatory inputs, climbing fibers from inferior olive and parallel fibers (PFs) from granule cells (GCs) that receive mossy fiber (MF) input derived from precerebellar nuclei. In this paper, we introduce a new mouse model with a selective knock-out of P/Q-type channels in rhombic lip derived neurons including PF- and MF-pathways (quirky). We found that in quirky mice, PF-PC synaptic transmission is reduced during low-frequency stimulation. Using focal light stimulation of GCs that express optogenetic light-sensitive channels, channelrhodopsin-2, we found that modulation of PC firing via GC input is reduced in quirky mice. Phenotypic analysis revealed that quirky mice display ataxia, dyskinesia and absence epilepsy. These results suggest that developmental alteration of patterned input confined to only one of the main afferent cerebellar excitatory synaptic pathways has a significant role in generating the neurological phenotype associated with the global genomic loss of P/Q-type channel function.

Maejima, Takashi; Wollenweber, Patric; Teusner, Lena U. C.; Noebels, Jeffrey L.; Herlitze, Stefan; Mark, Melanie D.

2013-01-01

182

Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala.  

PubMed

Recent studies indicate that the lateral subdivision of the central amygdala (CeL) is essential for fear learning. Specifically, fear conditioning induces cell-type-specific synaptic plasticity in CeL neurons that is required for the storage of fear memories. The CeL also controls fear expression by gating the activity of the medial subdivision of the central amygdala (CeM), the canonical amygdala output to areas that mediate defensive responses. In addition to the connection with CeM, the CeL sends long-range projections to innervate extra-amygdala areas. However, the long-range projection CeL neurons have not been well characterized, and their role in fear regulation is unknown. Here we show in mice that a subset of CeL neurons directly project to the midbrain periaqueductal gray (PAG) and the paraventricular nucleus of the thalamus, two brain areas implicated in defensive behavior. These long-range projection CeL neurons are predominantly somatostatin-positive (SOM(+)) neurons, which can directly inhibit PAG neurons, and some of which innervate both the PAG and paraventricular nucleus of the thalamus. Notably, fear conditioning potentiates excitatory synaptic transmission onto these long-range projection CeL neurons. Thus, our study identifies a subpopulation of SOM(+) CeL neurons that may contribute to fear learning and regulate fear expression independent of CeM. PMID:24523533

Penzo, Mario A; Robert, Vincent; Li, Bo

2014-02-12

183

Loss of Predominant Shank3 Isoforms Results in Hippocampus-Dependent Impairments in Behavior and Synaptic Transmission  

PubMed Central

The Shank3 gene encodes a scaffolding protein that anchors multiple elements of the postsynaptic density at the synapse. Previous attempts to delete the Shank3 gene have not resulted in a complete loss of the predominant naturally occurring Shank3 isoforms. We have now characterized a homozygous Shank3 mutation in mice that deletes exon 21, including the Homer binding domain. In the homozygous state, deletion of exon 21 results in loss of the major naturally occurring Shank3 protein bands detected by C-terminal and N-terminal antibodies, allowing us to more definitively examine the role of Shank3 in synaptic function and behavior. This loss of Shank3 leads to an increased localization of mGluR5 to both synaptosome and postsynaptic density-enriched fractions in the hippocampus. These mice exhibit a decrease in NMDA/AMPA excitatory postsynaptic current ratio in area CA1 of the hippocampus, reduced long-term potentiation in area CA1, and deficits in hippocampus-dependent spatial learning and memory. In addition, these mice also exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty, and minimal social abnormalities. These data suggest that Shank3 isoforms are required for normal synaptic transmission/plasticity in the hippocampus, as well as hippocampus-dependent spatial learning and memory.

Kouser, Mehreen; Speed, Haley E.; Dewey, Colleen M.; Reimers, Jeremy M.; Widman, Allie J.; Gupta, Natasha; Liu, Shunan; Jaramillo, Thomas C.; Bangash, Muhammad; Xiao, Bo; Worley, Paul F.

2013-01-01

184

Exposure to Cocaine Regulates Inhibitory Synaptic Transmission in the Nucleus Accumbens  

PubMed Central

Medium spiny neurons (MSNs) within the nucleus accumbens shell (NAc) function to gate and prioritize emotional/motivational arousals for behavioral output. The neuronal output NAc MSNs is mainly determined by the integration of membrane excitability and excitatory/inhibitory synaptic inputs. Whereas cocaine-induced alterations at excitatory synapses and membrane excitability have been extensively examined, the overall functional output of NAc MSNs following cocaine exposure still poorly defined because little is known about whether inhibitory synaptic input to these neurons is affected by cocaine. Here, our results demonstrate multidimensional alterations at inhibitory synapses in NAc neurons following cocaine self-administration in rats. Specifically, the amplitude of miniature (m) inhibitory postsynaptic currents (IPSCs) was decreased after 21-d withdrawal from 5-d cocaine self-administration. Upon re-exposure to cocaine after 21-day withdrawal, whereas the amplitude of mIPSCs remained down-regulated, the frequency became significantly higher. Furthermore, the reversal potential of IPSCs, which was not significantly altered during withdrawal, became more hyperpolarized upon cocaine re-exposure. Moreover, the relative weight of excitatory and inhibitory inputs to NAc MSNs was significantly decreased after 1-d cocaine withdrawal, increased after 21-d withdrawal, and returned to the basal level upon cocaine re-exposure after 21-d withdrawal. These results, taken together with previous results showing cocaine-induced adaptations at excitatory synapses and intrinsic membrane excitability of NAc MSNs, may provide a relatively thorough picture of the functional state of NAc MSNs following cocaine exposure.

Otaka, Mami; Ishikawa, Masago; Lee, Brian R.; Liu, Lei; Neumann, Peter A.; Cui, Ranji; Huang, Yanhua; Schluter, Oliver M.; Dong, Yan

2013-01-01

185

Crossover inhibition in the retina: circuitry that compensates for nonlinear rectifying synaptic transmission.  

PubMed

In the mammalian retina, complementary ON and OFF visual streams are formed at the bipolar cell dendrites, then carried to amacrine and ganglion cells via nonlinear excitatory synapses from bipolar cells. Bipolar, amacrine and ganglion cells also receive a nonlinear inhibitory input from amacrine cells. The most common form of such inhibition crosses over from the opposite visual stream: Amacrine cells carry ON inhibition to the OFF cells and carry OFF inhibition to the ON cells ("crossover inhibition"). Although these synapses are predominantly nonlinear, linear signal processing is required for computing many properties of the visual world such as average intensity across a receptive field. Linear signaling is also necessary for maintaining the distinction between brightness and contrast. It has long been known that a subset of retinal outputs provide exactly this sort of linear representation of the world; we show here that rectifying (nonlinear) synaptic currents, when combined thorough crossover inhibition can generate this linear signaling. Using simple mathematical models we show that for a large set of cases, repeated rounds of synaptic rectification without crossover inhibition can destroy information carried by those synapses. A similar circuit motif is employed in the electronics industry to compensate for transistor nonlinearities in analog circuits. PMID:19636690

Molnar, Alyosha; Hsueh, Hain-Ann; Roska, Botond; Werblin, Frank S

2009-12-01

186

Melamine impairs spatial cognition and hippocampal synaptic plasticity by presynaptic inhibition of glutamatergic transmission in infant rats.  

PubMed

The scandal of melamine-contamination has not been quite blown out, since the toxicity of melamine continues to raise concerns for public health. It has been well known that fetus and infant periods play the most important roles in brain development, whereas little has been done on the harmful effects of melamine on the center nervous system (CNS) of children. In the present study, we investigated the effects of melamine on behavioral and electrophysiology alternations in rats, and the effects of melamine on synaptic transmission were examined using whole-cell patch-clamp technique in the hippocampal CA1 neurons of infant rats. Morris water maze (MWM) test showed that learning and memory abilities were impaired significantly by melamine. The long-time potentiation (LTP) test exhibited that the field excitatory postsynaptic potential (fEPSP) slopes were significantly lower in melamine group compared to that in control group. Furthermore, the data of whole-cell patch-clamp experiments showed that melamine decreased the frequencies of both spontaneous EPSCs (sEPSCs) and minitura EPSCs (mEPSCs) to the same extent (about 76% and 78% respectively). However, there were no significant changes in sEPSC or mEPSC amplitude or kinetics after melamine addition, indicating that the effect of melamine on glutamatergic transmission was probably presynaptic. In conclusion, melamine reduced the release of glutamate in presynaptic transmission of hippocampus, which partly resulted in diminished LTP and further damaged the function of learning and memory. PMID:21867740

Yang, Jiajia; An, Lei; Yao, Yang; Yang, Zhuo; Zhang, Tao

2011-11-18

187

The effects of geometrical parameters on synaptic transmission: a Monte Carlo simulation study.  

PubMed Central

Monte Carlo simulations of transmitter diffusion and its interactions with postsynaptic receptors have been used to study properties of quantal responses at central synapses. Fast synaptic responses characteristic of those recorded at glycinergic junctions on the teleost Mauthner cell (time to peak approximately 0.3-0.4 ms and decay time constant approximately 3-6 ms) served as the initial reference, and smaller contacts with fewer postsynaptic receptors were also modeled. Consistent with experimental findings, diffusion, simulated using a random walk algorithm and assuming a diffusion coefficient of 0.5-1.0 x 10(-5) cm2 s(-1), was sufficiently fast to account for transmitter removal from the synaptic cleft. Transmitter-receptor interactions were modeled as a two-step binding process, with the double-bound state having opened and closed conformations. Addition of a third binding step only slightly decreased response amplitude but significantly slowed both its rising and decay phases. The model allowed us to assess the sources of response variability and the likelihood of postsynaptic saturation as functions of multiple kinetic and spatial parameters. The method of nonstationary fluctuation analysis, typically used to estimate the number of functional channels at a synapse and single channel current, proved unreliable, presumably because the receptors in the postsynaptic matrix are not uniformly exposed to the same profile of transmitter concentration. Thus, the time course of the probability of channel opening most likely varies among receptors. Finally, possible substrates for phenomena of synaptic plasticity, such as long-term potentiation, were explored, including the diameter of the contact zone, defined by the region of pre- and postsynaptic apposition, the number and distribution of the receptors, and the degree of vesicle filling. Surprisingly, response amplitude is quite sensitive to the size of the receptor-free annulus surrounding the receptor cluster, such that expansion of the contact zone could produce an appreciable increase in quantal size, normally attributed to either the presence of more receptors or the release of more transmitter molecules. Images FIGURE 1 FIGURE 3 FIGURE 9

Kruk, P J; Korn, H; Faber, D S

1997-01-01

188

Modulation of hippocampal synaptic transmission by low concentrations of cell-permeant Ca 2+ chelators: effects of Ca 2+ affinity, chelator structure and binding kinetics  

Microsoft Academic Search

Calcium chelators are commonly used for fluorescence and electrophysiological studies of neuronal Ca2+ signalling. Recently, they have also been used as neuroprotectants. Since they buffer calcium ions, these agents also modify the same signals which are being studied. These properties may be used to modulate Ca2+ signals such as those involved in synaptic transmission, and may explain their neuroprotective mechanism.

I Spigelman; M Tymianski; C. M Wallace; P. L Carlen; A. A Velumian

1996-01-01

189

Hypoxia-induced loss of synaptic transmission is exacerbated in hippocampal slices of transgenic mice expressing C-terminal fragments of Alzheimer amyloid precursor protein.  

PubMed

To investigate the possible involvement of beta-amyloid (A beta) in disrupting neuronal function during ischemia, we examined whether overexpression of C-terminal fragments of beta-amyloid precursor protein (beta-APP) in transgenic (Tg) mice is capable of altering the capacity of hippocampus slices to recover synaptic transmission after transient hypoxic episodes. Recovery of synaptic transmission was monitored in area CA1 of perfused hippocampal slices prepared from both control and Tg mice. The results obtained indicate that hippocampal slices prepared from Tg mice exhibited a much lower level of recovery in synaptic transmission following reoxygenation. This reduction in the capacity of Tg slices to recover from hypoxia-induced impairment of synaptic transmission in the hippocampus does not appear to be related to pre-existing alterations in either functional or biochemical properties of glutamate receptors in Tg mice. The present results provide the first experimental evidence that overexpression of the C-terminal fragment of APP exacerbates functional damage of hippocampal neurons after hypoxic episodes. PMID:10401636

Ghribi, O; Lapierre, L; Girard, M; Ohayon, M; Nalbantoglu, J; Massicotte, G

1999-01-01

190

Modulation of GABAergic synaptic transmission by terminal nicotinic acetylcholine receptors in the central autonomic nucleus of the neonatal rat spinal cord  

Microsoft Academic Search

Using patch clamp recordings from an in vitro spinal cord slice preparation of neonatal rats (9–15days old), we characterized the GABAergic synaptic transmission in sympathetic preganglionic neurones (SPN) of the central autonomic nucleus (CA) of lamina X. Local applications of isoguvacine (100?M), a selective agonist at GABAA receptors, induced in all cells tested a chloride current which was abolished by

Riad Seddik; Rémy Schlichter; Jérôme Trouslard

2006-01-01

191

High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring.  

PubMed

Maternal folic acid supplementation is essential to reduce the risk of neural tube defects. We hypothesize that high levels of folic acid throughout gestation may produce neural networks more susceptible to seizure in offspring. We hence administered large doses of folic acid to rats before and during gestation and found their offspring had a 42% decrease in their seizure threshold. In vitro, acute application of folic acid or its metabolite 4Hfolate to neurons induced hyper-excitability and bursting. Cultured neuronal networks which develop in the presence of a low concentration (50 nM) of 4Hfolate had reduced capacity to stabilize their network dynamics after a burst of high-frequency activity, and an increase in the frequency of mEPSCs. Networks reared in the presence of the folic acid metabolite 5M4Hfolate developed a spontaneous, distinctive bursting pattern, and both metabolites produced an increase in synaptic density. PMID:23492951

Girotto, Fernando; Scott, Lucas; Avchalumov, Yosef; Harris, Jacqueline; Iannattone, Stephanie; Drummond-Main, Chris; Tobias, Rose; Bello-Espinosa, Luis; Rho, Jong M; Davidsen, Jörn; Teskey, G Campbell; Colicos, Michael A

2013-01-01

192

High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring  

PubMed Central

Maternal folic acid supplementation is essential to reduce the risk of neural tube defects. We hypothesize that high levels of folic acid throughout gestation may produce neural networks more susceptible to seizure in offspring. We hence administered large doses of folic acid to rats before and during gestation and found their offspring had a 42% decrease in their seizure threshold. In vitro, acute application of folic acid or its metabolite 4Hfolate to neurons induced hyper-excitability and bursting. Cultured neuronal networks which develop in the presence of a low concentration (50?nM) of 4Hfolate had reduced capacity to stabilize their network dynamics after a burst of high-frequency activity, and an increase in the frequency of mEPSCs. Networks reared in the presence of the folic acid metabolite 5M4Hfolate developed a spontaneous, distinctive bursting pattern, and both metabolites produced an increase in synaptic density.

Girotto, Fernando; Scott, Lucas; Avchalumov, Yosef; Harris, Jacqueline; Iannattone, Stephanie; Drummond-Main, Chris; Tobias, Rose; Bello-Espinosa, Luis; Rho, Jong M.; Davidsen, Jorn; Teskey, G. Campbell; Colicos, Michael A.

2013-01-01

193

Synaptic vesicle endocytosis.  

PubMed

Neurons can sustain high rates of synaptic transmission without exhausting their supply of synaptic vesicles. This property relies on a highly efficient local endocytic recycling of synaptic vesicle membranes, which can be reused for hundreds, possibly thousands, of exo-endocytic cycles. Morphological, physiological, molecular, and genetic studies over the last four decades have provided insight into the membrane traffic reactions that govern this recycling and its regulation. These studies have shown that synaptic vesicle endocytosis capitalizes on fundamental and general endocytic mechanisms but also involves neuron-specific adaptations of such mechanisms. Thus, investigations of these processes have advanced not only the field of synaptic transmission but also, more generally, the field of endocytosis. This article summarizes current information on synaptic vesicle endocytosis with an emphasis on the underlying molecular mechanisms and with a special focus on clathrin-mediated endocytosis, the predominant pathway of synaptic vesicle protein internalization. PMID:22763746

Saheki, Yasunori; De Camilli, Pietro

2012-09-01

194

Kv1.3 channels regulate synaptic transmission in the nucleus of solitary tract  

PubMed Central

The voltage-gated K+ channel Kv1.3 has been reported to regulate transmitter release in select central and peripheral neurons. In this study, we evaluated its role at the synapse between visceral sensory afferents and secondary neurons in the nucleus of the solitary tract (NTS). We identified mRNA and protein for Kv1.3 in rat nodose ganglia using RT-PCR and Western blot analysis. In immunohistochemical experiments, anti-Kv1.3 immunoreactivity was very strong in internal organelles in the soma of nodose neurons with a weaker distribution near the plasma membrane. Anti-Kv1.3 was also identified in the axonal branches that project centrally, including their presynaptic terminals in the medial and commissural NTS. In current-clamp experiments, margatoxin (MgTx), a high-affinity blocker of Kv1.3, produced an increase in action potential duration in C-type but not A- or Ah-type neurons. To evaluate the role of Kv1.3 at the presynaptic terminal, we examined the effect of MgTx on tract evoked monosynaptic excitatory postsynaptic currents (EPSCs) in brain slices of the NTS. MgTx increased the amplitude of evoked EPSCs in a subset of neurons, with the major increase occurring during the first stimuli in a 20-Hz train. These data, together with the results from somal recordings, support the hypothesis that Kv1.3 regulates the duration of the action potential in the presynaptic terminal of C fibers, limiting transmitter release to the postsynaptic cell.

Ramirez-Navarro, Angelina; Glazebrook, Patricia A.; Kane-Sutton, Michelle; Padro, Caroline; Kline, David D.

2011-01-01

195

Kv1.3 channels regulate synaptic transmission in the nucleus of solitary tract.  

PubMed

The voltage-gated K(+) channel Kv1.3 has been reported to regulate transmitter release in select central and peripheral neurons. In this study, we evaluated its role at the synapse between visceral sensory afferents and secondary neurons in the nucleus of the solitary tract (NTS). We identified mRNA and protein for Kv1.3 in rat nodose ganglia using RT-PCR and Western blot analysis. In immunohistochemical experiments, anti-Kv1.3 immunoreactivity was very strong in internal organelles in the soma of nodose neurons with a weaker distribution near the plasma membrane. Anti-Kv1.3 was also identified in the axonal branches that project centrally, including their presynaptic terminals in the medial and commissural NTS. In current-clamp experiments, margatoxin (MgTx), a high-affinity blocker of Kv1.3, produced an increase in action potential duration in C-type but not A- or Ah-type neurons. To evaluate the role of Kv1.3 at the presynaptic terminal, we examined the effect of MgTx on tract evoked monosynaptic excitatory postsynaptic currents (EPSCs) in brain slices of the NTS. MgTx increased the amplitude of evoked EPSCs in a subset of neurons, with the major increase occurring during the first stimuli in a 20-Hz train. These data, together with the results from somal recordings, support the hypothesis that Kv1.3 regulates the duration of the action potential in the presynaptic terminal of C fibers, limiting transmitter release to the postsynaptic cell. PMID:21430270

Ramirez-Navarro, Angelina; Glazebrook, Patricia A; Kane-Sutton, Michelle; Padro, Caroline; Kline, David D; Kunze, Diana L

2011-06-01

196

Segmental actions of afferents of the interosseous nerve in the cat.  

PubMed Central

Electrical stimulation of the interosseous nerve evokes oligosynaptic inhibition of extensor motoneurones and excitation of flexor motoneurones. Lowest-threshold, shortest-latency post-synaptic potentials evoked at group I strength are attributed to the action of group Ib afferents. Post-synaptic potentials evoked at slightly higher stimulus strengths (within the higher group I and the group II range) and at longer latency are attributed to the action of afferents of Pacinian corpuscles. Facilitation of post-synaptic potentials evoked from afferents in the interosseous nerve by group I muscle afferents and by joint afferents is taken to indicate convergence of these afferents onto common interneurones in reflex pathways to motoneurones. Evidence is presented that afferents of Pacinian corpuscles project to the interneurones mediating group I (non-reciprocal) reflex actions to motoneurones. Unitary monosynaptic excitatory post-synaptic potentials (e.p.s.p.s) evoked from the interosseous nerve are taken to indicate that only a very small number of muscle spindle Ia afferents course through the interosseous nerve. Dorsal root potentials evoked by low-strength electrical stimulation of the interosseous nerve are largely attributable to the action of afferents of Pacinian corpuscles.

Harrison, P J; Johannisson, T

1983-01-01

197

Effects of prolyl-hydroxylase inhibition and chronic intermittent hypoxia on synaptic transmission and plasticity in the rat CA1 and dentate gyrus.  

PubMed

Chronic intermittent hypoxia (CIH) is an underlying component of obstructive sleep apnoea and has been shown to have deleterious and damaging effects on central neurons and to impair synaptic plasticity in the CA1 region of the rat hippocampus. CIH has previously been shown to impair synaptic plasticity and working memory. CIH is a potent inducer of hypoxia inducible factor (HIF), a key regulator in a cell's adaptation to hypoxia that plays an important role in the fate of neurons during ischemia. Levels of HIF-1? are regulated by the activity of a group of enzymes called HIF-prolyl 4-hydroxylases (PHDs) and these have become potential pharmacological targets for preconditioning against ischemia. However little is known about the effects of prolyl hydroxylase inhibition and CIH on synaptic transmission and plasticity in sub-regions of the hippocampus. Male Wistar rats were treated for 7-days with either saline, CIH or PHD inhibition (dimethyloxaloylglycine, DMOG; 50mg/kg, i.p.). At the end of treatment all three groups showed no change in synaptic excitability using paired pulse paradigms. However long-term potentiation (LTP) was impaired in the CA1 region of the hippocampus in both CIH and DMOG treated animals. LTP induced in the dentate gyrus was not significantly affected by either CIH or DMOG treatment. We also investigated the effect of 7-day CIH and DMOG treatment on the recovery of synaptic transmission following an acute 30min hypoxic insult. CIH treated animals showed an improved rate of recovery of synaptic transmission following re-oxygenation in both the CA1 and the dentate gyrus. These results suggest that LTP induction in the CA1 region is more sensitive to both CIH and DMOG treatments than the dentate gyrus. PMID:24055213

Wall, Audrey M; Corcoran, Alan E; O'Halloran, Ken D; O'Connor, John J

2014-02-01

198

Drosophila-Cdh1 (Rap/Fzr) a regulatory subunit of APC/C is required for synaptic morphology, synaptic transmission and locomotion.  

PubMed

The assembly of functional synapses requires the orchestration of the synthesis and degradation of a multitude of proteins. Protein degradation and modification by the conserved ubiquitination pathway has emerged as a key cellular regulatory mechanism during nervous system development and function (Kwabe and Brose, 2011). The anaphase promoting complex/cyclosome (APC/C) is a multi-subunit ubiquitin ligase complex primarily characterized for its role in the regulation of mitosis (Peters, 2002). In recent years, a role for APC/C in nervous system development and function has been rapidly emerging (Stegmuller and Bonni, 2005; Li et al., 2008). In the mammalian central nervous system the activator subunit, APC/C-Cdh1, has been shown to be a regulator of axon growth and dendrite morphogenesis (Konishi et al., 2004). In the Drosophila peripheral nervous system (PNS), APC2, a ligase subunit of the APC/C complex has been shown to regulate synaptic bouton size and activity (van Roessel et al., 2004). To investigate the role of APC/C-Cdh1 at the synapse we examined loss-of-function mutants of Rap/Fzr (Retina aberrant in pattern/Fizzy related), a Drosophila homolog of the mammalian Cdh1 during the development of the larval neuromuscular junction in Drosophila. Our cell biological, ultrastructural, electrophysiological, and behavioral data showed that rap/fzr loss-of-function mutations lead to changes in synaptic structure and function as well as locomotion defects. Data presented here show changes in size and morphology of synaptic boutons, and, muscle tissue organization. Electrophysiological experiments show that loss-of-function mutants exhibit increased frequency of spontaneous miniature synaptic potentials, indicating a higher rate of spontaneous synaptic vesicle fusion events. In addition, larval locomotion and peristaltic movement were also impaired. These findings suggest a role for Drosophila APC/C-Cdh1 mediated ubiquitination in regulating synaptic morphology, function and integrity of muscle structure in the peripheral nervous system. PMID:23933137

Wise, Alexandria; Schatoff, Emma; Flores, Julian; Hua, Shao-Ying; Ueda, Atsushi; Wu, Chun-Fang; Venkatesh, Tadmiri

2013-11-01

199

Electrical and Chemical Modulation of Synaptic Efficacy.  

National Technical Information Service (NTIS)

To investigate how electric currents associated with Synaptic activity and chemical factors released by the pre- and postsynapic cells affect the efficacy of synaptic transmission, in order to understand the plasticity of synaptic functions at single neur...

M. Poo

1997-01-01

200

Cholinergic efferent synaptic transmission regulates the maturation of auditory hair cell ribbon synapses  

PubMed Central

Spontaneous electrical activity generated by developing sensory cells and neurons is crucial for the maturation of neural circuits. The full maturation of mammalian auditory inner hair cells (IHCs) depends on patterns of spontaneous action potentials during a ‘critical period’ of development. The intrinsic spiking activity of IHCs can be modulated by inhibitory input from cholinergic efferent fibres descending from the brainstem, which transiently innervate immature IHCs. However, it remains unknown whether this transient efferent input to developing IHCs is required for their functional maturation. We used a mouse model that lacks the ?9-nicotinic acetylcholine receptor subunit (?9nAChR) in IHCs and another lacking synaptotagmin-2 in the efferent terminals to remove or reduce efferent input to IHCs, respectively. We found that the efferent system is required for the developmental linearization of the Ca2+-sensitivity of vesicle fusion at IHC ribbon synapses, without affecting their general cell development. This provides the first direct evidence that the efferent system, by modulating IHC electrical activity, is required for the maturation of the IHC synaptic machinery. The central control of sensory cell development is unique among sensory systems.

Johnson, Stuart L.; Wedemeyer, Carolina; Vetter, Douglas E.; Adachi, Roberto; Holley, Matthew C.; Elgoyhen, Ana Belen; Marcotti, Walter

2013-01-01

201

Linker mutations reveal the complexity of synaptotagmin 1 action during synaptic transmission.  

PubMed

The Ca(2+) sensor for rapid synaptic vesicle exocytosis, synaptotagmin 1 (syt), is largely composed of two Ca(2+)-sensing C2 domains, C2A and C2B. We investigated the apparent synergy between the tandem C2 domains by altering the length and rigidity of the linker that connects them. The behavior of the linker mutants revealed a correlation between the ability of the C2 domains to penetrate membranes in response to Ca(2+) and to drive evoked neurotransmitter release in cultured mouse neurons, uncovering a step in excitation-secretion coupling. Using atomic force microscopy, we found that the synergy between these C2 domains involved intra-molecular interactions between them. Thus, syt function is markedly affected by changes in the physical nature of the linker that connects its tandem C2 domains. Moreover, the linker mutations uncoupled syt-mediated regulation of evoked and spontaneous release, revealing that syt also acts as a fusion clamp before the Ca(2+) trigger. PMID:24657966

Liu, Huisheng; Bai, Hua; Xue, Renhao; Takahashi, Hirohide; Edwardson, J Michael; Chapman, Edwin R

2014-05-01

202

An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus  

PubMed Central

Neuroligins are evolutionarily conserved postsynaptic cell-adhesion molecules that function, at least in part, by forming trans-synaptic complexes with presynaptic neurexins. Different neuroligin isoforms perform diverse functions and exhibit distinct intracellular localizations, but contain similar cytoplasmic sequences whose role remains largely unknown. Here, we analysed the effect of a single amino-acid substitution (R704C) that targets a conserved arginine residue in the cytoplasmic sequence of all neuroligins, and that was associated with autism in neuroligin-4. We introduced the R704C mutation into mouse neuroligin-3 by homologous recombination, and examined its effect on synapses in vitro and in vivo. Electrophysiological and morphological studies revealed that the neuroligin-3 R704C mutation did not significantly alter synapse formation, but dramatically impaired synapse function. Specifically, the R704C mutation caused a major and selective decrease in AMPA receptor-mediated synaptic transmission in pyramidal neurons of the hippocampus, without similarly changing NMDA or GABA receptor-mediated synaptic transmission, and without detectably altering presynaptic neurotransmitter release. Our results suggest that the cytoplasmic tail of neuroligin-3 has a central role in synaptic transmission by modulating the recruitment of AMPA receptors to postsynaptic sites at excitatory synapses.

Etherton, Mark R; Tabuchi, Katsuhiko; Sharma, Manu; Ko, Jaewon; Sudhof, Thomas C

2011-01-01

203

Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice.  

PubMed

Familial hemiplegic migraine type 1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. In FHM1 knockin mice, excitatory neurotransmission at cortical pyramidal cell synapses is enhanced, but inhibitory neurotransmission at connected pairs of fast-spiking (FS) interneurons and pyramidal cells is unaltered, despite being initiated by CaV2.1 channels. The mechanism underlying the unaltered GABA release at cortical FS interneuron synapses remains unknown. Here, we show that the FHM1 R192Q mutation does not affect inhibitory transmission at autapses of cortical FS and other types of multipolar interneurons in microculture from R192Q knockin mice, and investigate the underlying mechanism. Lowering the extracellular [Ca(2+)] did not reveal gain-of-function of evoked transmission neither in control nor after prolongation of the action potential (AP) with tetraethylammonium, indicating unaltered AP-evoked presynaptic calcium influx at inhibitory autapses in FHM1 KI mice. Neither saturation of the presynaptic calcium sensor nor short duration of the AP can explain the unaltered inhibitory transmission in the mutant mice. Recordings of the P/Q-type calcium current in multipolar interneurons in microculture revealed that the current density and the gating properties of the CaV2.1 channels expressed in these interneurons are barely affected by the FHM1 mutation, in contrast with the enhanced current density and left-shifted activation gating of mutant CaV2.1 channels in cortical pyramidal cells. Our findings suggest that expression of specific CaV2.1 channels differentially sensitive to modulation by FHM1 mutations in inhibitory and excitatory cortical neurons underlies the gain-of-function of excitatory but unaltered inhibitory synaptic transmission and the likely consequent dysregulation of the cortical excitatory-inhibitory balance in FHM1. PMID:24907493

Vecchia, Dania; Tottene, Angelita; van den Maagdenberg, Arn M J M; Pietrobon, Daniela

2014-09-01

204

Dynamic tuning of electrical and chemical synaptic transmission in a network of motion coding retinal neurons.  

PubMed

Recently, we demonstrated that gap junction coupling in the population of superior coding ON-OFF directionally selective ganglion cells (DSGCs) genetically labeled in the Hb9::eGFP mouse retina allows the passage of lateral anticipatory signals that help track moving stimuli. Here, we examine the properties of gap junctions in the DSGC network, and address how interactions between electrical and chemical synapses and intrinsic membrane properties contribute to the dynamic tuning of lateral anticipatory signals. When DSGC subtypes coding all four cardinal directions were individually loaded with the gap junction-permeable tracer Neurobiotin, only superior coding DSGCs exhibited homologous coupling. Consistent with these anatomical findings, gap junction-dependent feedback spikelets were only observed in Hb9(+) DSGCs. Recordings from pairs of neighboring Hb9(+) DSGCs revealed that coupling was reciprocal, non-inactivating, and relatively weak, and provided a substrate for an extensive subthreshold excitatory receptive field around each cell. This subthreshold activity appeared to boost coincident light-driven chemical synaptic responses. However, during responses to moving stimuli, gap junction-mediated boosting appeared to be dynamically modulated such that upstream DSGCs primed downstream cells, but not vice versa, giving rise to highly skewed responses in individual cells. We show that the asymmetry in priming arises from a combination of spatially offset GABAergic inhibition and activity-dependent changes in intrinsic membrane properties of DSGCs. Thus, dynamic interactions between electrical and chemical synapses and intrinsic membrane properties allow the network of DSGCs to propagate anticipatory responses most effectively along their preferred direction without leading to runaway excitation. PMID:24027292

Trenholm, Stuart; McLaughlin, Amanda J; Schwab, David J; Awatramani, Gautam B

2013-09-11

205

Suppression by zinc of AMPA receptor-mediated synaptic transmission in the retina.  

PubMed

Zinc is strikingly co-localized with glutamate-containing vesicles in the synaptic terminals of retinal photoreceptors, and it is thought to be co-released with glutamate onto postsynaptic neurons such as horizontal cells and bipolar cells. Here we examined exogenous zinc modulation of glutamate receptors on cultured retinal horizontal cells using patch-clamp recording and endogenous zinc effect on intact horizontal cells using intracellular recording techniques. Application of 3, 30, and 300 microM zinc reduced the whole cell peak current of response to 200 microM glutamate by 2, 30, and 56%, respectively. Zinc suppression of glutamate response persisted in the presence of 10 microM cyclothiazide (CTZ). Glutamate responses of outside-out patches were completely abolished by 30 microM 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), and the receptor desensitization was blocked by 30 microM CTZ, indicating that receptor target for the zinc action on horizontal cells is alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproponic acid (AMPA) receptors. Zinc decreased the amplitude of outside-out patch peak current without an effect on either its 10-90% rise time or the rate of receptor desensitization. Dose-response curves for glutamate show that zinc reduced the maximal current evoked by glutamate and increased EC(50) from 50 +/- 3 to 70 +/- 6 microM without changing the Hill coefficient. Chelation of endogenous zinc with 1 mM Ca-EDTA depolarized horizontal cells in the intact retina by 3 mV, consistent with relief of the partial glutamate receptor inhibition by zinc. Overall, the results describe a unimodal form of zinc modulation of AMPA-type glutamate receptor responses not previously described in native neuronal preparations and a novel role for endogenous zinc in modulating neurotransmission. PMID:12205145

Zhang, Dao-Qi; Ribelayga, Christophe; Mangel, Stuart C; McMahon, Douglas G

2002-09-01

206

Effects of Vitamin B 1 Antagonists on Synaptic Transmission in a Striated Muscle of the Mouse  

Microsoft Academic Search

We studied the effects of antagonists of vitamin ?1, pyrithiamine and oxythiamine, on neuromuscular transmission in the diaphragmatic muscle of the mouse. In isolated phrenico-hemidiaphragmatic\\u000a preparations obtained from animals i.p. injected with 100 mg\\/kg pyrithiamine 1.5 h earlier, the amplitudes of miniature end-plate\\u000a potentials (mEPPs) and evoked end-plate potentials (EPPs), as well as an estimate of the quantum content of EPP, were

A. V. Romanenko; S. E. Shepelev

2008-01-01

207

[Facilitation of synaptic transmission and connections of entorhinal-hippocampal pathway by 5-HT2C receptor subtype: multi-electrode array recordings].  

PubMed

Using 64-channels (8 × 8) multi-electrode array technique (MED-64 system), the modulatory actions of 5-hydroxytryptamine (5-HT) 2C receptor subtype on the entorhinal (EC)-hippocampal synaptic transmission and connections were studied. One of freshly dissociated acute hippocampal slices of rats which was placed on the MED-64 probe, was subject to constant perfusion with oxygenated artificial cerebrospinal fluid (ACSF, 95% O2 and 5% CO2). Two hours after ACSF incubation, simultaneous multi-site electrophysiological recordings were performed. One electrode was selected to be used for perforant path (PP) stimulation, and the remaining 63 electrodes were used for recordings of network field excitatory postsynaptic potentials (fEPSPs) within both CA1 and dentate gyrus (DG) that have been previously proved to be mediated by glutamate non-NMDA receptors. After stability of network fEPSPs was achieved, (±)-1(2, 5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, an agonist of 5-HT2C receptor subtype), or SB242084 (6-Chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride hydrate) (a selective antagonist of 5-HT2C receptor subtype) was applied for 10 min perfusion, respectively. Two-dimensional current source density (2D-CSD) analysis was also transformed by bilinear interpolation at each point of the 64 electrodes for spatial imaging of the fEPSP network responses. Based upon the polarities of fEPSP and 2D-CSD imaging, it was clearly shown that synaptic activations were evoked to occur within the molecular layer of DG and pyramidal cell layer of CA1 by the PP stimulation in which negative-going field potentials and current sink (blue) could be recorded. While, positive-going field potentials and current source (yellow) were mainly localized within the granule cell layer and hilus of DG and alveus of CA1, reflecting spread of electrical signals derived from depolarized region toward CA3 area or subiculum and fimbria along the axons. Perfusion of the hippocampal slices with DOI resulted in a significant enlargement of synaptic connection size at network level and enhancement of synaptic efficacy. However, on the contrary, perfusion with SB242084 produced reversal effect with either reduction in synaptic network size or decreased magnitude of fEPSPs (amplitude and slope) in the CA1 and DG. These results suggest that endogenous 5-HT causes facilitation of EC-CA1 and EC-DG synaptic transmission and connections via acting on 5-HT2C receptor subtype, leading to gain in synaptic transmission and enlargement of synaptic connections. PMID:22717628

Xu, Yan; Jin, Jian-Hui; Wang, Yan; Wang, Rui-Rui; Li, Zhen; Chen, Jun

2012-06-25

208

The neurotrophin hypothesis for synaptic plasticity  

Microsoft Academic Search

The neurotrophin hypothesis proposes that neurotrophins participate in activity-induced modification of synaptic transmission. Increasingly, evidence indicates that the synthesis, secretion and actions of neurotrophins on synaptic transmission are regulated by electrical activity and that neurotrophins themselves can acutely modify synaptic efficacy. Neurotrophins appear to exert either a permissive or instructive role on activity-dependent synaptic potentiation and depression, which depends on

Alejandro F Schinder; Mu-ming Poo

2000-01-01

209

TH-9 (a theophylline derivative) induces long-lasting enhancement in excitatory synaptic transmission in the rat hippocampus that is occluded by frequency-dependent plasticity in vitro.  

PubMed

Dementia, especially Alzheimer's disease, is a rapidly increasing medical condition that presents with enormous challenge for treatment. It is characterized by impairment in memory and cognitive function often accompanied by changes in synaptic transmission and plasticity in relevant brain regions such as the hippocampus. We recently synthesized TH-9, a conjugate racetam-methylxanthine compound and tested if it had potential for enhancing synaptic function and possibly, plasticity, by examining its effect on hippocampal fast excitatory synaptic transmission and plasticity. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 hippocampal area of naïve juvenile male Sprague-Dawley rats using conventional electrophysiological recording techniques. TH-9 caused a concentration-dependent, long-lasting enhancement in fEPSPs. This effect was blocked by adenosine A1, acetylcholine (muscarinic and nicotinic) and glutamate (N-methyl-d-aspartate) receptor antagonists but not by a ?-aminobutyric acid receptor type B (GABA(B)) receptor antagonist. The TH-9 effect was also blocked by enhancing intracellular cyclic adenosine monophosphate and inhibiting protein kinase A. Pretreatment with TH-9 did not prevent the induction of long-term potentiation (LTP) or long-term depression (LTD). Conversely, induction of LTP or LTD completely occluded the ability of TH-9 to enhance fEPSPs. Thus, TH-9 utilizes cholinergic and adenosinergic mechanisms to cause long-lasting enhancement in fEPSPs which were occluded by LTP and LTD. TH-9 may therefore employ similar or convergent mechanisms with frequency-dependent synaptic plasticities to produce the observed long-lasting enhancement in synaptic transmission and may thus, have potential for use in improving memory. PMID:22728090

Nashawi, H; Bartl, T; Bartl, P; Novotny, L; Oriowo, M A; Kombian, S B

2012-09-18

210

Effect of insulin on excitatory synaptic transmission onto dopamine neurons of the ventral tegmental area in a mouse model of hyperinsulinemia  

PubMed Central

Obesity has drastically increased over the last few decades. Obesity is associated with elevated insulin levels, which can gain access to the brain, including into dopamine neurons of the ventral tegmental area (VTA), a brain region critical for mediating reward-seeking behavior. Synaptic plasticity of VTA dopamine neurons is associated with altered motivation to obtain reinforcing substances such as food and drugs of abuse. Under physiological circumstances, insulin in the VTA can suppress excitatory synaptic transmission onto VTA dopamine neurons and reduce aspects of palatable feeding behavior. However, it is unknown how insulin modulates excitatory synaptic transmission in pathological circumstances such as hyperinsulinemia. Using patch-clamp electrophysiology, we demonstrate that, in a hyperinsulinemic mouse model, insulin has reduced capacity to cause a synaptic depression of VTA dopamine neurons, although both low-frequency stimulation-induced long-term depression and cannabinoid-induced depression were normal. These results suggest that insulin action in the VTA during pathological hyperinsulinemia is disrupted and may lead to increased feeding behavior.

Liu, S; Labouebe, G; Karunakaran, S; Clee, S M; Borgland, S L

2013-01-01

211

The Nuclear Calcium Signaling Target, Activating Transcription Factor 3 (ATF3), Protects against Dendrotoxicity and Facilitates the Recovery of Synaptic Transmission after an Excitotoxic Insult.  

PubMed

The focal swellings of dendrites ("dendritic beading") are an early morphological hallmark of neuronal injury and dendrotoxicity. They are associated with a variety of pathological conditions, including brain ischemia, and cause an acute disruption of synaptic transmission and neuronal network function, which contribute to subsequent neuronal death. Here, we show that increased synaptic activity prior to excitotoxic injury protects, in a transcription-dependent manner, against dendritic beading. Expression of activating transcription factor 3 (ATF3), a nuclear calcium-regulated gene and member of the core gene program for acquired neuroprotection, can protect against dendritic beading. Conversely, knockdown of ATF3 exacerbates dendritic beading. Assessment of neuronal network functions using microelectrode array recordings revealed that hippocampal neurons expressing ATF3 were able to regain their ability for functional synaptic transmission and to participate in coherent neuronal network activity within 48 h after exposure to toxic concentrations of NMDA. Thus, in addition to attenuating cell death, synaptic activity and expression of ATF3 render hippocampal neurons more resistant to acute dendrotoxicity and loss of synapses. Dendroprotection can enhance recovery of neuronal network functions after excitotoxic insults. PMID:24515113

Ahlgren, Hanna; Bas-Orth, Carlos; Freitag, H Eckehard; Hellwig, Andrea; Ottersen, Ole Petter; Bading, Hilmar

2014-04-01

212

Neurones in the brain stem of the cat excited by vagal afferent fibres from the heart and lungs.  

PubMed Central

Extracellular recordings were made from 164 neurones in the nucleus tractus solitarius and dorsal motor vagal nucleus of the chloralose-anaesthetized cat. 139 neurones were excited synaptically and 25 non-synaptically by electrical stimulation of cardiac and pulmonary vagal branches. Synaptically excited neurones fall into two populations, one activated solely by myelinated afferent fibres and a second activated solely by non-myelinated afferent fibres. 94 neurones were synaptically excited by afferent fibres in a single vagal branch while 45 were excited by stimulation of two or three branches. Neurones responding to volleys in myelinated afferent fibres were located in both medial and lateral regions of the nucleus tractus solitarius whilst those excited by non-myelinated afferent fibres were restricted to the medial region. Consistent differences in the locations of neurones excited by stimulation of either cardiac or pulmonary or by single or several branches could not be distinguished.

Bennett, J A; Goodchild, C S; Kidd, C; McWilliam, P N

1985-01-01

213

RGS9-2 modulates nociceptive behaviour and opioid-mediated synaptic transmission in the spinal dorsal horn  

PubMed Central

The regulator of G protein signaling 9-2 (RGS9-2) is a constituent of G protein-coupled receptor (GPCR) macromolecular complexes with a major role in regulation of GPCR activity in the central nervous system. Previous in situ hybridization and Western blot studies revealed that RGS9-2 is expressed in the superficial dorsal horn of the spinal cord. In the present study, we monitored tail withdrawal latencies to noxious thermal stimuli and performed in vitro whole-cell patch clamp electrophysiological recordings from neurons in lamina II of the spinal dorsal horn to examine the role of RGS9-2 in the dorsal horn of the spinal cord in nociceptive behaviours and opiate mediated modulation of synaptic transmission. Our findings obtained from RGS9 knockout mice indicate that the lack of RGS9-2 protein decreases sensitivity to thermal stimuli and to the analgesic actions of morphine in the tail immersion paradigm. This modulatory role of RGS9-2 on opiate-mediated responses was further supported by electrophysiological studies showing that hyperpolarization of neurons in lamina II of the spinal dorsal horn evoked by application of DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin, a mu opioid receptor agonist) was diminished in RGS9 knockout mice. The results indicate that RGS9-2 enhances the effect of morphine and may play a crucial role in opiate-mediated analgesic mechanisms at the level of the spinal cord.

Papachatzaki, Maria Martha; Antal, Zsofia; Terzi, Dimitra; Szucs, Peter; Zachariou, Venetia; Antal, Miklos

2012-01-01

214

RGS9-2 modulates nociceptive behaviour and opioid-mediated synaptic transmission in the spinal dorsal horn.  

PubMed

The regulator of G protein signaling 9-2 (RGS9-2) is a constituent of G protein-coupled receptor (GPCR) macromolecular complexes with a major role in regulation of GPCR activity in the central nervous system. Previous in situ hybridization and Western blot studies revealed that RGS9-2 is expressed in the superficial dorsal horn of the spinal cord. In the present study, we monitored tail withdrawal latencies to noxious thermal stimuli and performed in vitro whole-cell patch clamp electrophysiological recordings from neurons in lamina II of the spinal dorsal horn to examine the role of RGS9-2 in the dorsal horn of the spinal cord in nociceptive behaviours and opiate mediated modulation of synaptic transmission. Our findings obtained from RGS9 knockout mice indicate that the lack of RGS9-2 protein decreases sensitivity to thermal stimuli and to the analgesic actions of morphine in the tail immersion paradigm. This modulatory role of RGS9-2 on opiate-mediated responses was further supported by electrophysiological studies showing that hyperpolarization of neurons in lamina II of the spinal dorsal horn evoked by application of DAMGO ([d-Ala2, N-MePhe4, Gly-ol]-enkephalin, a mu opioid receptor agonist) was diminished in RGS9 knockout mice. The results indicate that RGS9-2 enhances the effect of morphine and may play a crucial role in opiate-mediated analgesic mechanisms at the level of the spinal cord. PMID:21741448

Papachatzaki, Maria Martha; Antal, Zsófia; Terzi, Dimitra; Szücs, Péter; Zachariou, Venetia; Antal, Miklós

2011-08-21

215

The chemokine BRAK/CXCL14 regulates synaptic transmission in the adult mouse dentate gyrus stem cell niche  

PubMed Central

The chemokine BRAK/CXCL14 is an ancient member of the chemokine family whose functions in the brain are completely unknown. We examined the distribution of CXCL14 in the nervous system during development and in the adult. Generally speaking CXCL14 was not expressed in the nervous system prior to birth, but it was expressed in the developing whisker follicles (E14.5) and subsequently in the hair follicles and skin. Postnatally, CXCL14 was also highly expressed in many regions of the brain, including the cortex, basal ganglia, septum and hippocampus. CXCL14 was also highly expressed in the dorsal root ganglia. We observed that in the hippocampal dentate gyrus (DG) CXCL14 was expressed by GABAergic interneurons. We demonstrated that CXCL14 inhibited GABAergic transmission to nestin-EGFP expressing neural stem/progenitor cells in the adult DG. CXCL14 inhibited both the tonic and phasic effects of synaptically released GABA. In contrast CXCL12 enhanced the effects of GABA at these same synapses. CXCL14 increased [Ca2+]i in neural stem cells cultured from the postnatal brain indicating that they expressed the CXCL14 receptor. These observations are consistent with the view that CXCL12 and CXCL14 may normally act as positive and negative regulators of the effects of GABA in the adult DG stem cell niche.

Banisadr, Ghazal; Bhattacharyya, Bula; Belmadani, Abdelhak; Izen, Sarah C; Ren, Dongjun; Tran, Phuong B; Miller, Richard J

2011-01-01

216

Mutations that disrupt Ca2+-binding activity endow Doc2? with novel functional properties during synaptic transmission  

PubMed Central

Double C2-domain protein (Doc2) is a Ca2+-binding protein implicated in asynchronous and spontaneous neurotransmitter release. Here we demonstrate that each of its C2 domains senses Ca2+; moreover, the tethered tandem C2 domains display properties distinct from the isolated domains. We confirm that overexpression of a mutant form of Doc2?, in which two acidic Ca2+ ligands in the C2A domain and two in the C2B domain have been neutralized, results in markedly enhanced asynchronous release in synaptotagmin 1–knockout neurons. Unlike wild-type (wt) Doc2?, which translocates to the plasma membrane in response to increases in [Ca2+]i, the quadruple Ca2+-ligand mutant does not bind Ca2+ but is constitutively associated with the plasma membrane; this effect is due to substitution of Ca2+ ligands in the C2A domain. When overexpressed in wt neurons, Doc2? affects only asynchronous release; in contrast, Doc2? Ca2+-ligand mutants that constitutively localize to the plasma membrane enhance both the fast and slow components of synaptic transmission by increasing the readily releasable vesicle pool size; these mutants also increase the frequency of spontaneous release events. Thus, mutations in the C2A domain of Doc2? that were intended to disrupt Ca2+ binding result in an anomalous enhancement of constitutive membrane-binding activity and endow Doc2? with novel functional properties.

Gaffaney, Jon D.; Xue, Renhao; Chapman, Edwin R.

2014-01-01

217

The anti-dementia drug nefiracetam facilitates hippocampal synaptic transmission by functionally targeting presynaptic nicotinic ACh receptors.  

PubMed

Nefiracetam, a pyrrolidone derivative developed as an anti-dementia drug, persistently potentiated currents through neuronal nicotinic acetylcholine (ACh) receptors (alpha7, alpha4beta2) expressed in Xenopus oocytes, and the potentiation was blocked by either the selective protein kinase C (PKC) inhibitors, GF109203X and staurosporine, or co-expressed active PKC inhibitor peptide. In primary cultures of rat hippocampal neurons, nefiracetam increased the rate of nicotine-sensitive miniature excitatory postsynaptic currents, without affecting the amplitude, and the increase was inhibited by GF109203X. In addition, the drug caused a marked increase in the glutamate release from electrically stimulated guinea pig hippocampal slices, and the effect was abolished by the nicotinic ACh receptor antagonists, alpha-bungarotoxin and mecamylamine. Nefiracetam induced a long-lasting facilitation of synaptic transmission in both the CA1 area and the dentate gyrus of rat hippocampal slices, and the facilitation was inhibited by alpha-bungarotoxin and mecamylamine. Such facilitatory action was still found in the hippocampus with selective cholinergic denervation. The results of the present study, thus, suggest that nefiracetam enhances activity of nicotinic ACh receptors by interacting with a PKC pathway, thereby increasing glutamate release from presynaptic terminals, and then leading to a sustained facilitation of hippocampal neurotransmission. This may represent a cellular mechanism underlying the cognition-enhancing action of nefiracetam. The results also provide the possibility that nefiracetam could be developed as a promising therapeutic drug for senile dementia or Alzheimer's disease. PMID:11039729

Nishizaki, T; Nomura, T; Matuoka, T; Kondoh, T; Enikolopov, G; Enikolopo, G; Sumikawa, K; Watabe, S; Shiotani, T; Yoshii, M

2000-08-14

218

Inhibitory effects of dopamine on spinal synaptic transmission via dopamine D1-like receptors in neonatal rats  

PubMed Central

BACKGROUND AND PURPOSE Dopamine released from the endings of descending dopaminergic nerve fibres in the spinal cord may be involved in modulating functions such as locomotion and nociception. Here, we examined the effects of dopamine on spinal synaptic transmissions in rats. EXPERIMENTAL APPROACH Spinal reflex potentials, monosynaptic reflex potential (MSR) and slow ventral root potential (sVRP), were measured in the isolated spinal cord of the neonatal rat. Dopamine release was measured by HPLC. KEY RESULTS Dopamine at lower concentrations (<1 µM) depressed sVRP, which is a C fibre-evoked polysynaptic response and believed to reflect nociceptive transmission. At higher concentrations (>1 µM), in addition to a potent sVRP depression, dopamine depolarized baseline potential and slightly depressed MSR. Depression of sVRP by dopamine was partially reversed by dopamine D1-like but not by D2-like receptor antagonists. SKF83959 and SKF81297, D1-like receptor agonists, and methamphetamine, an endogenous dopamine releaser, also caused the inhibition of sVRP. Methamphetamine also depressed MSR, which was inhibited by ketanserin, a 5-HT2A/2C receptor antagonist. Methamphetamine induced the release of dopamine and 5-HT from spinal cords, indicating that the release of endogenous dopamine and 5-HT depresses sVRP and MSR respectively. CONCLUSION AND IMPLICATIONS These results suggested that dopamine at lower concentrations preferentially inhibited sVRP, which is mediated via dopamine D1-like and other unidentified receptors. The dopamine-evoked depression is involved in modulating the spinal functions by the descending dopaminergic pathways.

Kawamoto, K; Otsuguro, K; Ishizuka, M; Ito, S

2012-01-01

219

Presynaptic Calcium Stores Modulate Afferent Release in Vestibular Hair Cells  

Microsoft Academic Search

Hair cells, the mechanoreceptors of the acoustic and vestibular system, are presynaptic to primary afferent neurons of the eighth nerve and excite neural activity by the release of glutamate. In the present work, the role played by intracellular Ca 2 stores in afferent transmission was investigated, at the presynaptic level, by monitoring changes in the intracellular Ca 2 concentration ((Ca

Andrea Lelli; Paola Perin; Marta Martini; Catalin D. Ciubotaru; Ivo Prigioni; Paolo Valli; Maria L. Rossi; Fabio Mammano

2003-01-01

220

Histamine H 3 receptor-mediated suppression of inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine  

Microsoft Academic Search

Conventional intracellular microelectrodes and marker injection techniques were used to study the actions of histamine on inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine. Bath application of histamine (1–300 ?M) reversibly suppressed both noradrenergic and non-adrenergic slow inhibitory postsynaptic potentials in a concentration-dependent manner. These effects of histamine were mimicked by the selective histamine H3 receptor agonist

Sumei Liu; Yun Xia; Hong-Zhen Hu; Jun Ren; Chuanyun Gao; Jackie D. Wood

2000-01-01

221

Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.  

PubMed

The Pten and Tsc1 genes both encode proteins that repress mechanistic target of rapamycin (mTOR) signaling. Disruption of either gene in the brain results in epilepsy and autism-like symptoms in humans and mouse models, therefore it is important to understand the molecular and physiological events that lead from gene disruption to disease phenotypes. Given the similar roles these two molecules play in the regulation of cellular growth and the overlap in the phenotypes that result from their loss, we predicted that the deletion of either the Pten or Tsc1 gene from autaptic hippocampal neurons would have similar effects on neuronal morphology and synaptic transmission. Accordingly, we found that loss of either Pten or Tsc1 caused comparable increases in soma size, dendrite length and action potential properties. However, the effects of Pten and Tsc1 loss on synaptic transmission were different. Loss of Pten lead to an increase in both excitatory and inhibitory neurotransmission, while loss of Tsc1 did not affect excitatory neurotransmission and reduced inhibitory transmission by decreasing mIPSC amplitude. Although the loss of Pten or Tsc1 both increased downstream mTORC1 signaling, phosphorylation of Akt was increased in Pten-ko and decreased in Tsc1-ko neurons, potentially accounting for the different effects on synaptic transmission. Despite the different effects at the synaptic level, our data suggest that loss of Pten or Tsc1 may both lead to an increase in the ratio of excitation to inhibition at the network level, an effect that has been proposed to underlie both epilepsy and autism. PMID:24574959

Weston, Matthew C; Chen, Hongmei; Swann, John W

2014-01-01

222

Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures  

PubMed Central

The Pten and Tsc1 genes both encode proteins that repress mechanistic target of rapamycin (mTOR) signaling. Disruption of either gene in the brain results in epilepsy and autism-like symptoms in humans and mouse models, therefore it is important to understand the molecular and physiological events that lead from gene disruption to disease phenotypes. Given the similar roles these two molecules play in the regulation of cellular growth and the overlap in the phenotypes that result from their loss, we predicted that the deletion of either the Pten or Tsc1 gene from autaptic hippocampal neurons would have similar effects on neuronal morphology and synaptic transmission. Accordingly, we found that loss of either Pten or Tsc1 caused comparable increases in soma size, dendrite length and action potential properties. However, the effects of Pten and Tsc1 loss on synaptic transmission were different. Loss of Pten lead to an increase in both excitatory and inhibitory neurotransmission, while loss of Tsc1 did not affect excitatory neurotransmission and reduced inhibitory transmission by decreasing mIPSC amplitude. Although the loss of Pten or Tsc1 both increased downstream mTORC1 signaling, phosphorylation of Akt was increased in Pten-ko and decreased in Tsc1-ko neurons, potentially accounting for the different effects on synaptic transmission. Despite the different effects at the synaptic level, our data suggest that loss of Pten or Tsc1 may both lead to an increase in the ratio of excitation to inhibition at the network level, an effect that has been proposed to underlie both epilepsy and autism.

Weston, Matthew C.; Chen, Hongmei; Swann, John W.

2014-01-01

223

Targeted expression of tetanus toxin light chain in Drosophila specifically eliminates synaptic transmission and causes behavioral defects  

Microsoft Academic Search

Tetanus toxin cleaves the synaptic vesicle protein synaptobrevin, and the ensuing loss of neurotransmitter exocytosis has implicated synaptobrevin in this process. To further the study of synaptic function in a genetically tractable organism and to generate a tool to disable neuronal communication for behavioural studies, we have expressed a gene encoding tetanus toxin light chain in Drosophila. Toxin expression in

Sean T Sweeney; Kendal Broadie; John Keane; Heiner Niemann; Cahir J O'Kane

1995-01-01

224

Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling.  

PubMed

Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders (ASDs), including Neuroligins, Neurexins, and members of the ProSAP/Shank family, thereby suggesting that these genetic forms of autism may share common synaptic mechanisms. Initial studies of ASD-associated mutations in ProSAP2/Shank3 support a role for this protein in glutamate receptor function and spine morphology, but these synaptic phenotypes are not universally penetrant, indicating that other core facets of ProSAP2/Shank3 function must underlie synaptic deficits in patients with ASDs. In the present study, we have examined whether the ability of ProSAP2/Shank3 to interact with the cytoplasmic tail of Neuroligins functions to coordinate pre/postsynaptic signaling through the Neurexin-Neuroligin signaling complex in hippocampal neurons of Rattus norvegicus. Indeed, we find that synaptic levels of ProSAP2/Shank3 regulate AMPA and NMDA receptor-mediated synaptic transmission and induce widespread changes in the levels of presynaptic and postsynaptic proteins via Neurexin-Neuroligin transsynaptic signaling. ASD-associated mutations in ProSAP2/Shank3 disrupt not only postsynaptic AMPA and NMDA receptor signaling but also interfere with the ability of ProSAP2/Shank3 to signal across the synapse to alter presynaptic structure and function. These data indicate that ASD-associated mutations in a subset of synaptic proteins may target core cellular pathways that coordinate the functional matching and maturation of excitatory synapses in the CNS. PMID:23100419

Arons, Magali H; Thynne, Charlotte J; Grabrucker, Andreas M; Li, Dong; Schoen, Michael; Cheyne, Juliette E; Boeckers, Tobias M; Montgomery, Johanna M; Garner, Craig C

2012-10-24

225

Simvastatin Treatment Enhances NMDAR-Mediated Synaptic Transmission by Upregulating the Surface Distribution of the GluN2B Subunit.  

PubMed

The ramifications of statins on plasma cholesterol and coronary heart disease have been well documented. However, there is increasing evidence that inhibition of the mevalonate pathway may provide independent neuroprotective and procognitive pleiotropic effects, most likely via inhibition of isoprenoids, mainly farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). FPP and GGPP are the major donors of prenyl groups for protein prenylation. Modulation of isoprenoid availability impacts a slew of cellular processes including synaptic plasticity in the hippocampus. Our previous work has demonstrated that simvastatin (SV) administration improves hippocampus-dependent spatial memory, rescuing memory deficits in a mouse model of Alzheimer's disease. Treatment of hippocampal slices with SV enhances long-term potentiation (LTP), and this effect is dependent on the activation of Akt (protein kinase B). Further studies showed that SV-induced enhancement of hippocampal LTP is driven by depletion of FPP and inhibition of farnesylation. In the present study, we report the functional consequences of exposure to SV at cellular/synaptic and molecular levels. While application of SV has no effect on intrinsic membrane properties of CA1 pyramidal neurons, including hyperpolarization-activated cyclic-nucleotide channel-mediated sag potentials, the afterhyperpolarization (AHP), and excitability, SV application potentiates the N-methyl D-aspartate receptor (NMDAR)-mediated contribution to synaptic transmission. In mouse hippocampal slices and human neuronal cells, SV treatment increases the surface distribution of the GluN2B subunit of the NMDAR without affecting cellular cholesterol content. We conclude that SV-induced enhancement of synaptic plasticity in the hippocampus is likely mediated by augmentation of synaptic NMDAR components that are largely responsible for driving synaptic plasticity in the CA1 region. PMID:24687455

Parent, Marc-Alexander L T; Hottman, David A; Cheng, Shaowu; Zhang, Wei; McMahon, Lori L; Yuan, Li-Lian; Li, Ling

2014-07-01

226

Age-dependent actions of dopamine on inhibitory synaptic transmission in superficial layers of mouse prefrontal cortex  

PubMed Central

Numerous developmental changes in the nervous system occur during the first several weeks of the rodent lifespan. Therefore, many characteristics of neuronal function described at the cellular level from in vitro slice experiments conducted during this early time period may not generalize to adult ages. We investigated the effect of dopamine (DA) on inhibitory synaptic transmission in superficial layers of the medial prefrontal cortex (PFC) in prepubertal [postnatal age (P; days) 12–20], periadolescent (P30–48), and adult (P70–100) mice. The PFC is associated with higher-level cognitive functions, such as working memory, and is associated with initiation, planning, and execution of actions, as well as motivation and cognition. It is innervated by DA-releasing fibers that arise from the ventral tegmental area. In slices from prepubertal mice, DA produced a biphasic modulation of inhibitory postsynaptic currents (IPSCs) recorded in layer II/III pyramidal neurons. Activation of D2-like receptors leads to an early suppression of the evoked IPSC, which was followed by a longer-lasting facilitation of the IPSC mediated by D1-like DA receptors. In periadolescent mice, the D2 receptor-mediated early suppression was significantly smaller compared with the prepubertal animals and absent in adult animals. Furthermore, we found significant differences in the DA-mediated lasting enhancement of the inhibitory response among the developmental groups. Our findings suggest that behavioral paradigms that elicit dopaminergic release in the PFC differentially modulate inhibition of excitatory pyramidal neuron output in prepuberty compared with periadolescence and adulthood in the superficial layers (II/III) of the cortex.

Cox, Charles L.

2013-01-01

227

Excitatory and inhibitory synaptic transmission is differentially influenced by two ortho-substituted polychlorinated biphenyls in the hippocampal slice preparation  

SciTech Connect

Exposure to polychlorinated biphenyls impairs cognition and behavior in children. Two environmental PCBs 2,2',3,3',4,4',5-heptachlorobiphenyl (PCB170) and 2,2',3,5',6-pentachlorobiphenyl (PCB95) were examined in vitro for influences on synaptic transmission in rat hippocampal slices. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region using a multi-electrode array. Perfusion with PCB170 (10 nM) had no effect on fEPSP slope relative to baseline period, whereas (100 nM) initially enhanced then depressed fEPSP slope. Perfusion of PCB95 (10 or 100 nM) persistently enhanced fEPSP slope > 200%, an effect that could be inhibited by dantrolene, a drug that attenuates ryanodine receptor signaling. Perfusion with picrotoxin (PTX) to block GABA neurotransmission resulted in a modest increase in fEPSP slope, whereas PTX + PCB170 (1-100 nM) persistently enhanced fEPSP slope in a dose dependent manner. fEPSP slope reached > 250% of baseline period in the presence of PTX + 100 nM PCB170, conditions that evoked marked epileptiform after-potential discharges. PCB95 and PCB170 were found to differentially influence the Ca{sup 2+}-dependence of [{sup 3}H]ryanodine-binding to hippocampal ryanodine receptors. Non-coplanar PCB congeners can differentially alter neurotransmission in a manner suggesting they can elicit imbalances between inhibitory and excitatory circuits within the hippocampus. Differential sensitization of ryanodine receptors by Ca{sup 2+} appears to mediate, at least in part, hippocampal excitotoxicity by non-coplanar PCBs.

Kim, Kyung Ho [Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, 95616 (United States); Inan, Salim Yalcin; Berman, Robert F. [Department of Neurological Surgery, School of Medicine, University of California, Davis, California (United States); Pessah, Isaac N. [Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, 95616 (United States)], E-mail: inpessah@ucdavis.edu

2009-06-01

228

Primary afferent depolarization and flexion reflexes produced by radiant heat stimulation of the skin  

PubMed Central

1. The reflex effects of pulses of intense radiant heat applied to the skin of the central plantar pad have been studied in unanaesthetized (decerebrate) spinal cats. 2. Pad heat pulses produced flexion of the ipsilateral hind limb and increased ipsilateral flexor monosynaptic reflexes, due to post-synaptic excitation of flexor alpha motoneurones. These effects were accompanied by reduction of extensor monosynaptic reflexes and post-synaptic inhibition of extensor motoneurones. 3. Ipsilateral (and contralateral) pad heat pulses consistently evoked negative dorsal root potentials (DRPs) as well as increased excitability of both cutaneous and group Ib muscle afferent terminals. The excitability of group Ia afferents was sometimes also increased during pad heat pulses, but to a lesser extent. 4. Pad heat pulses produced negative DRPs in preparations in which positive DRP components could be demonstrated following electrical stimulation of both skin and muscle nerves. 5. The motor and primary afferent effects of heat pulses always accompanied one another, beginning after the pad surface temperature had reached rather high levels (usually 48-55° C). 6. Negative DRPs increased excitability of cutaneous and group Ib afferents, and motoneurone activation produced by pad heat pulses was essentially unmodified when conduction in large myelinated afferents from the central plantar pad was blocked by cooling the posterior tibial nerve trunk. 7. It is concluded that adequate noxious activation of cutaneous afferents of small diameter produces primary afferent depolarization in a variety of large diameter afferent fibres, as well as post-synaptic effects in alpha motoneurones.

Burke, R. E.; Rudomin, P.; Vyklicky, L.; Zajac, F. E.

1971-01-01

229

Neonatal tissue damage facilitates nociceptive synaptic input to the developing superficial dorsal horn via NGF-dependent mechanisms  

PubMed Central

Tissue injury during a critical period of early life can facilitate spontaneous glutamatergic transmission within developing pain circuits in the superficial dorsal horn (SDH) of the spinal cord. However, the extent to which neonatal tissue damage strengthens nociceptive synaptic input to specific subpopulations of SDH neurons, as well as the mechanisms underlying this distinct form of synaptic plasticity, remains unclear. Here we use in vitro whole-cell patch clamp recordings from rodent spinal cord slices to demonstrate that neonatal surgical injury selectively potentiates high-threshold primary afferent input to immature lamina II neurons. In addition, the increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs) after hindpaw incision was prevented by neonatal capsaicin treatment, suggesting that early tissue injury enhances glutamate release from nociceptive synapses. This occurs in a widespread manner within the developing SDH, as incision elevated mEPSC frequency in both GABAergic and presumed glutamatergic lamina II neurons of Gad-GFP transgenic mice. The administration of exogenous nerve growth factor (NGF) into the rat hindpaw mimicked the effects of early tissue damage on excitatory synaptic function, while blocking trkA receptors in vivo abolished the changes in both spontaneous and primary afferent-evoked glutamatergic transmission following incision. These findings illustrate that neonatal tissue damage can alter the gain of developing pain pathways by activating NGF-dependent signaling cascades which modify synaptic efficacy at the first site of nociceptive processing within the CNS.

Li, Jie; Baccei, Mark L.

2011-01-01

230

Positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators have different impact on synaptic transmission in the thalamus and hippocampus.  

PubMed

Earlier studies showed that positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors enhance synaptic responses and facilitate synaptic plasticity. Those studies focused mainly on hippocampal functions. However, AMPA receptors have regionally distinct subunit compositions and thus potencies and efficacies of modulators may vary across the brain. The present study compared the effects of CX546 [1-(1,4-benzodioxan-6-ylcarbonyl) piperidine], a benzamide-type modulator, on synaptic transmission in neurons of the reticular thalamic nucleus (RTN), which regulates the firing mode of relay cells in other thalamic nuclei, and on hippocampal CA1 pyramidal cells. CX546 greatly prolonged synaptic responses in CA1 pyramidal cells, but at the same concentration it had only weak modulatory effects in RTN neurons. Effects on miniature excitatory postsynaptic currents (EPSCs) were similar to those on EPSCs in both regions, suggesting that variations in neuronal morphology and transmitter release kinetics do not account for the differences. Relay cells in the ventrobasal thalamus also exhibited weak modulatory effects that were comparable with those in RTN neurons. Regionally different effects on response duration were also observed with CX516 [BDP-12, 1-(quinoxalin-6-ylcarbonyl)piperidine], a second benzamide drug. In contrast, 100 microM cyclothiazide produced comparable synaptic enhancements in hippocampus and RTN. The regional selectivity of benzamide drugs (ampakines) may be explained, at least in part, by a lower potency at thalamic AMPA receptors, perhaps due to the prevalence of the subunits GluR3 and 4. Although regional preferences of the ampakines were modest in their extent, they may be sufficient to be of relevance when considering future therapeutic applications of such compounds. PMID:15626725

Xia, Yan-Fang; Kessler, Markus; Arai, Amy C

2005-04-01

231

Asphyxia induced by umbilical cord occlusion alters glutamatergic and GABAergic synaptic transmission in neurons of the superior colliculus in fetal rats.  

PubMed

Using optical recordings, we studied the effects of asphyxia on intracellular Cl(-) and Ca(2+) concentrations ([Cl(-)]i; [Ca(2+)]i) in the superior colliculus of fetal rats, which were connected via the umbilical cord to the dam. Acute asphyxia was induced by umbilical cord occlusion. The number of fetal superior colliculus neurons showing GABA-mediated increases in [Cl(-)]i (leading to hyperpolarization) following local synaptic electrical stimulation had decreased by 3 h post-asphyxiation, while the number showing GABA-mediated decreases in [Cl(-)]i (leading to depolarization) increased. [Ca(2+)]i rise, which occurred after acute asphyxiation, was antagonized by both non-NMDA and NMDA receptor antagonists. The increase in [Ca(2+)]i following focal superior colliculus stimulation was markedly attenuated at 3 h post-asphyxiation. These findings suggest that asphyxia induced by umbilical occlusion induces changes in glutamatergic and GABAergic synaptic transmission in the fetal brain. PMID:23501474

Sakata, Yoshiyuki; Endoh, Hisashi; Matsushige, Takeshi; Furuya, Satoko; Nakamura, Shoji

2013-06-01

232

Dysfunctional astrocytic and synaptic regulation of hypothalamic glutamatergic transmission in a mouse model of early-life adversity: relevance to neurosteroids and programming of the stress response.  

PubMed

Adverse early-life experiences, such as poor maternal care, program an abnormal stress response that may involve an altered balance between excitatory and inhibitory signals. Here, we explored how early-life stress (ELS) affects excitatory and inhibitory transmission in corticotrophin-releasing factor (CRF)-expressing dorsal-medial (mpd) neurons of the neonatal mouse hypothalamus. We report that ELS associates with enhanced excitatory glutamatergic transmission that is manifested as an increased frequency of synaptic events and increased extrasynaptic conductance, with the latter associated with dysfunctional astrocytic regulation of glutamate levels. The neurosteroid 5?-pregnan-3?-ol-20-one (5?3?-THPROG) is an endogenous, positive modulator of GABAA receptors (GABAARs) that is abundant during brain development and rises rapidly during acute stress, thereby enhancing inhibition to curtail stress-induced activation of the hypothalamic-pituitary-adrenocortical axis. In control mpd neurons, 5?3?-THPROG potently suppressed neuronal discharge, but this action was greatly compromised by prior ELS exposure. This neurosteroid insensitivity did not primarily result from perturbations of GABAergic inhibition, but rather arose functionally from the increased excitatory drive onto mpd neurons. Previous reports indicated that mice (dams) lacking the GABAAR ? subunit (?(0/0)) exhibit altered maternal behavior. Intriguingly, ?(0/0) offspring showed some hallmarks of abnormal maternal care that were further exacerbated by ELS. Moreover, in common with ELS, mpd neurons of ?(0/0) pups exhibited increased synaptic and extrasynaptic glutamatergic transmission and consequently a blunted neurosteroid suppression of neuronal firing. This study reveals that increased synaptic and tonic glutamatergic transmission may be a common maladaptation to ELS, leading to enhanced excitation of CRF-releasing neurons, and identifies neurosteroids as putative early regulators of the stress neurocircuitry. PMID:24336719

Gunn, Benjamin G; Cunningham, Linda; Cooper, Michelle A; Corteen, Nicole L; Seifi, Mohsen; Swinny, Jerome D; Lambert, Jeremy J; Belelli, Delia

2013-12-11

233

Dysfunctional Astrocytic and Synaptic Regulation of Hypothalamic Glutamatergic Transmission in a Mouse Model of Early-Life Adversity: Relevance to Neurosteroids and Programming of the Stress Response  

PubMed Central

Adverse early-life experiences, such as poor maternal care, program an abnormal stress response that may involve an altered balance between excitatory and inhibitory signals. Here, we explored how early-life stress (ELS) affects excitatory and inhibitory transmission in corticotrophin-releasing factor (CRF)-expressing dorsal-medial (mpd) neurons of the neonatal mouse hypothalamus. We report that ELS associates with enhanced excitatory glutamatergic transmission that is manifested as an increased frequency of synaptic events and increased extrasynaptic conductance, with the latter associated with dysfunctional astrocytic regulation of glutamate levels. The neurosteroid 5?-pregnan-3?-ol-20-one (5?3?-THPROG) is an endogenous, positive modulator of GABAA receptors (GABAARs) that is abundant during brain development and rises rapidly during acute stress, thereby enhancing inhibition to curtail stress-induced activation of the hypothalamic-pituitary-adrenocortical axis. In control mpd neurons, 5?3?-THPROG potently suppressed neuronal discharge, but this action was greatly compromised by prior ELS exposure. This neurosteroid insensitivity did not primarily result from perturbations of GABAergic inhibition, but rather arose functionally from the increased excitatory drive onto mpd neurons. Previous reports indicated that mice (dams) lacking the GABAAR ? subunit (?0/0) exhibit altered maternal behavior. Intriguingly, ?0/0 offspring showed some hallmarks of abnormal maternal care that were further exacerbated by ELS. Moreover, in common with ELS, mpd neurons of ?0/0 pups exhibited increased synaptic and extrasynaptic glutamatergic transmission and consequently a blunted neurosteroid suppression of neuronal firing. This study reveals that increased synaptic and tonic glutamatergic transmission may be a common maladaptation to ELS, leading to enhanced excitation of CRF-releasing neurons, and identifies neurosteroids as putative early regulators of the stress neurocircuitry.

Gunn, Benjamin G.; Cunningham, Linda; Cooper, Michelle A.; Corteen, Nicole L.; Seifi, Mohsen; Swinny, Jerome D.; Lambert, Jeremy J.

2013-01-01

234

Depression of synaptic transmission by vascular endothelial growth factor in adult rat hippocampus and evidence for increased efficacy after chronic seizures.  

PubMed

In addition to its potent effects on vasculature, it has become clear that vascular endothelial growth factor (VEGF) has effects on both neurons and glia, and recent studies suggest that it can be neuroprotective. To determine potential mechanisms underlying this neuroprotection, recombinant human VEGF was bath applied to adult rat hippocampal slices, and both extracellular and intracellular recordings were used to examine intrinsic properties and synaptic responses of hippocampal principal neurons. Initial studies in area CA1 showed that VEGF significantly reduced the amplitude of responses elicited by Schaffer collateral stimulation, without influencing membrane properties. Similar effects occurred in CA3 pyramidal cells and dentate gyrus granule cells when their major glutamatergic afferents were stimulated. Because VEGF expression is increased after seizures, effects of VEGF were also examined in rats with recurrent spontaneous seizures. VEGF reduced spontaneous discharges in slices from these rats but had surprisingly little effect on epileptiform discharges produced by disinhibition of slices from control rats. These results demonstrate a previously unknown effect of VEGF on neuronal activity and also demonstrate a remarkable potency in the epileptic brain. Based on this, we suggest that VEGF or VEGF-related targets could provide useful endpoints to direct novel therapeutic strategies for epilepsy. PMID:16192378

McCloskey, Daniel P; Croll, Susan D; Scharfman, Helen E

2005-09-28

235

Depression of Synaptic Transmission by Vascular Endothelial Growth Factor in Adult Rat Hippocampus and Evidence for Increased Efficacy after Chronic Seizures  

PubMed Central

In addition to its potent effects on vasculature, it has become clear that vascular endothelial growth factor (VEGF) has effects on both neurons and glia, and recent studies suggest that it can be neuroprotective. To determine potential mechanisms underlying this neuroprotection, recombinant human VEGF was bath applied to adult rat hippocampal slices, and both extracellular and intracellular recordings were used to examine intrinsic properties and synaptic responses of hippocampal principal neurons. Initial studies in area CA1 showed that VEGF significantly reduced the amplitude of responses elicited by Schaffer collateral stimulation, without influencing membrane properties. Similar effects occurred in CA3 pyramidal cells and dentate gyrus granule cells when their major glutamatergic afferents were stimulated. Because VEGF expression is increased after seizures, effects of VEGF were also examined in rats with recurrent spontaneous seizures. VEGF reduced spontaneous discharges in slices from these rats but had surprisingly little effect on epileptiform discharges produced by disinhibition of slices from control rats. These results demonstrate a previously unknown effect of VEGF on neuronal activity and also demonstrate a remarkable potency in the epileptic brain. Based on this, we suggest that VEGF or VEGF-related targets could provide useful endpoints to direct novel therapeutic strategies for epilepsy.

McCloskey, Daniel P.; Croll, Susan D.; Scharfman, Helen E.

2005-01-01

236

Effects of quisqualate, N-methyl-D-aspartate, and some amino acid antagonists on synaptic transmission in ampullae of Lorenzini  

Microsoft Academic Search

The effects of quisqualic acid (QA), N-methyl-D-aspartate (NMDA), and a number of NMDA and non-NMDA receptor antagonists on background and induced activity in afferent nerve fibers were investigated in skates by means of bath application to the basal membrane of electroreceptors (ampullae of Lorenzini). Perfusion with physiological saline containing QA or NMDA (minimum concentrations required: 10-8 and 10-5 M respectively)

G. N. Akoev; Yu. N. Andrianov; B. Bromm; T. Szabo; N. O. Sherman

1989-01-01

237

PHARMACOLOGY OF THE VESTIBULAR HAIR CELL-AFFERENT FIBER SYNAPSE IN THE FROG  

Microsoft Academic Search

Abstract The isolated, intact, membranous labyrinth of the frog (Rana temporuria) has been investigated electrophys- iologically,in vitro to determine,the,nature,of the,transmitter,substance,at the,synapse,between,the,vestibular hair,cells,and,afferent,fibers. Spontaneous,synaptic,activity,can,be,monitored,with,intra-axonal,recordings from the afferents. Increased K+ in the bath results in an increase in frequency of presynaptic release, as indicated,by an,increased,frequency,of spontaneous,synaptic,potentials.,Adding,Mg2+ and,lowering,Ca2+ results in a decrease in synaptic potential frequency (often to zero) with no change in

J.-M. ANNONI; S. L. COCHRAN; W. PRECHT

238

Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels.  

PubMed

Central neuropathic pain (CNP) in the spinal cord, such as chronic pain after spinal cord injury (SCI), is an incurable ailment. However, little is known about the spinal cord mechanisms underlying CNP. Recently, reactive oxygen species (ROS) have been recognized to play an important role in CNP of the spinal cord. However, it is unclear how ROS affect synaptic transmission in the dorsal horn of the spinal cord. To clarify how ROS impact on synaptic transmission, we investigated the effects of ROS on synaptic transmission in rat spinal cord substantia gelatinosa (SG) neurons using whole-cell patch-clamp recordings. Administration of tert-butyl hydroperoxide (t-BOOH), an ROS donor, into the spinal cord markedly increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in SG neurons. This t-BOOH-induced enhancement was not suppressed by the Na(+) channel blocker tetrodotoxin. However, in the presence of a non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, t-BOOH did not generate any sEPSCs. Furthermore, in the presence of a transient receptor potential ankyrin 1 (TRPA1) channel antagonist (HC-030031) or a transient receptor potential vanilloid 1 (TRPV1) channel antagonist (capsazepine or AMG9810), the t-BOOH-induced increase in the frequency of sEPSCs was inhibited. These results indicate that ROS enhance the spontaneous release of glutamate from presynaptic terminals onto SG neurons through TRPA1 and TRPV1 channel activation. Excessive activation of these ion channels by ROS may induce central sensitization in the spinal cord and result in chronic pain such as that following SCI. PMID:23707800

Nishio, N; Taniguchi, W; Sugimura, Y K; Takiguchi, N; Yamanaka, M; Kiyoyuki, Yasukuni; Yamada, H; Miyazaki, N; Yoshida, M; Nakatsuka, T

2013-09-01

239

In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization.  

PubMed

Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and A?-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention. PMID:22095157

Ford, Anthony P

2012-02-01

240

Dopaminergic enhancement of excitatory synaptic transmission in layer II entorhinal neurons is dependent on D?-like receptor-mediated signaling.  

PubMed

The modulatory neurotransmitter dopamine induces concentration-dependent changes in synaptic transmission in the entorhinal cortex, in which high concentrations of dopamine suppress evoked excitatory postsynaptic potentials (EPSPs) and lower concentrations induce an acute synaptic facilitation. Whole-cell current-clamp recordings were used to investigate the dopaminergic facilitation of synaptic responses in layer II neurons of the rat lateral entorhinal cortex. A constant bath application of 1 ?M dopamine resulted in a consistent facilitation of EPSPs evoked in layer II fan cells by layer I stimulation; the size of the facilitation was more variable in pyramidal neurons, and synaptic responses in a small group of multiform neurons were not modulated by dopamine. Isolated inhibitory synaptic responses were not affected by dopamine, and the facilitation of EPSPs was not associated with a change in paired-pulse facilitation ratio. Voltage-clamp recordings of ?-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor-mediated excitatory postsynaptic currents (EPSCs) were facilitated by dopamine, but N-methyl-D-aspartate receptor-mediated currents were not. Bath application of the dopamine D?-like receptor blocker SCH23390 (50 ?M), but not the D?-like receptor blocker sulpiride (50 ?M), prevented the facilitation, indicating that it is dependent upon D?-like receptor activation. Dopamine D? receptors lead to activation of protein kinase A (PKA), and including the PKA inhibitor H-89 or KT 5720 in the recording pipette solution prevented the facilitation of EPSCs. PKA-dependent phosphorylation of inhibitor 1 or the dopamine- and cAMP-regulated protein phosphatase (DARPP-32) can lead to a facilitation of AMPA receptor responses by inhibiting the activity of protein phosphatase 1 (PP1) that reduces dephosphorylation of AMPA receptors, and we found here that inhibition of PP1 occluded the facilitatory effect of dopamine. The dopamine-induced facilitation of AMPA receptor-mediated synaptic responses in layer II neurons of the lateral entorhinal cortex is therefore likely mediated via a D? receptor-dependent increase in PKA activity and a resulting inhibition in PP1-dependent dephosphorylation of AMPA receptors. PMID:24220689

Glovaci, I; Caruana, D A; Chapman, C A

2014-01-31

241

Detachment of structurally intact nerve endings from chromatolytic neurones of rat superior cervical ganglion during the depression of synaptic transmission induced by post-ganglionic axotomy.  

PubMed Central

1. Electrophysiological studies showed that injury of post-ganglionic nerve fibres leads to severe and prolonged depression of synaptic transmission through the rat superior cervical ganglion, beginning within 24 h. This is in line with the results of previous studies in other species and upon other neurones. 2. electron microscopy after post-ganglionic axotomy revealed nerve endings of presynaptic type with all the specialized membrane-related features of a synaptic zone, but which were not apposed to any post-synaptic nervous element. These umusual profiles were interpreted as detached presynaptic nerve endings. In normal and control ganglia, such profiles formed at most 0-5% of all vesicle-containing profiles of presynaptic type; in ganglia with all major post-ganglionic branches cut the proportion rose to approximately 7%, between 3 and 7 d post-operatively. Over this period, the mean incidence of chromatolytic neurones was 74-6%. 3. Concomitantly, the incidence of synapses within the ganglion fell by about 75%, reaching its lowest levels between 3 and 7 d post-operatively. There was strikingly little evidence of persistence of post-synaptic membrane specializations ('membrane thickenings') following detachment of synapses. 4. At longer survival intervals the incidence of synapses gradually increased, and that of detached nerve endings gradually decreased; recovery was well advanced by 42 d. 5. The fall in the incidence of synapses was closely paralleled by a fall in the incidence of desmosome-like attachments in the ganglion; the incidence of such attachments was found to be correlated to a significant degree with that of synapses. 6. It is concluded that most or all of the synapses upon sympathetic neurones become physically dissociated during the chromatolytic reaction of these neurones to axotomy. The failure to persist of ultrastructurally specialized post-synaptic sites, and the loss of desmosomes (particularly marked for those involving purely post-ganglionic nervous elements) suggest that the post-ganglionic neurone is losing all its specializations for attachment. 7. Some evidence suggests that the satellite cells may effect the final separation between pre- and post-synaptic structures. Images Plate 2 a b c Plate 4 Plate 5 Plate 6 a b Plate 1

Matthews, M R; Nelson, V H

1975-01-01

242

Colocalization of Ion Channels Involved in Frequency Selectivity and Synaptic Transmission at Presynaptic Active Zones of Hair Cells  

Microsoft Academic Search

Calcium ions serve as intracellular messengers in 2 activities of hair cells: in conjunction with Ca*+-activated K+ channels, they produce the electrical resonance that tunes each cell to a specific frequency of stimulation, and they trigger the release of a chemical synaptic transmitter. Our experiments indicate that both of these functions are conducted within a region that extends a few

William M. Roberts; R. A. Jacobs; A. J. Hudspeth

1990-01-01

243

Efferent fibers innervate gustatory and mechanosensitive afferent fibers in frog fungiform papillae.  

PubMed

A possibility of efferent innervation of gustatory and mechanosensitive afferent fiber endings was studied in frog fungiform papillae with a suction electrode. The amplitude of antidromic impulses in a papillary afferent fiber induced by antidromically stimulating an afferent fiber of glossopharyngeal nerve (GPN) with low voltage pulses was inhibited for 40 s after the parasympathetic efferent fibers of GPN were stimulated orthodromically with high voltage pulses at 30 Hz for 10 s. This implies that electrical positivity of the outer surface of papillary afferent membrane was reduced by the efferent fiber-induced excitatory postsynaptic potential. The inhibition of afferent responses in the papillae was blocked by substance P receptor blocker, L-703,606, indicating that substance P is probably released from the efferent fiber terminals. Slow negative synaptic potential, which corresponded to a slow depolarizing synaptic potential, was extracellularly induced in papillary afferent terminals for 45 s by stimulating the parasympathetic efferent fibers of GPN with high voltage pulses at 30 Hz for 10 s. This synaptic potential was also blocked by L-703,606. These data indicate that papillary afferent fiber endings are innervated by parasympathetic efferent fibers. PMID:21994412

Sato, Toshihide; Nishishita, Kazuhisa; Okada, Yukio; Toda, Kazuo

2012-05-01

244

Adenosine receptor activation is responsible for prolonged depression of synaptic transmission after spreading depolarization in brain slices.  

PubMed

Spreading depolarization (SD) is a slowly propagating, coordinated depolarization of brain tissue, which is followed by a transient (5-10min) depression of synaptic activity. The mechanisms for synaptic depression after SD are incompletely understood. We examined the relative contributions of action potential failure and adenosine receptor activation to the suppression of evoked synaptic activity in murine brain slices. Focal micro-injection of potassium chloride (KCl) was used to induce SD and synaptic potentials were evoked by electrical stimulation of Schaffer collateral inputs to hippocampal area Cornu Ammonis area 1 (CA1). SD was accompanied by loss of both presynaptic action potentials (as assessed from fiber volleys) and field excitatory postsynaptic potentials (fEPSPs). Fiber volleys recovered rapidly upon neutralization of the extracellular direct current (DC) potential, whereas fEPSPs underwent a secondary suppression phase lasting several minutes. Paired-pulse ratio was elevated during the secondary suppression period, consistent with a presynaptic mechanism of synaptic depression. A transient increase in extracellular adenosine concentration was detected during the period of secondary suppression. Antagonists of adenosine A1 receptors (8-cyclopentyl-1,3-dipropylxanthine [DPCPX] or 8-cyclopentyl-1,3-dimethylxanthine [8-CPT]) greatly accelerated fEPSP recovery and abolished increases in paired-pulse ratio normally observed after SD. The duration of fEPSP suppression was correlated with both the duration of the DC shift and the area of tissue depolarized, consistent with the model that adenosine accumulates in proportion to the metabolic burden of SD. These results suggest that in brain slices, the duration of the DC shift approximately defined the period of action potential failure, but the secondary depression of evoked responses was in large part due to endogenous adenosine accumulation after SD. PMID:22864185

Lindquist, B E; Shuttleworth, C W

2012-10-25

245

Neutralization of inhibitory molecule NG2 improves synaptic transmission, retrograde transport, and locomotor function after spinal cord injury in adult rats.  

PubMed

NG2 belongs to the family of chondroitin sulfate proteoglycans that are upregulated after spinal cord injury (SCI) and are major inhibitory factors restricting the growth of fibers after SCI. Neutralization of NG2's inhibitory effect on axon growth by anti-NG2 monoclonal antibodies (NG2-Ab) has been reported. In addition, recent studies show that exogenous NG2 induces a block of axonal conduction. In this study, we demonstrate that acute intraspinal injections of NG2-Ab prevented an acute block of conduction by NG2. Chronic intrathecal infusion of NG2-Ab improved the following deficits induced by chronic midthoracic lateral hemisection (HX) injury: (1) synaptic transmission to lumbar motoneurons, (2) retrograde transport of fluororuby anatomical tracer from L5 to L1, and (3) locomotor function assessed by automated CatWalk gait analysis. We collected data in an attempt to understand the cellular and molecular mechanisms underlying the NG2-Ab-induced improvement of synaptic transmission in HX-injured spinal cord. These data showed the following: (1) that chronic NG2-Ab infusion improved conduction and axonal excitability in chronically HX-injured rats, (2) that antibody treatment increased the density of serotonergic axons with ventral regions of spinal segments L1-L5, (3) and that NG2-positive processes contact nodes of Ranvier within the nodal gap at the location of nodal Na(+) channels, which are known to be critical for propagation of action potentials along axons. Together, these results demonstrate that treatment with NG2-Ab partially improves both synaptic and anatomical plasticity in damaged spinal cord and promotes functional recovery after HX SCI. Neutralizing antibodies against NG2 may be an excellent way to promote axonal conduction after SCI. PMID:23447612

Petrosyan, Hayk A; Hunanyan, Arsen S; Alessi, Valentina; Schnell, Lisa; Levine, Joel; Arvanian, Victor L

2013-02-27

246

The activation of nicotinic acetylcholine receptors enhances the inhibitory synaptic transmission in the deep dorsal horn neurons of the adult rat spinal cord  

PubMed Central

Somatosensory information can be modulated by nicotinic acetylcholine receptors (nAChRs) in the superficial dorsal horn of the spinal cord. Nonetheless, the functional significance of nAChRs in the deep dorsal horn of adult animals remains unclear. Using whole-cell patch-clamp recordings from lamina V neurons in the adult rat spinal cord, we investigated whether the activation of nAChRs could modulate the inhibitory synaptic transmission in the deep dorsal horn. In the presence of CNQX and APV to block excitatory glutamatergic synaptic transmission, bath applications of nicotine (100 ?M) significantly increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in almost all neurons tested. The effect of nicotine was mimicked by N-methyl-4-(3-pyridinyl)-3-butene-1-amine (RJR-2403, 100 ?M), an ?4?2-nAChR agonist, and was also mimicked by choline (10 mM), an ?7-nAChR agonist. The effect of nicotine was completely blocked by the nAChR antagonist mecamylamine (5 ?M). In the presence of tetrodotoxin (0.5 ?M), nicotine (100 ?M) significantly increased the miniature IPSC frequency. On the other hand, RJR-2403 (100 ?M) or choline (10 mM) did not affect miniature IPSCs. The application of nicotine (100 ?M) also evoked a large inward current in all lamina V neurons tested when cells were held at -60 mV. Similarly, RJR-2403 (100 ?M) induced inward currents in the majority of lamina V neurons examined. On the other hand, choline (10 mM) did not elicit any detectable whole-cell currents. These results suggest that several nAChR subtypes are expressed on the presynaptic terminals, preterminals, and neuronal cell bodies within lamina V and that these nAChRs are involved in the modulation of inhibitory synaptic activity in the deep dorsal horn of the spinal cord.

Takeda, Daisuke; Nakatsuka, Terumasa; Gu, Jianguo G; Yoshida, Munehito

2007-01-01

247

D2 Dopamine Receptors Recruit a GABA Component for Their Attenuation of Excitatory Synaptic Transmission in the Adult Rat Prefrontal Cortex  

PubMed Central

The dopamine modulation of neuronal excitability in the prefrontal cortex (PFC) changes during critical late periods of postnatal development. In particular, D2 receptors activate fast-spiking interneurons after, and not before, adolescence. To test the functional impact of this change, we investigated the effects of dopamine agonists on PFC excitatory synaptic transmission with whole-cell recordings from deep-layer pyramidal neurons in brain slices obtained from prepubertal [postnatal day (PD) 28–35] and postpubertal (PD > 51) rats. Electrical stimulation of superficial layers elicited a fast AMPA/kainate excitatory postsynaptic potential (EPSP). In the adult PFC, the D2 agonist quinpirole decreased EPSP amplitude, an effect that lasted for at least 25 min after drug washout and was blocked by the D2 antagonist eticlopride. The late component of this effect was blocked by the GABA-A antagonist picrotoxin without affecting the early inhibition. Quinpirole also decreased EPSP amplitude in deep-layer pyramidal neurons from prepubertal rats, but this response was not affected by picrotoxin. A D1 agonist, on the other hand, did not affect the pyramidal neuron EPSP. These results indicate that D2, not D1, receptors attenuate local excitatory synaptic transmission in the adult PFC, and this effect of D2 involves a recruitment of local GABAergic activity.

TSENG, KUEI Y.; O'DONNELL, PATRICIO

2008-01-01

248

Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes.  

PubMed

Endogenous cannabinoids play important roles in a variety of functions in the mammalian brain, including the regulation reward-related information processing. The primary mechanism through which this is achieved is the presynaptic modulation of synaptic transmission. During reward- and reinforcement-related behavior dopamine levels increase in forebrain areas and this has recently been shown to be modulated by the endocannabinoid system. Therefore, understanding how endocannabinoids are mobilized to modulate synaptic inputs impinging on midbrain dopamine neurons is crucial to a complete understanding of the roles that these molecules play in reward behavior, drug abuse and addiction. Here we summarize the literature describing short-term and long-term regulation of afferent connections on dopamine neurons in the ventral tegmental area via endocannabinoid activation of cannabinoid CB1 receptors, and describe the mechanisms through which these molecules are released during reward-based behavior and exposure to abused drugs. PMID:24495779

Wang, Huikun; Lupica, Carl R

2014-07-01

249

Synaptic plasticity  

Microsoft Academic Search

Synaptic plasticity is manifested by long-lasting changes in synaptic potency. Increased potency is of special importance in relation to the neural basis of memory. Even mild repetitive stimulation evokes large and prolonged potentiations of hippocampal synapses, as is revealed by electrical recording either in vivo or in vitro. More importantly there is a matching hypertrophy of the synaptic spines on

John C. Eccles

1979-01-01

250

Modulation of glycinergic synaptic transmission in the trigeminal and hypoglossal motor nuclei by the nitric oxide-cyclicGMP signaling pathway.  

PubMed

In a previous work we found that nitric oxide (NO) and cyclicGMP (cGMP) inhibit glutamatergic synaptic transmission in trigeminal motoneurons (MnV). Here we study the actions of the NO/cGMP signaling pathway on glycinergic synaptic transmission in trigeminal and hypoglossal motoneurons (MnXII) in brain stem slices of neonatal rats. Glycinergic inhibitory postsynaptic currents (IPSCs) were recorded in MnV by stimulation of the supratrigeminal nucleus (SuV) and in MnXII by stimulation of the nucleus of Roller. The NO donor DETA/NONOate (DETA/NO) reduced the amplitude of the IPSC to 58.1±4.2% of control values in MnV. In the presence of YC-1, a modulator of guanylate cyclase that acts as a NO sensitizer, lower and otherwise ineffective concentrations of DETA/NO induced a reduction of the IPSC to 47.2±15.6%. NO effects were mimicked by 8 bromo cyclicGMP (8BrcGMP). They were accompanied by an increase in the paired pulse facilitation (PPF) and in the failure rate of evoked IPSCs. 8BrcGMP did not modify the glycinergic currents elicited by exogenous glycine. In MnXII the IPSCs were also reduced by NO donors and 8BrcGMP to 52.9±6.3% and 45.9±4% of control values, respectively. In these neurons, but not in MnV, we also observed excitatory postsynaptic actions of NO donors. We propose that the differences between the two motor pools may be due to a differential development of the nitrergic system in the two nuclei. Our data show that NO, through its second messenger cGMP, reduces inhibitory glycinergic synaptic transmission in both MnV and MnXII. For MnV, evidence in favor of presynaptic inhibition of glycine release is presented. Given our previous data together with the current results, we propose that the NO/cGMP signaling pathway participates pre- and postsynaptically in the combined regulation of MnV and MnXII activities in motor acts in which they participate. PMID:24626159

Pose, I; Silveira, V; Damián, A; Higgie, R; Morales, F R

2014-05-16

251

Convergence in segmental reflex pathways from nociceptive and non-nociceptive afferents to alpha-motoneurones in the cat.  

PubMed Central

1. Reflex interaction between nociceptive and non-nociceptive segmental afferents was investigated by testing for spatial facilitation of postsynaptic potentials (PSPs) in alpha-motoneurones recorded in anaemically decapitated, high spinal cats. Nociceptive segmental afferents were activated by applying noxious radiant heat to the skin. Non-nociceptive skin mechanoreceptors were activated by puffs of air. Non-nociceptive skin, joint and group I-III muscle afferents were stimulated by electrical pulses delivered to various nerves. 2. Conditioning by stimulation of nociceptive afferents facilitated transmission in various ipsilateral segmental pathways. Such spatial facilitation occurred in both excitatory and inhibitory pathways. Pathways that were facilitated included those activated by low to medium threshold cutaneous afferents, joint afferents, and group Ib and II muscle afferents. 3. In contrast, monosynaptic EPSPs evoked by stimulating ipsilateral group Ia muscle afferents did not show spatial facilitation but rather inhibition during conditioning stimulation of nociceptive afferents. Spatial facilitation of reciprocal group Ia IPSPs was rare and small if it occurred. 4. Pathways activated by cutaneous and group II muscle afferents were depressed by contralateral stimulation of nociceptive afferents. 5. We conclude that spatial facilitation observed between nociceptive and non-nociceptive afferents results from a convergence of inputs on common interneurones in the reflex pathways to alpha-motoneurones. Therefore nociceptive afferents have to be regarded as constituents of flexor reflex afferents (FRAs) and may add a specific nocifensive function to the FRA system.

Steffens, H; Schomburg, E D

1993-01-01

252

Variation in response dynamics of regular and irregular vestibular-nerve afferents during sinusoidal head rotations and currents in the chinchilla  

PubMed Central

In mammals, primary vestibular afferents that innervate only type I hair cells (calyx-only afferents) respond nearly in phase with head acceleration for high-frequency motion, whereas afferents that innervate both type I and type II (dimorphic) or only type II (bouton-only) hair cells respond more in phase with head velocity. Afferents that exhibit irregular background firing rates have a larger phase lead re head velocity than those that fire more regularly. We wanted to examine what is the cause of the variation in phase lead between regular and irregular afferents at high frequency head rotations. Under the assumption that externally applied galvanic currents act directly on the nerve, we derived a transfer function describing the dynamics of a semicircular canal and its hair cells through comparison of responses to sinusoidally modulated head velocity and currents. All afferent responses were well fit with a transfer function with one zero (lead term). Best-fit lead terms describing responses to current for each group of afferents were similar to the lead term describing responses to head velocity for regular afferents (0.006s + 1). This shows that the pre synaptic/synaptic inputs to regular afferents are pure velocity transducers. However, the variation in phase lead between regular and irregular afferents cannot be explained solely by the ratio of type I to II hair cells (Baird et al. 1988) suggesting that the variation is caused by a combination of pre- (type of hair cell) and post- synaptic properties.

Kim, Kyu-Sung; Minor, Lloyd B.; Della Santina, Charles; Lasker, David M.

2014-01-01

253

The activation of nicotinic acetylcholine receptors enhances the inhibitory synaptic transmission in the deep dorsal horn neurons of the adult rat spinal cord.  

PubMed

Somatosensory information can be modulated by nicotinic acetylcholine receptors (nAChRs) in the superficial dorsal horn of the spinal cord. Nonetheless, the functional significance of nAChRs in the deep dorsal horn of adult animals remains unclear. Using whole-cell patch-clamp recordings from lamina V neurons in the adult rat spinal cord, we investigated whether the activation of nAChRs could modulate the inhibitory synaptic transmission in the deep dorsal horn. In the presence of CNQX and APV to block excitatory glutamatergic synaptic transmission, bath applications of nicotine (100 microM) significantly increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in almost all neurons tested. The effect of nicotine was mimicked by N-methyl-4-(3-pyridinyl)-3-butene-1-amine (RJR-2403, 100 microM), an alpha 4 beta 2-nAChR agonist, and was also mimicked by choline (10 mM), an alpha 7-nAChR agonist. The effect of nicotine was completely blocked by the nAChR antagonist mecamylamine (5 microM). In the presence of tetrodotoxin (0.5 microM), nicotine (100 microM) significantly increased the miniature IPSC frequency. On the other hand, RJR-2403 (100 microM) or choline (10 mM) did not affect miniature IPSCs. The application of nicotine (100 microM) also evoked a large inward current in all lamina V neurons tested when cells were held at -60 mV. Similarly, RJR-2403 (100 microM) induced inward currents in the majority of lamina V neurons examined. On the other hand, choline (10 mM) did not elicit any detectable whole-cell currents. These results suggest that several nAChR subtypes are expressed on the presynaptic terminals, preterminals, and neuronal cell bodies within lamina V and that these nAChRs are involved in the modulation of inhibitory synaptic activity in the deep dorsal horn of the spinal cord. PMID:17894865

Takeda, Daisuke; Nakatsuka, Terumasa; Gu, Jianguo G; Yoshida, Munehito

2007-01-01

254

ETHANOL-INDUCED DELTA-OPIOID RECEPTOR MODULATION OF GLUTAMATE SYNAPTIC TRANSMISSION AND CONDITIONED PLACE PREFERENCE IN CENTRAL AMYGDALA  

PubMed Central

Alcoholism involves compulsive behaviors of alcohol drinking, which is thought to be related at least initially to the rewarding effect of alcohol. It has been shown that mu-opioid receptors play an essential role in drug reward and dependence for many drugs of abuse including alcohol, but the function of delta-opioid receptors (DOR) in drug reward remains largely unknown at present. Previous animal studies using systemic approaches with DOR antagonists or DOR knockout animals have yielded inconsistent results, showing a decrease, an increase or no change in alcohol consumption and behaviors of alcohol reward after DOR inhibition or deletion. In the present study, we used ethanol-conditioned rats to investigate adaptive DOR function in neurons of the central nucleus of the amygdala (CeA), a key brain site for alcohol reward and addiction. We found that functional DOR was absent in glutamate synapses of CeA neurons from control rats, but it emerged and inhibited glutamate synaptic currents in CeA neurons from rats displaying ethanol-induced behavior of conditioned place preference (CPP). Analysis of paired-pulse ratios and miniature glutamate synaptic currents revealed that the recruited DOR was present on glutamatergic presynaptic terminals. Similar induction of functional DOR was also found on GABA synapses. Furthermore, microinjection of a DOR antagonist into the CeA reversed ethanol-induced CPP behavior in rats in vivo. These results suggest that repeated alcohol exposure recruits new functional DOR on CeA glutamate and GABA synapses, which may be involved in the expression or maintenance of ethanol-induced CPP behavior.

Bie, Bihua; Zhu, Wei; Pan, Zhizhong Z.

2009-01-01

255

Haploinsufficiency in peptidylglycine ?-amidating monooxygenase leads to altered synaptic transmission in the amygdala and impaired emotional responses  

PubMed Central

The mammalian amygdala expresses various neuropeptides whose signaling has been implicated in emotionality. Many neuropeptides require amidation for full activation by peptidylglycine ?-amidating monooxygenase (PAM), a transmembrane vesicular cuproenzyme and regulator of the secretory pathway. Mice heterozygous for the Pam gene (PAM+/?) exhibit physiological and behavioral abnormalities related to specific peptidergic pathways. In the present study, we evaluated emotionality and examined molecular and cellular responses that characterize neurophysiological differences in the PAM+/? amygdala. PAM+/? mice presented with anxiety-like behaviors in the zero maze that were alleviated by diazepam. PAM+/? animals were deficient in short- and long-term contextual and cued fear conditioning and required higher shock intensities to establish fear-potentiated startle than their wildtype littermates. Immunohistochemical analysis of the amygdala revealed PAM expression in pyramidal neurons and local interneurons that synthesize ?-aminobutyric acid (GABA). We performed whole-cell recordings of pyramidal neurons in the PAM+/? amygdala to elucidate neurophysiological correlates of the fear behavioral phenotypes. Consistent with these observations, thalamic afferent synapses in the PAM+/? lateral nucleus were deficient in long-term potentiation. This deficit was apparent in the absence and presence of the GABAA receptor antagonist picrotoxin and was abolished when both GABAA and GABAB receptors were blocked. Both evoked and spontaneous excitatory signals were enhanced in the PAM+/? lateral nucleus. Phasic GABAergic signaling was also augmented in the PAM+/? amygdala, and this difference was comprised of activity-independent and activity-dependent components. These physiological findings represent perturbations in the PAM+/? amygdala that may underlie the aberrant emotional responses in the intact animal.

Gaier, ED; Rodriguiz, RM; Ma, XM; Sivaramakrishnan, S; Bousquet-Moore, D; Wetsel, WC; Eipper, BA

2010-01-01

256

Synaptic retinoic acid signaling and homeostatic synaptic plasticity.  

PubMed

One of the defining features of the nervous system is its ability to modify synaptic strength in an experience-dependent manner. Chronic elevation or reduction of network activity activates compensatory mechanisms that modulate synaptic strength in the opposite direction (i.e. reduced network activity leads to increased synaptic strength), a process called homeostatic synaptic plasticity. Among the many mechanisms that mediate homeostatic synaptic plasticity, retinoic acid (RA) has emerged as a novel signaling molecule that is critically involved in homeostatic synaptic plasticity induced by blockade of synaptic activity. In neurons, silencing of synaptic transmission triggers RA synthesis. RA then acts at synapses by a non-genomic mechanism that is independent of its well-known function as a transcriptional regulator, but operates through direct activation of protein translation in neuronal dendrites. Protein synthesis is activated by RA-binding to its receptor RAR?, which functions locally in dendrites in a non-canonical manner as an RNA-binding protein that mediate RA's effect on translation. The present review will discuss recent progress in our understanding of the novel role of RA, which led to the identification of RA as a critical synaptic signaling molecule that mediates activity-dependent regulation of protein synthesis in neuronal dendrites. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'. PMID:23270606

Chen, Lu; Lau, Anthony G; Sarti, Federica

2014-03-01

257

Synaptic Plasticity and Memory Function.  

National Technical Information Service (NTIS)

Research was conducted to test the hypothesis that activation of the calcium-dependent protease, calpain, is involved in the induction of long-term potentiation (LTP) of synaptic transmission and memory storage in the mammalian brain. Evidence indicates t...

G. Lynch

1988-01-01

258

Neuronal MHC Class I Molecules are Involved in Excitatory Synaptic Transmission at the Hippocampal Mossy Fiber Synapses of Marmoset Monkeys  

PubMed Central

Several recent studies suggested a role for neuronal major histocompatibility complex class I (MHCI) molecules in certain forms of synaptic plasticity in the hippocampus of rodents. Here, we report for the first time on the expression pattern and functional properties of MHCI molecules in the hippocampus of a nonhuman primate, the common marmoset monkey (Callithrix jacchus). We detected a presynaptic, mossy fiber-specific localization of MHCI proteins within the marmoset hippocampus. MHCI molecules were present in the large, VGlut1-positive, mossy fiber terminals, which provide input to CA3 pyramidal neurons. Furthermore, whole-cell recordings of CA3 pyramidal neurons in acute hippocampal slices of the common marmoset demonstrated that application of antibodies which specifically block MHCI proteins caused a significant decrease in the frequency, and a transient increase in the amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in CA3 pyramidal neurons. These findings add to previous studies on neuronal MHCI molecules by describing their expression and localization in the primate hippocampus and by implicating them in plasticity-related processes at the mossy fiber–CA3 synapses. In addition, our results suggest significant interspecies differences in the localization of neuronal MHCI molecules in the hippocampus of mice and marmosets, as well as in their potential function in these species. Electronic supplementary material The online version of this article (doi:10.1007/s10571-010-9510-3) contains supplementary material, which is available to authorized users.

Zhang, Mingyue; Schlumbohm, Christina; Matz-Rensing, Kerstin; Uchanska-Ziegler, Barbara; Flugge, Gabriele; Zhang, Weiqi; Walter, Lutz; Fuchs, Eberhard

2010-01-01

259

Mice lacking brain/kidney phosphate-activated glutaminase (GLS1) have impaired glutamatergic synaptic transmission, altered breathing, disorganized goal-directed behavior and die shortly after birth  

PubMed Central

Neurotransmitter glutamate has been thought to derive mainly from glutamine via the action of glutaminase type 1 (GLS1). To address the importance of this pathway in glutamatergic transmission, we knocked out GLS1 in mice. The insertion of a STOP cassette by homologous recombination produced a null allele that blocked transcription, encoded no immunoreactive protein and abolished GLS1 enzymatic activity. Null mutants were slightly smaller, were deficient in goal-directed behavior, hypoventilated and died in the first post-natal day. No gross or microscopic defects were detected in peripheral organs or in the central nervous system. In cultured neurons from the null mutants, miniature EPSC amplitude and duration were normal; however, the amplitude of evoked EPSCs decayed more rapidly with sustained 10 Hz stimulation, consistent with an observed reduction in depolarization-evoked glutamate release. Because of this activity-dependent impairment in glutamatergic transmission, we surmised that respiratory networks, which require temporal summation of synaptic input, would be particularly affected. We found that the amplitude of inspirations was decreased in vivo, chemosensitivity to CO2 was severely altered, and the frequency of pacemaker activity recorded in the respiratory generator in the Pre-Bötzinger complex, a glutamatergic brainstem network that can be isolated in vitro, was increased. Our results show that while alternate pathways to GLS1 glutamate synthesis support baseline glutamatergic transmission, the GLS1 pathway is essential for maintaining the function of active synapses, and so the mutation is associated with impaired respiratory function, abnormal goal-directed behavior and neonatal demise.

Masson, Justine; Darmon, Michele; Conjard, Agnes; Chuhma, Nao; Ropert, Nicole; Thoby-Brisson, Muriel; Foutz, Arthur S.; Parrot, Sandrine; Miller, Gretchen M.; Jorisch, Renee; Polan, Jonathan; Hamon, Michel; Hen, Rene; Rayport, Stephen

2009-01-01

260

Hydrogen sulfide augments synaptic neurotransmission in the nucleus of the solitary tract.  

PubMed

Within the brain stem, the nucleus tractus solitarii (NTS) serves as a principal central site for sensory afferent integration from the cardiovascular and respiratory reflexes. Neuronal activity and synaptic transmission in the NTS are highly pliable and subject to neuromodulation. In the central nervous system, hydrogen sulfide (H?S) is a gasotransmitter generated primarily by the enzyme cystathionine-?-synthase (CBS). We sought to determine the role of H?S, and its generation by CBS, in NTS excitability. Real-time RT-PCR, immunoblot, and immunohistochemistry analysis identified the presence of CBS in the NTS. Patch-clamp electrophysiology in brain stem slices examined excitatory postsynaptic currents (EPSCs) and membrane properties in monosynaptically driven NTS neurons. Confocal imaging of labeled afferent synaptic terminals in NTS slices monitored intracellular calcium. Exogenous H?S significantly increased the amplitude of evoked solitary tract (TS)-EPSCs, frequency of miniature (m)EPSCs, and presynaptic terminal calcium fluorescence in the NTS. H?S did not alter action potential discharge or postsynaptic properties. On the other hand, the CBS inhibitor aminooxyacetate (AOA) significantly reduced the amplitude of TS-EPSCs and presynaptic terminal calcium fluorescence in the NTS without altering postsynaptic properties. Taken together, these data support a presynaptic role for endogenous H?S in modulation of excitatory neurotransmission in the NTS. PMID:21734104

Austgen, James R; Hermann, Gerlinda E; Dantzler, Heather A; Rogers, Richard C; Kline, David D

2011-10-01

261

Transfer characteristics of the hair cell's afferent synapse  

NASA Astrophysics Data System (ADS)

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

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

2006-04-01

262

Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina  

Microsoft Academic Search

Retinal neural transmission represents a key function of the eye. Identifying the molecular components of this vital process is helped by studies of selected human genetic eye disorders. For example, mutations in the calcium channel subunit gene CACNA1F cause incomplete X-linked congenital stationary night blindness (CSNB2 or iCSNB), a human retinal disorder with abnormal electrophysiological response and visual impair- ments

Fiona Mansergh; Noelle C. Orton; John P. Vessey; Melanie R. Lalonde; William K. Stell; Francois Tremblay; Steven Barnes; Derrick E. Rancourt; N. Torben

2005-01-01

263

Central clock excites vasopressin neurons by waking osmosensory afferents during late sleep  

Microsoft Academic Search

Osmoregulated vasopressin release is facilitated during the late sleep period (LSP) to prevent dehydration and enuresis. Previous work has shown that clock neurons in the suprachiasmatic nucleus (SCN) have low firing rates during the LSP, but it is not known how this reduced activity enhances vasopressin release. We found that synaptic excitation of rat supraoptic nucleus neurons by osmosensory afferents

Eric Trudel; Charles W Bourque

2010-01-01

264

Betahistine Produces Postsynaptic Inhibition of the Excitability of the Primary Afferent Neurons in the Vestibular Endorgans  

Microsoft Academic Search

Soto E, Chavez H, Valli P, Benvenuti C, Vega R. Betahistine produces post-synaptic inhibition of the excitability of the primary afferent neurons in the estibular endorgans. Acta Otolaryngol 2001; Suppl 545: 19-24. Betahistine has been used to treat several vestibular disorders of both central and peripheral origin. The objective of this work was to study the action of betahistine in

Enrique Soto; Hortencia Chávez; Paolo Valli; Claudio Benvenuti; Rosario Vega

2001-01-01

265

TRPA1-expressing primary afferents synapse with a morphologically identified subclass of substantia gelatinosa neurons in the adult rat spinal cord.  

PubMed

The TRPA1 channel has been proposed to be a molecular transducer of cold and inflammatory nociceptive signals. It is expressed on a subset of small primary afferent neurons both in the peripheral terminals, where it serves as a sensor, and on the central nerve endings in the dorsal horn. The substantia gelatinosa (SG) of the spinal cord is a key site for integration of noxious inputs. The SG neurons are morphologically and functionally heterogeneous and the precise synaptic circuits of the SG are poorly understood. We examined how activation of TRPA1 channels affects synaptic transmission onto SG neurons using whole-cell patch-clamp recordings and morphological analyses in adult rat spinal cord slices. Cinnamaldehyde (TRPA1 agonist) elicited a barrage of excitatory postsynaptic currents (EPSCs) in a subset of the SG neurons that responded to allyl isothiocyanate (less specific TRPA1 agonist) and capsaicin (TRPV1 agonist). Cinnamaldehyde evoked EPSCs in vertical and radial but not islet or central SG cells. Notably, cinnamaldehyde produced no change in inhibitory postsynaptic currents and nor did it produce direct postsynaptic effects. In the presence of tetrodotoxin, cinnamaldehyde increased the frequency but not amplitude of miniature EPSCs. Intriguingly, cinnamaldehyde had a selective inhibitory action on monosynaptic C- (but not Adelta-) fiber-evoked EPSCs. These results indicate that activation of spinal TRPA1 presynaptically facilitates miniature excitatory synaptic transmission from primary afferents onto vertical and radial cells to initiate action potentials. The presence of TRPA1 channels on the central terminals raises the possibility of bidirectional modulatory action in morphologically identified subclasses of SG neurons. PMID:20497466

Uta, Daisuke; Furue, Hidemasa; Pickering, Anthony E; Rashid, Md Harunor; Mizuguchi-Takase, Hiroko; Katafuchi, Toshihiko; Imoto, Keiji; Yoshimura, Megumu

2010-06-01

266

Primary afferent depolarization in the in vitro frog olfactory bulb  

PubMed Central

1. Experiments on the frog olfactory bulb have been performed in vitro in order to determine whether primary afferent transmission is modified by presynaptic inhibition. 2. Stimulation of the olfactory nerve resulted in a prolonged depolarization of the olfactory nerve as recorded across a sucrose gap. Unstimulated olfactory nerve fibres adjacent to the stimulated fibres were also depolarized. 3. An excitability increase of the olfactory nerve terminals was found that lasted the entire duration of the olfactory nerve depolarization, indicating that the terminals themselves were depolarized. Both the olfactory nerve depolarization and the excitability increase were blocked by cobalt and manganese ions. 4. Low concentrations of glutamate were found to produce a substantial depolarization of the olfactory nerve. Although gamma-aminobutyric acid (GABA) also elicited a depolarization of the olfactory nerve, picrotoxin, a GABA antagonist, did not reduce the stimulus-evoked olfactory nerve depolarization. 5. Recording with potassium-sensitive electrodes in the olfactory nerve terminal region demonstrated an increase in extracellular potassium with the same rise time and duration as the olfactory nerve depolarization. Cobalt and manganese blocked the potassium increase and the olfactory nerve depolarization without affecting the presynaptic action potential. 6. The focally recorded extracellular current resulting from orthodromic synaptic excitation of the secondary olfactory relay neurones was blocked at short intervals by paired stimulation and decreased for the duration of the olfactory nerve depolarization. This suggests a decreased release of transmitter from the olfactory nerve terminals. 7. The possible role of potassium and/or a neurotransmitter in generating the olfactory nerve depolarization and inhibition is discussed.

Jahr, C. E.; Nicoll, R. A.

1981-01-01

267

Peripheral innervation patterns of vestibular nerve afferents in the bullfrog utriculus  

NASA Technical Reports Server (NTRS)

Vestibular nerve afferents innervating the bullfrog utriculus differ in their response dynamics and sensitivity to natural stimulation. They also supply hair cells that differ markedly in hair bundle morphology. To examine the peripheral innervation patterns of individual utricular afferents more closely, afferent fibers were labeled by the extracellular injection of horseradish peroxidase (HRP) into the vestibular nerve after sectioning the vestibular nerve medial to Scarpa's ganglion to allow the degeneration of sympathetic and efferent fibers. The peripheral arborizations of individual afferents were then correlated with the diameters of their parent axons, the regions of the macula they innervate, and the number and type of hair cells they supply. The utriculus is divided by the striola, a narrow zone of distinctive morphology, into media and lateral parts. Utiricular afferents were classified as striolar or extrastriolar according to the epithelial entrance of their parent axons and the location of their terminal fields. In general, striolar afferents had thicker parent axons, fewer subepithelial bifurcations, larger terminal fields, and more synaptic endings than afferents in extrstriolar regions. Afferents in a juxtastriolar zone, immediately adjacent to the medial striola, had innervation patterns transitional between those in the striola and more peripheral parts of the medial extrastriola. moast afferents innervated only a single macular zone. The terminal fields of striolar afferents, with the notable exception of a few afferents with thin parent axons, were generally confined to one side of the striola. Hair cells in the bullfrog utriculus have perviously been classified into four types based on hair bundle morphology. Afferents in the extrastriolar and juxtastriolar zones largely or exclusively innervated Type B hair cells, the predominant hair cell type in the utricular macula. Striolar afferents supplied a mixture of four hair cell types, but largely contacted Type B and Type C hair cells, particularly on the outer rows of the medial striola. Afferents supplying more central striolar regions innervated fewer Type B and larger numbers of Type E and Type F hair cells. Striolar afferents with thin parent axons largely supplied Type E hair cells with bulbed kniocilia in the innermost striolar rows.

Baird, Richard A.; Schuff, N. R.

1994-01-01

268

Spinal projection of spindle afferents of the longissimus lumborum muscles of the cat  

PubMed Central

The connections and monosynaptic projections of muscle spindle afferents of individual heads of the longissimus lumborum have been studied in cats by natural stimulation, by electrical stimulation and by spike-triggered averaging from single identified afferents. The spindle afferents were classified by sensitivity to vibration and by the effect of succinylcholine on their response to ramp-and-hold muscle stretches. Axonal conduction and synaptic effects were recorded as field potentials and focal synaptic potentials during systematic exploration of the spinal cord in segments L1 to L4 with extracellular metal microelectrodes, singly and in linear arrays. Ascending branches of afferent axons within the cord had a significantly higher mean conduction velocity (CV: 56.5 m s?1) than descending branches (40.8 m s?1). The CV of ascending branches was significantly positively correlated with a measure of the strength of intrafusal bag2 muscle fibre contacts, but not to a measure of bag1 contacts. Two sites of monosynaptic excitatory projection in the cord were identified, namely to the intermediate region (laminae V, VI and VII) and to ventral horn region (laminae VIII and IX). In tests of 154 single afferents, signs of central projection were detected for 60, providing 122 regions of maximum negative focal synaptic potentials (FSPs) of mean amplitude 7.51 ?V. Their longitudinal spacing indicated that axons gave off descending collaterals at intervals of 1.5–3.5 mm. Based on the amplitude of FSPs, the projection of secondary afferents is stronger than that of primaries in the intermediate region and possibly also in the ventral horn region. Evidence is also presented that spindle afferent input from different heads of the longissimus converges into any given spinal segment and that input in one spinal root projects to adjacent segments. It is concluded that the organization of the longissimus monosynaptic spindle input favours relatively tonic and diffuse stretch reflexes.

Durbaba, R; Taylor, A; Ellaway, P H; Rawlinson, S

2007-01-01

269

Region-specific impairments in striatal synaptic transmission and impaired instrumental learning in a mouse model of Angelman syndrome.  

PubMed

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation and impaired speech. Because patients with this disorder often exhibit motor tremor and stereotypical behaviors, which are associated with basal ganglia pathology, we hypothesized that AS is accompanied by abnormal functioning of the striatum, the input nucleus of the basal ganglia. Using mutant mice with maternal deficiency of AS E6-AP ubiquitin protein ligase Ube3a (Ube3a(m-/p+) ), we assessed the effects of Ube3a deficiency on instrumental conditioning, a striatum-dependent task. We used whole-cell patch-clamp recording to measure glutamatergic transmission in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). Ube3a(m-/p+) mice were severely impaired in initial acquisition of lever pressing. Whereas the lever pressing of wild-type controls was reduced by outcome devaluation and instrumental contingency reversal, the performance of Ube3a(m-/p+) mice were more habitual, impervious to changes in outcome value and action-outcome contingency. In the DMS, but not the DLS, Ube3a(m-/p+) mice showed reduced amplitude and frequency of miniature excitatory postsynaptic currents. These results show for the first time a selective deficit in instrumental conditioning in the Ube3a deficient mouse model, and suggest a specific impairment in glutmatergic transmission in the associative corticostriatal circuit in AS. PMID:24329862

Hayrapetyan, Volodya; Castro, Stephen; Sukharnikova, Tatyana; Yu, Chunxiu; Cao, Xinyu; Jiang, Yong-Hui; Yin, Henry H

2014-03-01

270

High Frequency Stimulation of the Subthalamic Nucleus Leads to Presynaptic GABA(B)-Dependent Depression of Subthalamo-Nigral Afferents  

PubMed Central

Patients with akinesia benefit from chronic high frequency stimulation (HFS) of the subthalamic nucleus (STN). Among the mechanisms contributing to the therapeutic success of HFS-STN might be a suppression of activity in the output region of the basal ganglia. Indeed, recordings in the substantia nigra pars reticulata (SNr) of fully adult mice revealed that HFS-STN consistently produced a reduction of compound glutamatergic excitatory postsynaptic currents at a time when the tetrodotoxin-sensitive components of the local field potentials had already recovered after the high frequency activation. These observations suggest that HFS-STN not only alters action potential conduction on the way towards the SNr but also modifies synaptic transmission within the SNr. A classical conditioning-test paradigm was then designed to better separate the causes from the indicators of synaptic depression. A bipolar platinum-iridium macroelectrode delivered conditioning HFS trains to a larger group of fibers in the STN, while a separate high-ohmic glass micropipette in the rostral SNr provided test stimuli at minimal intensity to single fibers. The conditioning-test interval was set to 100 ms, i.e. the time required to recover the excitability of subthalamo-nigral axons after HFS-STN. The continuity of STN axons passing from the conditioning to the test sites was examined by an action potential occlusion test. About two thirds of the subthalamo-nigral afferents were occlusion-negative, i.e. they were not among the fibers directly activated by the conditioning STN stimulation. Nonetheless, occlusion-negative afferents exhibited signs of presynaptic depression that could be eliminated by blocking GABA(B) receptors with CGP55845 (1 µM). Further analysis of single fiber-activated responses supported the proposal that the heterosynaptic depression of synaptic glutamate release during and after HFS-STN is mainly caused by the tonic release of GABA from co-activated striato-nigral afferents to the SNr. This mechanism would be consistent with a gain-of-function hypothesis of DBS.

Dvorzhak, Anton; Gertler, Christoph; Harnack, Daniel; Grantyn, Rosemarie

2013-01-01

271

Modulation of GABAergic synaptic transmission by terminal nicotinic acetylcholine receptors in the central autonomic nucleus of the neonatal rat spinal cord.  

PubMed

Using patch clamp recordings from an in vitro spinal cord slice preparation of neonatal rats (9-15days old), we characterized the GABAergic synaptic transmission in sympathetic preganglionic neurones (SPN) of the central autonomic nucleus (CA) of lamina X. Local applications of isoguvacine (100microM), a selective agonist at GABA(A) receptors, induced in all cells tested a chloride current which was abolished by bicuculline, a competitive antagonist at GABA(A) receptors. In addition, 25% of the recorded cells displayed spontaneous tetrodotoxin-insensitive and bicuculline-sensitive chloride miniature inhibitory postsynaptic currents (mIPSCs). Acetylcholine (100microM) increased the frequency of GABAergic mIPSCs without affecting their amplitudes or their kinetic properties indicating a presynaptic site of action. The presynaptic effect of ACh was restricted to GABAergic neurones synapsing onto sympathetic preganglionic neurones. The facilitatory effect of ACh was abolished in the absence of external calcium or in the presence of 100microM cadmium added to the bath solution. Choline 10mM, an agonist at alpha7 nicotinic acetylcholine receptors (nAChRs) or muscarine (10microM), a muscarinic receptor agonist, did not reproduce the presynaptic effect of ACh. The presynaptic effect of ACh was blocked by 1microM of dihydro-beta-erythroidine (DHbetaE), an antagonist of non-alpha7 nAChRs but was insensitive to alpha7 nAChRs antagonists (strychnine, alpha-bungarotoxin and methyllycaconitine) or to the muscarinic receptor antagonist atropine (10microM). It was concluded that SPNs of the central autonomic nucleus displayed a functional GABAergic transmission which is facilitated by terminal non alpha7 nAChRs. PMID:16678861

Seddik, Riad; Schlichter, Rémy; Trouslard, Jérôme

2006-07-01

272

Physiological effects of sustained blockade of excitatory synaptic transmission on spontaneously active developing neuronal networks—an inquiry into the reciprocal linkage between intrinsic biorhythms and neuroplasticity in early ontogeny  

Microsoft Academic Search

Spontaneous bioelectric activity (SBA) taking the form of extracellularly recorded spike trains (SBA) has been quantitatively analyzed in organotypic neonatal rat visual cortex explants at different ages in vitro, and the effects investigated of both short- and long-term pharmacological suppression of glutamatergic synaptic transmission. In the presence of APV, a selective NMDA receptor blocker, 1–2- (but not 3-)week-old cultures recovered

M. A Corner; J van Pelt; P. S Wolters; R. E Baker; R. H Nuytinck

2002-01-01

273

Role of P2 purinergic receptors in synaptic transmission under normoxic and ischaemic conditions in the CA1 region of rat hippocampal slices  

PubMed Central

The role of ATP and its stable analogue ATP?S [adenosine-5?-o-(3-thio)triphosphate] was studied in rat hippocampal neurotransmission under normoxic conditions and during oxygen and glucose deprivation (OGD). Field excitatory postsynaptic potentials (fEPSPs) from the dendritic layer or population spikes (PSs) from the soma were extracellularly recorded in the CA1 area of the rat hippocampus. Exogenous application of ATP or ATP?S reduced fEPSP and PS amplitudes. In both cases the inhibitory effect was blocked by the selective A1 adenosine receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) and was potentiated by different ecto-ATPase inhibitors: ARL 67156 (6-N,N-diethyl-D-?,?-dibromomethylene), BGO 136 (1-hydroxynaphthalene-3,6-disulfonate) and PV4 [hexapotassium dihydrogen monotitanoundecatungstocobaltate(II) tridecahydrate, K6H2[TiW11CoO40]·13H2O]. ATP?S-mediated inhibition was reduced by the P2 antagonist suramin [8-(3-benzamido-4-methylbenzamido)naphthalene-1,3,5-trisulfonate] at the somatic level and by other P2 blockers, PPADS (pyridoxalphosphate-6-azophenyl-2?,4?-disulfonate) and MRS 2179 (2?-deoxy-N6-methyladenosine 3?,5?-bisphosphate), at the dendritic level. After removal of both P2 agonists, a persistent increase in evoked synaptic responses was recorded both at the dendritic and somatic levels. This effect was prevented in the presence of different P2 antagonists. A 7-min OGD induced tissue anoxic depolarization and was invariably followed by irreversible loss of fEPSP. PPADS, suramin, MRS2179 or BBG (brilliant blue G) significantly prevented the irreversible failure of neurotransmission induced by 7-min OGD. Furthermore, in the presence of these P2 antagonists, the development of anoxic depolarization was blocked or significantly delayed. Our results indicate that P2 receptors modulate CA1 synaptic transmission under normoxic conditions by eliciting both inhibitory and excitatory effects. In the same brain region, P2 receptor stimulation plays a deleterious role during a severe OGD insult.

Coppi, Elisabetta; Pugliese, Anna Maria; Stephan, Holger; Muller, Christa E.

2007-01-01

274

Role of Neurotrophin Receptor TrkB in the Maturation of Rod Photoreceptors and Establishment of Synaptic Transmission to the Inner Retina  

PubMed Central

Brain-derived neurotrophic factor (BDNF) acts through TrkB, a receptor with kinase activity, and mitigates light-induced apoptosis in adult mouse rod photoreceptors. To determine whether TrkB signaling is necessary for rod development and function, we examined the retinas of mice lacking all isoforms of the TrkB receptor. Rod migration and differentiation occur in the mutant retina, but proceed at slower rates than in wild-type mice. In postnatal day 16 (P16) mutants, rod outer segment dimensions and rhodopsin content are comparable with those of photoreceptors in P12 wild type (WT). Quantitative analyses of the photoreceptor component in the electroretinogram (ERG) indicate that the gain and kinetics of the rod phototransduction signal in dark-adapted P16 mutant and P12 WT retinas are similar. In contrast to P12 WT, however, the ERG in mutant mice entirely lacks a b-wave, indicating a failure of signal transmission in the retinal rod pathway. In the inner retina of mutant mice, although cells appear anatomically and immunohistochemically normal, they fail to respond to prolonged stroboscopic illumination with the normal expression of c-fos. Absence of the b-wave and failure of c-fos expression, in view of anatomically normal inner retinal cells, suggest that lack of TrkB signaling causes a defect in synaptic signaling between rods and inner retinal cells. Retinal pigment epithelial cells and cells in the inner retina, including Müller, amacrine, and retinal ganglion cells, express the TrkB receptor, but rod photoreceptors do not. Moreover, inner retinal cells respond to exogenous BDNF with c-fos expression and extracellular signal-regulated kinase phosphorylation. Thus, interactions of rods with TrkB-expressing cells must be required for normal rod development.

Rohrer, Baerbel; Korenbrot, Juan I.; LaVail, Matthew M.; Reichardt, Louis F.; Xu, Baoji

2009-01-01

275

Role of neurotrophin receptor TrkB in the maturation of rod photoreceptors and establishment of synaptic transmission to the inner retina.  

PubMed

Brain-derived neurotrophic factor (BDNF) acts through TrkB, a receptor with kinase activity, and mitigates light-induced apoptosis in adult mouse rod photoreceptors. To determine whether TrkB signaling is necessary for rod development and function, we examined the retinas of mice lacking all isoforms of the TrkB receptor. Rod migration and differentiation occur in the mutant retina, but proceed at slower rates than in wild-type mice. In postnatal day 16 (P16) mutants, rod outer segment dimensions and rhodopsin content are comparable with those of photoreceptors in P12 wild type (WT). Quantitative analyses of the photoreceptor component in the electroretinogram (ERG) indicate that the gain and kinetics of the rod phototransduction signal in dark-adapted P16 mutant and P12 WT retinas are similar. In contrast to P12 WT, however, the ERG in mutant mice entirely lacks a b-wave, indicating a failure of signal transmission in the retinal rod pathway. In the inner retina of mutant mice, although cells appear anatomically and immunohistochemically normal, they fail to respond to prolonged stroboscopic illumination with the normal expression of c-fos. Absence of the b-wave and failure of c-fos expression, in view of anatomically normal inner retinal cells, suggest that lack of TrkB signaling causes a defect in synaptic signaling between rods and inner retinal cells. Retinal pigment epithelial cells and cells in the inner retina, including Müller, amacrine, and retinal ganglion cells, express the TrkB receptor, but rod photoreceptors do not. Moreover, inner retinal cells respond to exogenous BDNF with c-fos expression and extracellular signal-regulated kinase phosphorylation. Thus, interactions of rods with TrkB-expressing cells must be required for normal rod development. PMID:10516311

Rohrer, B; Korenbrot, J I; LaVail, M M; Reichardt, L F; Xu, B

1999-10-15

276

L-Arginyl-3,4-Spermidine is neuroprotective in several in vitro models of neurodegeneration and in vivo ischaemia without suppressing synaptic transmission  

PubMed Central

Stroke is the third most common cause of death in the world, and there is a clear need to develop new therapeutics for the stroke victim. To address this need, we generated a combinatorial library of polyamine compounds based on sFTX-3.3 toxin from which L-Arginyl-3,4-Spermidine (L-Arg-3,4) emerged as a lead neuroprotective compound. In the present study, we have extended earlier results to examine the compound's neuroprotective actions in greater detail. In an in vitro ischaemia model, L-Arg-3,4 significantly reduced CA1 cell death when administered prior to induction of 60 min of ischaemia as well as when administered immediately after ischaemia. Surprisingly, L-Arg-3,4 continued to prevent cell death significantly when administration was delayed for as long as 60 min after ischaemia. L-Arg-3,4 significantly reduced cell death in excitotoxicity models mediated by glutamate, NMDA, AMPA, or kainate. Unlike glutamate receptor antagonists, 300 ?M L-Arg-3,4 did not suppress synaptic transmission as measured by evoked responses in acute hippocampal slices. L-Arg-3,4 provided significant protection, in vitro, in a superoxide mediated injury model and prevented an increase of superoxide production after AMPA or NMDA stimulation. It also decreased nitric oxide production after in vitro ischaemia and NMDA stimulation, but did so without inhibiting nitric oxide synthase directly. Furthermore, L-Arg-3,4 was significantly neuroprotective in an in vivo model of global forebrain ischaemia, without any apparent neurological side-effects. Taken together, these results demonstrate that L-Arg-3,4 is protective in several models of neurodegeneration and may have potential as a new therapeutic compound for the treatment of stroke, trauma, and other neurodegenerative diseases.

Morrison, Barclay; Pringle, Ashley K; McManus, Terence; Ellard, John; Bradley, Mark; Signorelli, Francesco; Iannotti, Fausto; Sundstrom, Lars E

2002-01-01

277

Onset coding is degraded in auditory nerve fibers from mutant mice lacking synaptic ribbons  

PubMed Central

Synaptic ribbons, found at the pre-synaptic membrane of sensory cells in both ear and eye, have been implicated in the vesicle-pool dynamics of synaptic transmission. To elucidate ribbon function, we characterized the response properties of single auditory nerve fibers in mice lacking Bassoon, a scaffolding protein involved in anchoring ribbons to the membrane. In Bassoon mutants, immunohistochemistry showed fewer than 3% of the hair cells’ afferent synapses retained anchored ribbons. Auditory nerve fibers from mutants had normal threshold, dynamic range and post-onset adaptation in response to tone bursts, and they were able to phase-lock with normal precision to amplitude-modulated tones. However, spontaneous and sound-evoked discharge rates were reduced, and the reliability of spikes, particularly at stimulus onset, was significantly degraded as shown by an increased variance of first-spike latencies. Modeling based on in vitro studies of normal and mutant hair cells links these findings to reduced release rates at the synapse. The degradation of response reliability in these mutants suggests that the ribbon and/or bassoon normally facilitate high rates of exocytosis and that its absence significantly compromises the temporal resolving power of the auditory system.

Buran, B.N.; Strenzke, N.; Neef, A.; Gundelfinger, E.D.; Moser, T.; Liberman, M.C.

2010-01-01

278

Efferent Control of Hair Cell and Afferent Responses in the Semicircular Canals  

PubMed Central

The sensations of sound and motion generated by the inner ear are controlled by the brain through extensive centripetal innervation originating within the brain stem. In the semicircular canals, brain stem efferent neurons make synaptic contacts with mechanosensory hair cells and with the dendrites of afferent neurons. Here, we examine the relative contributions of efferent action on hair cells and afferents. Experiments were performed in vivo in the oyster toadfish, Opsanus tau. The efferent system was activated via electrical pulses to the brain stem and sensory responses to motion stimuli were quantified by simultaneous voltage recording from afferents and intracellular current- and/or voltage-clamp recordings from hair cells. Results showed synaptic inputs to both afferents and hair cells leading to relatively long-latency intracellular signaling responses: excitatory in afferents and inhibitory in hair cells. Generally, the net effect of efferent action was an increase in afferent background discharge and a simultaneous decrease in gain to angular motion stimuli. Inhibition of hair cells was likely the result of a ligand-gated opening of a major basolateral conductance. The reversal potential of the efferent-evoked current was just below the hair cell resting potential, thus resulting in a small hyperpolarization. The onset latency averaged about 90 ms and latency to peak response was 150–400 ms. Hair cell inhibition often outlasted afferent excitation and, in some cases, latched hair cells in the “off” condition for >1 s following cessation of stimulus. These features endow the animal with a powerful means to adjust the sensitivity and dynamic range of motion sensation.

Boyle, Richard; Rabbitt, Richard D.; Highstein, Stephen M.

2009-01-01

279

Synaptic Tag  

NSDL National Science Digital Library

In this outdoor activity, learners review the parts of the synapse and their functions by playing a game. The object of the game is to get as many neurotransmitters across the synapse to the dendrite without being caught (deactivated) by the enzyme. This game models the process by which enzymes break down neurotransmitters (e.g., acetylcholine) in the synaptic cleft.

Yoshioka, Melissa

2009-01-01

280

Voltage-gated K(+) channels contributing to temporal precision at the inner hair cell-auditory afferent nerve fiber synapses in the mammalian cochlea.  

PubMed

To perform auditory tasks such as sound localization in the space, auditory neurons in the brain must distinguish sub-millisecond temporal differences in signals from two ears. Such high temporal resolution is possible when each neuron in the ascending auditory pathway fires brief action potential at very accurate timing. Various pre- and postsynaptic machineries ensuring such high temporal precision of auditory synaptic transmission have been identified. Of particular, in this review, the role of K(+) channels in shortening the duration of synaptic potentials will be discussed. First, the contribution of K(+) channels to AP firing of general auditory neurons will be discussed. Then, the focus will be moved to the inner hair cell (IHC)-auditory afferent nerve fiber (ANF) synapses, the first synapses of ascending auditory pathway. Molecular and immunohistological techniques have revealed various K(+) channels in the cell bodies and their processes of ANFs. Since the development of patch-clamp recordings from the ANF dendrites in 2002, it became possible to monitor the IHC-ANF synaptic transmission in greater detail. As revealed in brain auditory synapses, several different K(+) channels appear to participate in reducing the duration of synaptic potentials at the IHC-ANF synapses. In addition, K(+) channels at the ANF dendrites might act as potential targets of efferent feedback from the brain. The hypothesis is that, upon loud sound exposure, efferent neurotransmitters released onto the ANF dendrites activate certain K(+) channels and prevent excitotoxicity of ANFs. Therefore, K(+) channels of the ANF dendrites might provide potential sites of pharmacological actions to prevent noise-induced hearing loss. PMID:24925343

Oak, Min-Ho; Yi, Eunyoung

2014-07-01

281

Role of afferents in the differentiation of bipolar cells in the mouse retina.  

PubMed

To establish dendritic arbors that integrate properly into a neural circuit, neurons must rely on cues from the local environment. The neurons presynaptic to these arbors, the afferents, are one potential source of these cues, but the particular dendritic features they regulate remain unclear. Retinal bipolar cells can be classified by the type of photoreceptor, cone or rod, forming synaptic contacts with their dendrites, suggesting a potential role of these afferents in shaping the bipolar cell dendritic arbor. In the present investigation, the role of photoreceptors in directing the differentiation of bipolar cells has been studied using two genetically modified "coneless" and "conefull" mice. Single cone (Type 7/CB4a) and rod bipolar cells were labeled with DiI to reveal the entire dendritic arbor and subsequently analyzed for several morphological features. For both cone and rod bipolar cells, the dendritic field area, number of dendritic terminals, and stratification of terminals in the outer plexiform layer were comparable among coneless, conefull, and wild-type retinas, and the overall morphological appearance of each type of cell was essentially conserved, indicating an independence from afferent specification. The presence of normal afferents was, however, found to be critical for the proper spatial distribution of dendritic terminals, exhibiting a clustered distribution for the cone bipolar cells and a dispersed distribution for the rod bipolar cells. These results demonstrate a selectivity in the afferent dependency of bipolar cell differentiation, their basic morphogenetic plan commanded cell intrinsically, and their fine terminal connectivity directed by the afferents themselves. PMID:20130177

Keeley, Patrick W; Reese, Benjamin E

2010-02-01

282

Drug-evoked synaptic plasticity: beyond metaplasticity.  

PubMed

Addictive drugs such as cocaine induce synaptic plasticity in the ventral tegmental area and its projection areas, which may represent the cellular correlate of an addiction trace. Cocaine induces changes in excitatory transmission primarily in the VTA, which persists for days after a single exposure. These initial alterations in synaptic transmission represent a metaplasticity that is permissive for late stages of remodeling throughout the mesocorticolimbic circuitry, specifically in the NAc. Specific synaptic and cellular changes in the NAc persist following prolonged exposure to cocaine, and this remodeling may contribute to altered behavior. By manipulating synaptic activity in the NAc, it may be possible to reverse pathological synaptic transmission and its associated abnormal behavior following exposure to addictive drugs. PMID:23571119

Creed, Meaghan C; Lüscher, Christian

2013-08-01

283

Growth factors in synaptic function  

PubMed Central

Synapses are increasingly recognized as key structures that malfunction in disorders like schizophrenia, mental retardation, and neurodegenerative diseases. The importance and complexity of the synapse has fuelled research into the molecular mechanisms underlying synaptogenesis, synaptic transmission, and plasticity. In this regard, neurotrophic factors such as netrin, Wnt, transforming growth factor-? (TGF-?), tumor necrosis factor-? (TNF-?), and others have gained prominence for their ability to regulate synaptic function. Several of these factors were first implicated in neuroprotection, neuronal growth, and axon guidance. However, their roles in synaptic development and function have become increasingly clear, and the downstream signaling pathways employed by these factors have begun to be elucidated. In this review, we will address the role of these factors and their downstream effectors in synaptic function in vivo and in cultured neurons.

Poon, Vivian Y.; Choi, Sojoong; Park, Mikyoung

2013-01-01

284

Opioid Actions in Primary-Afferent Fibers--Involvement in Analgesia and Anesthesia  

PubMed Central

Opioids inhibit glutamatergic excitatory transmission from the periphery by activating G-protein coupled opioid receptors in the central terminals of primary-afferent neurons in the spinal substantia gelatinosa, resulting in antinociception. Opioid receptor activation in the peripheral terminals of primary-afferent neurons inhibits the production of action potentials in response to nociceptive stimuli given to the periphery, leading to antinociception. Opioids also exhibit a local anesthetic effect without opioid receptor activation in peripheral nerve fibers. This review article will focus on analgesia and anesthesia produced by the actions of opioids on primary-afferent fibers.

Kumamoto, Eiichi; Mizuta, Kotaro; Fujita, Tsugumi

2011-01-01

285

SNARE proteins and schizophrenia : linking synaptic and neurodevelopmental hypotheses  

Microsoft Academic Search

- ceptual model has fostered efforts to define the exact synaptic pathology further. Synaptic pro - teins are obvious candidates for such studies, and the integral role of the SNARE complex, and SNARE-associated proteins, in synaptic transmission will ensure that it is the focus of much of this research. Significant new insights into the role of this complex are arising

Reuben D. Johnson; Peter L. Oliver; Kay E. Davies

2008-01-01

286

A new cytochemical method for in situ detection of cholinergic synaptic transmission by staining of Cu2+ incorporated in frog neuromuscular junction during nerve stimulation.  

PubMed

A new cytochemical method was devised in order to visualize Cu2+ ions in the synaptic area after their intracellular penetration during nerve stimulation of the frog neuromuscular junction (NMJ). The motor nerves were stimulated in presence of Cu2+. After total blockade of the neuromuscular junction, the tissue was treated by ferrocyanide, a precipitating agent of Cu2+, and fixed for optical and electron microscopic observation. The oxidoreductase-like catalytic activity of the copper ferrocyanide precipitate was used to amplify the cytochemical staining by a treatment with diaminobenzidine and H2O2, after permeabilization of cell membranes by Triton X-100. At optical level, an intense staining was observed in the synaptic area. Application of d-tubocurarine (d-TC), a selective inhibitor of nicotinic acetylcholine receptors (nAChRs), markedly reduced the staining. No reaction could be observed in absence of membrane permeabilization. These results suggest that Cu2+ was localized in the cytoplasm of muscle cells after its penetration through nAChRs. At electron microscopic level, cytochemical reaction was found in the cytoplasm of muscle cells near the postsynaptic membrane, and in a few synaptic vesicles in the vicinity of the active zone. This method may be used for the identification of cholinergic inputs in central and peripheral nerve systems and, generally speaking, for the detection of synaptic activity elicited by specific nerve stimulation. PMID:16847358

Hirai, Keiji; Tanaka, Eiichiro; Motelica-heino, Ion; Katayama, Yoshifumi; Higashi, Hideo; Tsuji, Shigeru

2006-06-01

287

Nonnociceptive afferent activity depresses nocifensive behavior and nociceptive synapses via an endocannabinoid-dependent mechanism.  

PubMed

Previously, low-frequency stimulation (LFS) of a nonnociceptive touch-sensitive neuron has been found to elicit endocannabinoid-dependent long-term depression (eCB-LTD) in nociceptive synapses in the leech central nervous system (CNS) that requires activation of a presynaptic transient receptor potential vanilloid (TRPV)-like receptor by postsynaptically synthesized 2-arachidonoyl glycerol (2-AG). This capacity of nonnociceptive afferent activity to reduce nociceptive signaling resembles gate control of pain, albeit longer lasting in these synaptic experiments. Since eCB-LTD has been observed at a single sensory-motor synapse, this study examines the functional relevance of this mechanism, specifically whether this form of synaptic plasticity has similar effects at the behavioral level in which additional, intersegmental neural circuits are engaged. Experiments were carried out using a semi-intact preparation that permitted both synaptic recordings and monitoring of the leech whole body shortening, a defensive withdrawal reflex that was elicited via intracellular stimulation of a single nociceptive neuron (the N cell). The same LFS of a nonnociceptive afferent that induced eCB-LTD in single synapses also produced an attenuation of the shortening reflex. Similar attenuation of behavior was also observed when 2-AG was applied. LFS-induced behavioral and synaptic depression was blocked by tetrahydrolipstatin (THL), a diacylglycerol lipase inhibitor, and by SB366791, a TRPV1 antagonist. The effects of both THL and SB366791 were observed following either bath application of the drug or intracellular injection into the presynaptic (SB366791) or postsynaptic (THL) neuron. These findings demonstrate a novel, endocannabinoid-based mechanism by which nonnociceptive afferent activity may modulate nocifensive behaviors via action on primary afferent synapses. PMID:24027102

Yuan, Sharleen; Burrell, Brian D

2013-12-01

288

Afferent Deprivation Elicits a Transcriptional Response Associated with Neuronal Survival After a Critical Period in the Mouse Cochlear Nucleus  

PubMed Central

The mechanisms underlying enhanced plasticity of synaptic connections and susceptibilities to manipulations of afferent activity in developing sensory systems are not well understood. One example is the rapid and dramatic neuron death that occurs after removal of afferent input to the cochlear nucleus (CN) of young mammals and birds. The molecular basis of this critical period of neuronal vulnerability and the transition to survival independent of afferent input remains to be defined. Here we used microarray analyses, real time RT PCR, and immunohistochemistry of the mouse CN to show that deafferentation results in strikingly different sets of regulated genes in vulnerable (postnatal day (P) 7) and invulnerable (P21) CN. An unexpectedly large set of immune-related genes was induced by afferent deprivation after the critical period, which corresponded with glial proliferation over the same time frame. Apoptotic gene expression was not highly regulated in the vulnerable CN after afferent deprivation but, surprisingly, did increase after deafferentation at P21, when all neurons ultimately survive. Pharmacological activity blockade in the 8th nerve mimicked afferent deprivation for only a subset of the afferent deprivation regulated genes, indicating the presence of an additional factor not dependent on action potential-mediated signaling that is also responsible for transcriptional changes. Overall, our results suggest that the cell death machinery during this critical period is mainly constitutive, whereas after the critical period neuronal survival could be actively promoted by both constitutive and induced gene expression.

Harris, Julie A.; Iguchi, Fukuichiro; Seidl, Armin H.; Lurie, Diana I.; Rubel, Edwin W

2008-01-01

289

EDITORIAL: Synaptic electronics Synaptic electronics  

NASA Astrophysics Data System (ADS)

Conventional computers excel in logic and accurate scientific calculations but make hard work of open ended problems that human brains handle easily. Even von Neumann—the mathematician and polymath who first developed the programming architecture that forms the basis of today's computers—was already looking to the brain for future developments before his death in 1957 [1]. Neuromorphic computing uses approaches that better mimic the working of the human brain. Recent developments in nanotechnology are now providing structures with very accommodating properties for neuromorphic approaches. This special issue, with guest editors James K Gimzewski and Dominique Vuillaume, is devoted to research at the serendipitous interface between the two disciplines. 'Synaptic electronics', looks at artificial devices with connections that demonstrate behaviour similar to synapses in the nervous system allowing a new and more powerful approach to computing. Synapses and connecting neurons respond differently to incident signals depending on the history of signals previously experienced, ultimately leading to short term and long term memory behaviour. The basic characteristics of a synapse can be replicated with around ten simple transistors. However with the human brain having around 1011 neurons and 1015 synapses, artificial neurons and synapses from basic transistors are unlikely to accommodate the scalability required. The discovery of nanoscale elements that function as 'memristors' has provided a key tool for the implementation of synaptic connections [2]. Leon Chua first developed the concept of the 'The memristor—the missing circuit element' in 1971 [3]. In this special issue he presents a tutorial describing how memristor research has fed into our understanding of synaptic behaviour and how they can be applied in information processing [4]. He also describes, 'The new principle of local activity, which uncovers a minuscule life-enabling "Goldilocks zone", dubbed the edge of chaos, where complex phenomena, including creativity and intelligence, may emerge'. Also in this issue R Stanley Williams and colleagues report results from simulations that demonstrate the potential for using Mott transistors as building blocks for scalable neuristor-based integrated circuits without transistors [5]. The scalability of neural chip designs is also tackled in the design reported by Narayan Srinivasa and colleagues in the US [6]. Meanwhile Carsten Timm and Massimiliano Di Ventra describe simulations of a molecular transistor in which electrons strongly coupled to a vibrational mode lead to a Franck-Condon (FC) blockade that mimics the spiking action potentials in synaptic memory behaviour [7]. The 'atomic switches' used to demonstrate synaptic behaviour by a collaboration of researchers in California and Japan also come under further scrutiny in this issue. James K Gimzewski and colleagues consider the difference between the behaviour of an atomic switch in isolation and in a network [8]. As the authors point out, 'The work presented represents steps in a unified approach of experimentation and theory of complex systems to make atomic switch networks a uniquely scalable platform for neuromorphic computing'. Researchers in Germany [9] and Sweden [10] also report on theoretical approaches to modelling networks of memristive elements and complementary resistive switches for synaptic devices. As Vincent Derycke and colleagues in France point out, 'Actual experimental demonstrations of neural network type circuits based on non-conventional/non-CMOS memory devices and displaying function learning capabilities remain very scarce'. They describe how their work using carbon nanotubes provides a rare demonstration of actual function learning with synapses based on nanoscale building blocks [11]. However, this is far from the only experimental work reported in this issue, others include: short-term memory of TiO2-based electrochemical capacitors [12]; a neuromorphic circuit composed of a nanoscale 1-kbit resistive random-access memory (RRAM

Demming, Anna; Gimzewski, James K.; Vuillaume, Dominique

2013-09-01

290

Novel Afferent Terminal Structure in the Crista Ampullaris of the Goldfish, Carassius auratus  

NASA Technical Reports Server (NTRS)

Using transmission electron microscopy, we have identified a new type of afferent terminal structure in the crista ampullaris of the goldfish Carassius auratus. In addition to the bouton-type afferent terminals previously described in the ear of this species, the crista also contained enlarged afferent terminals that enveloped a portion of the basolateral hair cell membrane. The hair cell membrane was evaginated and protruded into the afferent terminal in a glove-and-finger configuration. The membranes of the two cells were regularly aligned in the protruded region of the contact and had a distinct symmetrical electron density. The electron-dense profiles of these contacts were easily identified and were present in every crista sampled. In some cases, efferent terminals synapsed onto the afferents at a point where the hair cell protruded into the terminal. The ultrastructural similarities of the goldfish crista afferents to calyx afferents found in amniotes (birds, reptiles, and mammals) are discussed. The results of the study support the hypothesis that structural variation in the vertebrate inner ear may have evolved much earlier in evolution than previously supposed.

Lanford, Pamela J.; Popper, Arthur N.

1996-01-01

291

Analysis of the Effects of Cannabinoids on Synaptic Transmission between Basket and Purkinje Cells in the Cerebellar Cortex of the Rat  

Microsoft Academic Search

The hypothesis of the present work was that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission be- tween basket and Purkinje cells in the cerebellar cortex. The aim was to test this hypothesis under near-physiological conditions. Action potentials of basket cells and spontaneous inhibitory postsynaptic currents (sIPSCs) in synaptically coupled Purkinje cells were recorded simultaneously in rat brain slices. The

Bela Szabo; Marta Than; David Thorn; Ilka Wallmichrath

2004-01-01

292

Hippocampal tauopathy in tau transgenic mice coincides with impaired hippocampus-dependent learning and memory, and attenuated late-phase long-term depression of synaptic transmission  

Microsoft Academic Search

We evaluated various forms of hippocampus-dependent learning and memory, and hippocampal synaptic plasticity in THY-Tau22 transgenic mice, a murine tauopathy model that expresses double-mutated 4-repeat human tau, and shows neuropathological tau hyperphosphorylation and aggregation throughout the brain. Focussing on hippocampus, immunohistochemical studies in aged THY-Tau22 mice revealed prominent hyper- and abnormal phosphorylation of tau in CA1 region, and an increase

Ann Van der Jeugd; Tariq Ahmed; Sylvie Burnouf; Karim Belarbi; Malika Hamdame; Marie-Eve Grosjean; Sandrine Humez; Detlef Balschun; David Blum; Luc Buée; Rudi D’Hooge

2011-01-01

293

A Model of Bidirectional Synaptic Plasticity: From Signaling Network to Channel Conductance  

ERIC Educational Resources Information Center

In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of…

Castellani, Gastone C.; Quinlan, Elizabeth M.; Bersani, Ferdinando; Cooper, Leon N.; Shouval, Harel Z.

2005-01-01

294

Selective activation of primary afferent fibers evaluated by sine-wave electrical stimulation  

PubMed Central

Transcutaneous sine-wave stimuli at frequencies of 2000, 250 and 5 Hz (Neurometer) are thought to selectively activate A?, A? and C afferent fibers, respectively. However, there are few reports to test the selectivity of these stimuli at the cellular level. In the present study, we analyzed action potentials (APs) generated by sine-wave stimuli applied to the dorsal root in acutely isolated rat dorsal root ganglion (DRG) preparations using intracellular recordings. We also measured excitatory synaptic responses evoked by transcutaneous stimuli in substantia gelatinosa (SG) neurons of the spinal dorsal horn, which receive inputs predominantly from C and A? fibers, using in vivo patch-clamp recordings. In behavioral studies, escape or vocalization behavior of rats was observed with both 250 and 5 Hz stimuli at intensity of ~0.8 mA (T5/ T250), whereas with 2000 Hz stimulation, much higher intensity (2.14 mA, T2000) was required. In DRG neurons, APs were generated at T5/T250 by 2000 Hz stimulation in A?, by 250 Hz stimulation both in A? and A?, and by 5 Hz stimulation in all three classes of DRG neurons. However, the AP frequencies elicited in A? and A? by 5 Hz stimulation were much less than those reported previously in physiological condition. With in vivo experiments large amplitude of EPSCs in SG neurons were elicited by 250 and 5 Hz stimuli at T5/ T250. These results suggest that 2000 Hz stimulation excites selectively A? fibers and 5 Hz stimulation activates noxious transmission mediated mainly through C fibers. Although 250 Hz stimulation activates both A? and A? fibers, tactile sensation would not be perceived when painful sensation is produced at the same time. Therefore, 250 Hz was effective stimulus frequency for activation of A? fibers initiating noxious sensation. Thus, the transcutaneous sine-wave stimulation can be applied to evaluate functional changes of sensory transmission by comparing thresholds with the three stimulus frequencies.

Koga, Kohei; Furue, Hidemasa; Rashid, Md Harunor; Takaki, Atsushi; Katafuchi, Toshihiko; Yoshimura, Megumu

2005-01-01

295

Alterations in Corticostriatal Synaptic Plasticity in Mice Over-Expressing Human ?-Synuclein  

PubMed Central

Most forms of Parkinson’s Disease (PD) are sporadic in nature, but some have genetic causes as first described for the ?-synuclein gene. The ?-synuclein protein also accumulates as insoluble aggregates in Lewy bodies in sporadic PD as well as in most inherited forms of PD. The focus of the present study is the modulation of synaptic plasticity in the corticostriatal pathway of transgenic (Tg) mice that over express the human ?-synuclein protein throughout the brain (ASOTg). Paired-pulse facilitation was detected in vitro by activation of corticostriatal afferents in ASOTg mice, consistent with a presynaptic effect of elevated human ?-synuclein. However basal synaptic transmission was unchanged in ASOTg, suggesting that human ?-synuclein could impact paired-pulse facilitation via a presynaptic mechanism not directly related to the probability of neurotransmitter release. Mice lacking ?-synuclein or those expressing normal and A53T human ?-synuclein in tyrosine hydroxylase-containing neurons showed, instead, paired-pulse depression. High-frequency stimulation induced a presynaptic form of long-term depression solely in ASOTg striatum. A presynaptic, NMDA receptor-independent form of chemical long-term potentiation induced by forskolin (FSK) was enhanced in ASOTg striatum, while FSK-induced cAMP levels were reduced in ASOTg synaptoneurosome fractions. Overall the results suggest that elevated human ?-synuclein alters presynaptic plasticity in the corticostriatal pathway, possibly reflecting a reduction in glutamate at corticostriatal synapses by modulation of adenylyl cyclase signaling pathways. ASOTg mice may recapitulate an early stage in PD during which over expressed ?-synuclein dampens corticostriatal synaptic transmission and reduces movement.

Watson, J.B.; Hatami, A.; David, H.; Masliah, E.; Roberts, K.; Evans, C. E.; Levine, M.S.

2009-01-01

296

Synaptic vesicle pools and dynamics.  

PubMed

Synaptic vesicles release neurotransmitter at chemical synapses, thus initiating the flow of information in neural networks. To achieve this, vesicles undergo a dynamic cycle of fusion and retrieval to maintain the structural and functional integrity of the presynaptic terminals in which they reside. Moreover, compelling evidence indicates these vesicles differ in their availability for release and mobilization in response to stimuli, prompting classification into at least three different functional pools. Ongoing studies of the molecular and cellular bases for this heterogeneity attempt to link structure to physiology and clarify how regulation of vesicle pools influences synaptic strength and presynaptic plasticity. We discuss prevailing perspectives on vesicle pools, the role they play in shaping synaptic transmission, and the open questions that challenge current understanding. PMID:22745285

Alabi, AbdulRasheed A; Tsien, Richard W

2012-08-01

297

Synaptic Vesicle Pools and Dynamics  

PubMed Central

Synaptic vesicles release neurotransmitter at chemical synapses, thus initiating the flow of information in neural networks. To achieve this, vesicles undergo a dynamic cycle of fusion and retrieval to maintain the structural and functional integrity of the presynaptic terminals in which they reside. Moreover, compelling evidence indicates these vesicles differ in their availability for release and mobilization in response to stimuli, prompting classification into at least three different functional pools. Ongoing studies of the molecular and cellular bases for this heterogeneity attempt to link structure to physiology and clarify how regulation of vesicle pools influences synaptic strength and presynaptic plasticity. We discuss prevailing perspectives on vesicle pools, the role they play in shaping synaptic transmission, and the open questions that challenge current understanding.

Alabi, AbdulRasheed A.; Tsien, Richard W.

2012-01-01

298

Identity of Endogenous NMDAR Glycine Site Agonist in Amygdala Is Determined by Synaptic Activity Level  

PubMed Central

Mechanisms of NMDA receptor-dependent synaptic plasticity contribute to the acquisition and retention of conditioned fear memory. However, synaptic rules which may determine the extent of NMDA receptor activation in the amygdala, a key structure implicated in fear learning, remain unknown. Here we show that the identity of the NMDAR glycine site agonist at synapses in the lateral nucleus of the amygdala may depend on the level of synaptic activation. Tonic activation of NMDARs at synapses in the amygdala under low-activity conditions is supported by ambient D-serine, whereas glycine may be released from astrocytes in response to afferent impulses. The release of glycine may decode the increases in afferent activity levels into enhanced NMDAR-mediated synaptic events, serving an essential function in the induction of NMDAR-dependent long-term potentiation in fear conditioning pathways.

Li, Yan; Sacchi, Silvia; Pollegioni, Loredano; Basu, Alo C.; Coyle, Joseph T.; Bolshakov, Vadim Y.

2013-01-01

299

Specificity of afferent synapses onto plane-polarized hair cells in the posterior lateral line of the zebrafish  

PubMed Central

The proper wiring of the vertebrate brain represents an extraordinary developmental challenge, requiring billions of neurons to select their appropriate synaptic targets. In view of this complexity, simple vertebrate systems provide necessary models for understanding how synaptic specificity arises. The posterior lateral-line organ of larval zebrafish consists of polarized hair cells organized in discrete clusters known as neuromasts. Here we show that each afferent neuron of the posterior lateral line establishes specific contacts with hair cells of the same hair-bundle polarity. We quantify this specificity by modeling the neuron as a biased selector of hair-cell polarity and find evidence for bias from as early as 2.5 days post-fertilization. More than half of the neurons form contacts on multiple neuromasts, but the innervated organs are spatially consecutive and the polarity preference is consistent. Using a novel reagent for correlative electron microscopy, HRP-mCherry, we show that these contacts are indeed afferent synapses bearing vesicle-loaded synaptic ribbons. Moreover, afferent neurons reassume their biased innervation pattern after hair-cell ablation and regeneration. By documenting specificity in the pattern of neuronal connectivity during development and in the context of organ regeneration, these results establish the posterior lateral-line organ as a vertebrate system for the in vivo study of synaptic target selection.

Nagiel, Aaron; Andor-Ardo, Daniel

2009-01-01

300

In vivo imaging reveals dendritic targeting of laminated afferents by zebrafish retinal ganglion cells.  

PubMed

Targeting of axons and dendrites to particular synaptic laminae is an important mechanism by which precise patterns of neuronal connectivity are established. Although axons target specific laminae during development, dendritic lamination has been thought to occur largely by pruning of inappropriately placed arbors. We discovered by in vivo time-lapse imaging that retinal ganglion cell (RGC) dendrites in zebrafish show growth patterns implicating dendritic targeting as a mechanism for contacting appropriate synaptic partners. Populations of RGCs labeled in transgenic animals establish distinct dendritic strata sequentially, predominantly from the inner to outer retina. Imaging individual cells over successive days confirmed that multistratified RGCs generate strata sequentially, each arbor elaborating within a specific lamina. Simultaneous imaging of RGCs and subpopulations of presynaptic amacrine interneurons revealed that RGC dendrites appear to target amacrine plexuses that had already laminated. Dendritic targeting of prepatterned afferents may thus be a novel mechanism for establishing proper synaptic connectivity. PMID:17114046

Mumm, Jeff S; Williams, Philip R; Godinho, Leanne; Koerber, Amy; Pittman, Andrew J; Roeser, Tobias; Chien, Chi-Bin; Baier, Herwig; Wong, Rachel O L

2006-11-22

301

Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis.  

PubMed

Activity-dependent regulation of dendritic protein synthesis is critical for enduring changes in synaptic function, but how the unique features of distinct activity patterns are decoded by the dendritic translation machinery remains poorly understood. Here, we identify eukaryotic elongation factor-2 (eEF2), which catalyzes ribosomal translocation during protein synthesis, as a biochemical sensor in dendrites that is specifically and locally tuned to the quality of neurotransmission. We show that intrinsic action potential (AP)-mediated network activity in cultured hippocampal neurons maintains eEF2 in a relatively dephosphorylated (active) state, whereas spontaneous neurotransmitter release (i.e., miniature neurotransmission) strongly promotes the phosphorylation (and inactivation) of eEF2. The regulation of eEF2 phosphorylation is responsive to bidirectional changes in miniature neurotransmission and is controlled locally in dendrites. Finally, direct spatially controlled inhibition of eEF2 phosphorylation induces local translational activation, suggesting that eEF2 is a biochemical sensor that couples miniature synaptic events to local translational suppression in neuronal dendrites. PMID:17698016

Sutton, Michael A; Taylor, Anne M; Ito, Hiroshi T; Pham, Anh; Schuman, Erin M

2007-08-16

302

Hippocampal tauopathy in tau transgenic mice coincides with impaired hippocampus-dependent learning and memory, and attenuated late-phase long-term depression of synaptic transmission.  

PubMed

We evaluated various forms of hippocampus-dependent learning and memory, and hippocampal synaptic plasticity in THY-Tau22 transgenic mice, a murine tauopathy model that expresses double-mutated 4-repeat human tau, and shows neuropathological tau hyperphosphorylation and aggregation throughout the brain. Focussing on hippocampus, immunohistochemical studies in aged THY-Tau22 mice revealed prominent hyper- and abnormal phosphorylation of tau in CA1 region, and an increase in glial fibrillary acidic protein (GFAP) in hippocampus, but without signs of neuronal loss. These mice displayed spatial, social, and contextual learning and memory defects that could not be reduced to subtle neuromotor disability. The behavioral defects coincided with changes in hippocampal synaptic functioning and plasticity as measured in paired-pulse and novel long-term depression protocols. These results indicate that hippocampal tauopathy without neuronal cell loss can impair neural and behavioral plasticity, and further show that transgenic mice, such as the THY-Tau22 strain, might be useful for preclinical research on tauopathy pathogenesis and possible treatment. PMID:21167950

Van der Jeugd, Ann; Ahmed, Tariq; Burnouf, Sylvie; Belarbi, Karim; Hamdame, Malika; Grosjean, Marie-Eve; Humez, Sandrine; Balschun, Detlef; Blum, David; Buée, Luc; D'Hooge, Rudi

2011-03-01

303

Muscle spindle afferent studies in the baboon  

PubMed Central

1. The muscle spindle afferent conduction velocity and response to muscle twitch and stretch in young baboons has been recorded in order to find a conduction velocity that can be used to separate primary and secondary afferents. 2. A number of the features of the response of the spindle afferents to stretch were examined. It was found that none could distinguish between primary and secondary afferents with greater certainty than the conduction velocity. 3. Spindle afferents with conduction velocities below 50 m/sec can be classified as secondary and those with conduction velocities above 68 m/sec can be classified as primary with a reasonable degree of certainty. 4. The spindle afferents with conduction velocities between 51 and 67 m/sec are most likely not a separate intermediate group but represent a region of overlap between the two groups. 5. Comparisons of the difference between the response of primary and secondary afferents to overstretch suggested a mechanism to explain the saturation of the primary afferent response at frequencies far below those at which it is capable of firing.

Koeze, T. H.

1973-01-01

304

Afferent Fibers with Multiple Encoding Sites.  

National Technical Information Service (NTIS)

A primary afferent fiber with the capability for initiating impulses at more than one sensory terminal belongs to one of two classes. The first, termed simulanteous reset, appears to be more common in nature, including most, if not all myelinated afferent...

J. P. Eagles R. L. Purple

1974-01-01

305

Impact of Synaptic Neurotransmitter Concentration Time Course on the Kinetics and Pharmacological Modulation of Inhibitory Synaptic Currents  

PubMed Central

The time course of synaptic currents is a crucial determinant of rapid signaling between neurons. Traditionally, the mechanisms underlying the shape of synaptic signals are classified as pre- and post-synaptic. Over the last two decades, an extensive body of evidence indicated that synaptic signals are critically shaped by the neurotransmitter time course which encompasses several phenomena including pre- and post-synaptic ones. The agonist transient depends on neurotransmitter release mechanisms, diffusion within the synaptic cleft, spill-over to the extra-synaptic space, uptake, and binding to post-synaptic receptors. Most estimates indicate that the neurotransmitter transient is very brief, lasting between one hundred up to several hundreds of microseconds, implying that post-synaptic activation is characterized by a high degree of non-equilibrium. Moreover, pharmacological studies provide evidence that the kinetics of agonist transient plays a crucial role in setting the susceptibility of synaptic currents to modulation by a variety of compounds of physiological or clinical relevance. More recently, the role of the neurotransmitter time course has been emphasized by studies carried out on brain slice models that revealed a striking, cell-dependent variability of synaptic agonist waveforms ranging from rapid pulses to slow volume transmission. In the present paper we review the advances on studies addressing the impact of synaptic neurotransmitter transient on kinetics and pharmacological modulation of synaptic currents at inhibitory synapses.

Barberis, Andrea; Petrini, Enrica Maria; Mozrzymas, Jerzy W.

2011-01-01

306

Synchronous afferent discharge from a passive muscle of the cat: significance for interpreting spike-triggered averages.  

PubMed Central

Evidence is presented for the existence of synchrony between the spike trains of muscle afferents of the passive cat medial gastrocnemius muscle held at fixed length. Synchrony between the spike trains of a population of muscle afferents was quantified by means of a synchronization index (Is), derived from spike-triggered averages of the muscle-nerve neurogram and the rectified neurogram. A previously used test based solely upon the neurogram average (Watt, Stauffer, Taylor, Reinking & Stuart, 1976) is shown to be invalid. The differences between experimentally derived Is values and theoretical Is values derived for the condition of asynchrony were compared to estimated confidence limits for those differences. This comparison revealed that twenty-two of fifty-three muscle-afferent spike trains whose rectified averages satisfied certain conditions for interpreting the Is were synchronized with the discharge of other afferents. The form of the rectified averages of another eight afferents suggested that these afferents might also have been synchronized. Synchrony in the discharge of muscle afferents was found in three experiments in which the neurogram was recorded from a single nerve branch to medial gastrocnemius, as well as in the data of experiments in which the whole muscle nerve was used. The degree of synchrony was similar for Ia, spindle group II and Ib afferents. The magnitude of the synchrony found in these experiments was judged by comparison to the results of analog simulations and the increase in Is values resulting from the application of small, quick stretches to the medial gastrocnemius muscle. The degree of synchrony found on average was approximately equivalent to that of a single spike occurring once for every four discharges of the reference spike train. Simulations were performed to determine the distortion of monosynaptic excitatory post-synaptic potentials (e.p.s.p.s) obtained by spike-triggered averaging which would be produced by synchrony between the spike trains of Ia and spindle group II afferents of the magnitude found in this study. These simulations indicate that the apparent amplitude would be increased by approximately 4 microV on average. Both the 10-90% rise time and the half-width would increase, the effects being greater for smaller e.p.s.p.s. Consequently, the synchrony found in this study is of most concern in the study of small post-synaptic potentials, such as those due to spindle group II afferents.

Hamm, T M; Reinking, R M; Roscoe, D D; Stuart, D G

1985-01-01

307

Vagal afferent fibres determine the oxytocin-induced modulation of gastric tone  

PubMed Central

Oxytocin (OXT) inputs to the dorsal vagal complex (DVC; nucleus of the tractus solitarius (NTS) dorsal motor nucleus of the vagus (DMV) and area postrema) decrease gastric tone and motility. Our first aim was to investigate the mechanism(s) of OXT-induced gastric relaxation. We demonstrated recently that vagal afferent inputs modulate NTS–DMV synapses involved in gastric and pancreatic reflexes via group II metabotropic glutamate receptors (mGluRs). Our second aim was to investigate whether group II mGluRs similarly influence the response of vagal motoneurons to OXT. Microinjection of OXT in the DVC decreased gastric tone in a dose-dependent manner. The OXT-induced gastric relaxation was enhanced following bethanechol and reduced by l-NAME administration, suggesting a nitrergic mechanism of gastroinhibition. DVC application of the group II mGluR antagonist EGLU induced a gastroinhibition that was not dose dependent and shifted the gastric effects of OXT to a cholinergic-mediated mechanism. Evoked and miniature GABAergic synaptic currents between NTS and identified gastric-projecting DMV neurones were not affected by OXT in any neurones tested, unless the brainstem slice was (a) pretreated with EGLU or (b) derived from rats that had earlier received a surgical vagal deafferentation. Conversely, OXT inhibited glutamatergic currents even in naive slices, but their responses were unaffected by EGLU pretreatment. These results suggest that the OXT-induced gastroinhibition is mediated by activation of the NANC pathway. Inhibition of brainstem group II mGluRs, however, uncovers the ability of OXT to modulate GABAergic transmission between the NTS and DMV, resulting in the engagement of an otherwise silent cholinergic vagal neurocircuit.

Holmes, Gregory M; Browning, Kirsteen N; Babic, Tanja; Fortna, Samuel R; Coleman, F Holly; Travagli, R Alberto

2013-01-01

308

Depressed GABA and glutamate synaptic signaling by 5-HT1A receptors in the nucleus tractus solitarii and their role in cardiorespiratory function.  

PubMed

Serotonin (5-HT), and its 5-HT1A receptor (5-HT1AR) subtype, is a powerful modulator of the cardiorespiratory system and its sensory reflexes. The nucleus tractus solitarii (nTS) serves as the first central station for visceral afferent integration and is critical for cardiorespiratory reflex responses. However, the physiological and synaptic role of 5-HT1ARs in the nTS is relatively unknown. In the present study, we examined the distribution and modulation of 5-HT1ARs on cardiorespiratory and synaptic parameters in the nTS. 5-HT1ARs were widely distributed to cell bodies within the nTS but not synaptic terminals. In anesthetized rats, activation of 5-HT1ARs by microinjection of the 5-HT1AR agonist 8-OH-DPAT into the caudal nTS decreased minute phrenic neural activity via a reduction in phrenic amplitude. In brain stem slices, 8-OH-DPAT decreased the amplitude of glutamatergic tractus solitarii-evoked excitatory postsynaptic currents, and reduced overall spontaneous excitatory nTS network activity. These effects persisted in the presence of GABAA receptor blockade and were antagonized by coapplication of 5-HT1AR blocker WAY-100135. 5-HT1AR blockade alone had no effect on tractus solitarii-evoked excitatory postsynaptic currents, but increased excitatory network activity. On the other hand, GABAergic nTS-evoked inhibitory postsynaptic currents did not change by activation of the 5-HT1ARs, but spontaneous inhibitory nTS network activity decreased. Blocking 5-HT1ARs tended to increase nTS-evoked inhibitory postsynaptic currents and inhibitory network activity. Taken together, 5-HT1ARs in the caudal nTS decrease breathing, likely via attenuation of afferent transmission, as well as overall nTS network activity. PMID:24671532

Ostrowski, Tim D; Ostrowski, Daniela; Hasser, Eileen M; Kline, David D

2014-06-15

309

Labeling hair cells and afferent neurons in the posterior lateral-line system of zebrafish.  

PubMed

The lateral line is a mechanosensory system that comprises a set of discrete sense organs called neuromasts, which are arranged in reproducible patterns on the surface of fish and amphibians. The posterior component of the system, the posterior lateral line, comprises the neuromasts on the body and tail. Each neuromast has a core of mechanosensory hair cells, each of which is depolarized by water motion in one direction and hyperpolarized by motion in the other direction, thereby enabling fish to extract information from the movements of water around their body. Neuromasts are innervated by a few afferent neurons (usually two, but sometimes more), which have their cell bodies clustered in cranial ganglia and project their central axons to the hindbrain, where they extend longitudinally along all rhombomeres. Hair cells are readily labeled by small cationic styryl pyridinium dyes such as DiASP. Afferent fibers are also progressively labeled with this dye, presumably by trans-synaptic uptake. Adjusting the dye concentration and incubation time can lead to the labeling of the entire afferent system, thereby providing a fast and easy method for visualizing the central projection in the hindbrain of live fish. The simplicity of the method makes it potentially useful for screens based on forward or reverse genetic approaches. Here we present protocols for labeling hair cells in live zebrafish and for labeling afferent neurons in zebrafish embryos. PMID:24298034

Schuster, Kevin; Ghysen, Alain

2013-12-01

310

Synaptic dysfunction in Parkinson's disease.  

PubMed

Activity-dependent modifications in synaptic efficacy, such as long-term depression (LTD) and long-term potentiation (LTP), represent key cellular substrates for adaptive motor control and procedural memory. The impairment of these two forms of synaptic plasticity in the nucleus striatum could account for the onset and the progression of motor and cognitive symptoms of Parkinson's disease (PD), characterized by the massive degeneration of dopaminergic neurons. In fact, both LTD and LTP are peculiarly controlled and modulated by dopaminergic transmission coming from nigrostriatal terminals. Changes in corticostriatal and nigrostriatal neuronal excitability may influence profoundly the threshold for the induction of synaptic plasticity, and changes in striatal synaptic transmission efficacy are supposed to play a role in the occurrence of PD symptoms. Understanding of these maladaptive forms of synaptic plasticity has mostly come from the analysis of experimental animal models of PD. A series of cellular and synaptic alterations occur in the striatum of experimental parkinsonism in response to the massive dopaminergic loss. In particular, dysfunctions in trafficking and subunit composition of glutamatergic NMDA receptors on striatal efferent neurons contribute to the clinical features of the experimental parkinsonism. Interestingly, it has become increasingly evident that in striatal spiny neurons, the correct assembly of NMDA receptor complex at the postsynaptic site is a major player in early phases of PD, and it is sensitive to distinct degrees of DA denervation. The molecular defects at the basis of PD progression may be not confined just at the postsynaptic neuron: accumulating evidences have recently shown that the genes linked to PD play a critical role at the presynaptic site. DA release into the synaptic cleft relies on a proper presynaptic vesicular transport; impairment of SV trafficking, modification of DA flow, and altered presynaptic plasticity have been described in several PD animal models. Furthermore, an impaired DA turnover has been described in presymptomatic PD patients. Thus, given the pathological events occurring precociously at the synapses of PD patients, post- and presynaptic sites may represent an adequate target for early therapeutic intervention. PMID:22351072

Picconi, Barbara; Piccoli, Giovanni; Calabresi, Paolo

2012-01-01

311

Differential content of vesicular glutamate transporters in subsets of vagal afferents projecting to the nucleus tractus solitarii in the rat.  

PubMed

The vagus nerve contains primary visceral afferents that convey sensory information from cardiovascular, pulmonary, and gastrointestinal tissues to the nucleus tractus solitarii (NTS). The heterogeneity of vagal afferents and their central terminals within the NTS is a common obstacle for evaluating functional groups of afferents. To determine whether different anterograde tracers can be used to identify distinct subpopulations of vagal afferents within NTS, we injected cholera toxin B subunit (CTb) and isolectin B4 (IB4) into the vagus nerve. Confocal analyses of medial NTS following injections of both CTb and IB4 into the same vagus nerve resulted in labeling of two exclusive populations of fibers. The ultrastructural patterns were also distinct. CTb was found in both myelinated and unmyelinated vagal axons and terminals in medial NTS, whereas IB4 was found only in unmyelinated afferents. Both tracers were observed in terminals with asymmetric synapses, suggesting excitatory transmission. Because glutamate is thought to be the neurotransmitter at this first primary afferent synapse in NTS, we determined whether vesicular glutamate transporters (VGLUTs) were differentially distributed among the two distinct populations of vagal afferents. Anterograde tracing from the vagus with CTb or IB4 was combined with immunohistochemistry for VGLUT1 or VGLUT2 in medial NTS and evaluated with confocal microscopy. CTb-labeled afferents contained primarily VGLUT2 (83%), whereas IB4-labeled afferents had low levels of vesicular transporters, VGLUT1 (5%) or VGLUT2 (21%). These findings suggest the possibility that glutamate release from unmyelinated vagal afferents may be regulated by a distinct, non-VGLUT, mechanism. PMID:23897509

Hermes, Sam M; Colbert, James F; Aicher, Sue A

2014-02-15

312

Synaptic dynamics: Linear model and adaptation algorithm.  

PubMed

In this research, temporal processing in brain neural circuitries is addressed by a dynamic model of synaptic connections in which the synapse model accounts for both pre- and post-synaptic processes determining its temporal dynamics and strength. Neurons, which are excited by the post-synaptic potentials of hundred of the synapses, build the computational engine capable of processing dynamic neural stimuli. Temporal dynamics in neural models with dynamic synapses will be analyzed, and learning algorithms for synaptic adaptation of neural networks with hundreds of synaptic connections are proposed. The paper starts by introducing a linear approximate model for the temporal dynamics of synaptic transmission. The proposed linear model substantially simplifies the analysis and training of spiking neural networks. Furthermore, it is capable of replicating the synaptic response of the non-linear facilitation-depression model with an accuracy better than 92.5%. In the second part of the paper, a supervised spike-in-spike-out learning rule for synaptic adaptation in dynamic synapse neural networks (DSNN) is proposed. The proposed learning rule is a biologically plausible process, and it is capable of simultaneously adjusting both pre- and post-synaptic components of individual synapses. The last section of the paper starts with presenting the rigorous analysis of the learning algorithm in a system identification task with hundreds of synaptic connections which confirms the learning algorithm's accuracy, repeatability and scalability. The DSNN is utilized to predict the spiking activity of cortical neurons and pattern recognition tasks. The DSNN model is demonstrated to be a generative model capable of producing different cortical neuron spiking patterns and CA1 Pyramidal neurons recordings. A single-layer DSNN classifier on a benchmark pattern recognition task outperforms a 2-Layer Neural Network and GMM classifiers while having fewer numbers of free parameters and decides with a shorter observation of data. DSNN performance in the benchmark pattern recognition problem shows 96.7% accuracy in classifying three classes of spiking activity. PMID:24867390

Yousefi, Ali; Dibazar, Alireza A; Berger, Theodore W

2014-08-01

313

Connexin 30 sets synaptic strength by controlling astroglial synapse invasion.  

PubMed

Astrocytes play active roles in brain physiology by dynamic interactions with neurons. Connexin 30, one of the two main astroglial gap-junction subunits, is thought to be involved in behavioral and basic cognitive processes. However, the underlying cellular and molecular mechanisms are unknown. We show here in mice that connexin 30 controls hippocampal excitatory synaptic transmission through modulation of astroglial glutamate transport, which directly alters synaptic glutamate levels. Unexpectedly, we found that connexin 30 regulated cell adhesion and migration and that connexin 30 modulation of glutamate transport, occurring independently of its channel function, was mediated by morphological changes controlling insertion of astroglial processes into synaptic clefts. By setting excitatory synaptic strength, connexin 30 plays an important role in long-term synaptic plasticity and in hippocampus-based contextual memory. Taken together, these results establish connexin 30 as a critical regulator of synaptic strength by controlling the synaptic location of astroglial processes. PMID:24584052

Pannasch, Ulrike; Freche, Dominik; Dallérac, Glenn; Ghézali, Grégory; Escartin, Carole; Ezan, Pascal; Cohen-Salmon, Martine; Benchenane, Karim; Abudara, Veronica; Dufour, Amandine; Lübke, Joachim H R; Déglon, Nicole; Knott, Graham; Holcman, David; Rouach, Nathalie

2014-04-01

314

Finite Post Synaptic Potentials Cause a Fast Neuronal Response  

PubMed Central

A generic property of the communication between neurons is the exchange of pulses at discrete time points, the action potentials. However, the prevalent theory of spiking neuronal networks of integrate-and-fire model neurons relies on two assumptions: the superposition of many afferent synaptic impulses is approximated by Gaussian white noise, equivalent to a vanishing magnitude of the synaptic impulses, and the transfer of time varying signals by neurons is assessable by linearization. Going beyond both approximations, we find that in the presence of synaptic impulses the response to transient inputs differs qualitatively from previous predictions. It is instantaneous rather than exhibiting low-pass characteristics, depends non-linearly on the amplitude of the impulse, is asymmetric for excitation and inhibition and is promoted by a characteristic level of synaptic background noise. These findings resolve contradictions between the earlier theory and experimental observations. Here we review the recent theoretical progress that enabled these insights. We explain why the membrane potential near threshold is sensitive to properties of the afferent noise and show how this shapes the neural response. A further extension of the theory to time evolution in discrete steps quantifies simulation artifacts and yields improved methods to cross check results.

Helias, Moritz; Deger, Moritz; Rotter, Stefan; Diesmann, Markus

2011-01-01

315

Entorhinal Denervation Induces Homeostatic Synaptic Scaling of Excitatory Postsynapses of Dentate Granule Cells in Mouse Organotypic Slice Cultures  

PubMed Central

Denervation-induced changes in excitatory synaptic strength were studied following entorhinal deafferentation of hippocampal granule cells in mature (?3 weeks old) mouse organotypic entorhino-hippocampal slice cultures. Whole-cell patch-clamp recordings revealed an increase in excitatory synaptic strength in response to denervation during the first week after denervation. By the end of the second week synaptic strength had returned to baseline. Because these adaptations occurred in response to the loss of excitatory afferents, they appeared to be in line with a homeostatic adjustment of excitatory synaptic strength. To test whether denervation-induced changes in synaptic strength exploit similar mechanisms as homeostatic synaptic scaling following pharmacological activity blockade, we treated denervated cultures at 2 days post lesion for 2 days with tetrodotoxin. In these cultures, the effects of denervation and activity blockade were not additive, suggesting that similar mechanisms are involved. Finally, we investigated whether entorhinal denervation, which removes afferents from the distal dendrites of granule cells while leaving the associational afferents to the proximal dendrites of granule cells intact, results in a global or a local up-scaling of granule cell synapses. By using computational modeling and local electrical stimulations in Strontium (Sr2+)-containing bath solution, we found evidence for a lamina-specific increase in excitatory synaptic strength in the denervated outer molecular layer at 3–4 days post lesion. Taken together, our data show that entorhinal denervation results in homeostatic functional changes of excitatory postsynapses of denervated dentate granule cells in vitro.

Vlachos, Andreas; Becker, Denise; Jedlicka, Peter; Winkels, Raphael; Roeper, Jochen; Deller, Thomas

2012-01-01

316

Neurotrophins as synaptic modulators  

Microsoft Academic Search

The role of neurotrophins as regulatory factors that mediate the differentiation and survival of neurons has been well described. More recent evidence indicates that neurotrophins may also act as synaptic modulators. Here, I review the evidence that synaptic activity regulates the synthesis, secretion and action of neurotrophins, which can in turn induce immediate changes in synaptic efficacy and morphology. By

Mu-ming Poo

2001-01-01

317

The fraction of activated N-methyl-d-Aspartate receptors during synaptic transmission remains constant in the presence of the glutamate release inhibitor riluzole  

PubMed Central

Excessive N-methyl-d-aspartate (NMDA) receptor activation is widely accepted to mediate calcium-dependent glutamate excitotoxicity. The uncompetitive, voltage-dependent NMDA receptor antagonist memantine has been successfully used clinically in the treatment of neurodegenerative dementia and is internationally registered for the treatment of moderate to severe Alzheimer?s disease. Glutamate release inhibitors (GRIs) may also be promising for the therapy of some neurodegenerative diseases. During the clinical use of GRIs, it could be questioned whether there would still be a sufficient number of active NMDA receptors to allow any additional effects of memantine or similar NMDA receptor antagonists. To address this question, we determined the fraction of NMDA receptors contributing to postsynaptic events in the presence of therapeutically relevant concentrations of the GRI riluzole (1 ?M) using an in vitro hippocampal slice preparation. We measured the charge transfer of pharmacologically isolated excitatory synaptic responses before and after the application of the selective, competitive NMDA receptor antagonist D-AP5 (100 ?M). The fraction of activated NMDA receptors under control conditions did not differ from those in the presence of riluzole. It is therefore likely that NMDA receptor antagonists would be able to exert additional therapeutic effects in combination therapy with GRIs.

Zieglgansberger, W.; Parsons, C. G.

2008-01-01

318

Transmission from the dominant input shapes the stereotypic ratio of photoreceptor inputs onto horizontal cells.  

PubMed

Many neurons receive synapses in stereotypic proportions from converging but functionally distinct afferents. However, developmental mechanisms regulating synaptic convergence are not well understood. Here we describe a heterotypic mechanism by which one afferent controls synaptogenesis of another afferent, but not vice versa. Like other CNS circuits, zebrafish retinal H3 horizontal cells (HC) undergo an initial period of remodelling, establishing synapses with ultraviolet and blue cones while eliminating red and green cone contacts. As development progresses, the HCs selectively synapse with ultraviolet cones to generate a 5:1 ultraviolet-to-blue cone synapse ratio. Blue cone synaptogenesis increases in mutants lacking ultraviolet cones, and when transmitter release or visual stimulation of ultraviolet cones is perturbed. Connectivity is unaltered when blue cone transmission is suppressed. Moreover, there is no cell-autonomous regulation of cone synaptogenesis by neurotransmission. Thus, biased connectivity in this circuit is established by an unusual activity-dependent, unidirectional control of synaptogenesis exerted by the dominant input. PMID:24832361

Yoshimatsu, Takeshi; Williams, Philip R; D'Orazi, Florence D; Suzuki, Sachihiro C; Fadool, James M; Allison, W Ted; Raymond, Pamela A; Wong, Rachel O

2014-01-01

319

Nicotine and Synaptic Plasticity in Prefrontal Cortex  

NSDL National Science Digital Library

Nicotinic receptor activation enhances working memory and attention. The prefrontal cortex is a key brain area involved in working memory, and plasticity of excitatory synaptic transmission within the cortex is likely an important cellular mechanism of memory. A recent study has explored the cellular and synaptic basis of nicotine’s effects on excitability within the prefrontal cortex. The findings suggest that nicotine enhances inhibitory synaptic inputs to layer V pyramidal cells, which suppresses induction of long-term potentiation (LTP). This inhibitory effect can be overcome by stimulating the pyramidal cells in bursts, which suggests a modification in the signal-to-noise ratio for synaptic input. Thus, the impact of strong stimuli on working memory would be enhanced when combined with nicotinic receptor activity. These findings may lead to novel and more effective treatments for memory disorders.

Daniel S. McGehee (University of Chicago;Department of Anesthesia and Critical Care REV)

2007-08-14

320

Synaptic Acidification Enhances GABAA Signaling  

PubMed Central

To determine the role of cellularly generated protons in synaptic signaling, we recorded GABA miniature inhibitory post-synaptic currents (mIPSCs) from cultured rat cerebellar granule cells (CGC) while varying the extracellular pH buffering capacity. Consistent with previous reports, we found that increasing pH from 7.4 to 8.0 sped mIPSC rise time, and suppressed both amplitude of the current and total charge transferred. Conversely, acidification (from pH 7.4 to 6.8) slowed the rise time and increased current amplitude and total charge transferred. In a manner consistent with alkalinization, increasing the buffering capacity from 3 to 24 mM HEPES at pH 7.4, resulted in faster mIPSC rise time, a 37% reduction in amplitude, and a 48% reduction in charge transferred. Supplementing the normal physiological buffers (24 mM HCO3?/5%CO2) with 10 mM HEPES similarly diminished mIPSCs in a manner consistent with alkalinization, resulting in faster rise time, a 39% reduction in amplitude and a 51% reduction in charge transferred. These findings suggest the existence of an acidifying synaptic force that is overcome by commonly used concentrations (10 mM) of HEPES buffer. Here we show that Na+/H+ exchanger (NHE) activity appears to, in part, contribute to this synaptic acidification as inhibition of NHE by amiloride or lithium under physiological or weak buffering conditions alters mIPSCs in a manner consistent with alkalinization. These results suggest that acidification of the synaptic cleft occurs physiologically during GABAergic transmission and that NHE plays a critical role in generating the acidic nano-environment at the synapse.

Dietrich, Craig J.

2010-01-01

321

Primary afferent depolarization of myelinated fibres in the joint and interosseous nerves of the cat.  

PubMed Central

1. Changes in the excitability of the intraspinal terminals of fibres in the posterior knee joint and interosseous nerves were used as a measure of primary afferent depolarization (PAD) which is associated with presynaptic inhibition of transmission from afferent fibres. These were estimated from changes in the intensity of electrical stimuli required to activate the fibres in 50% of trials. In order to avoid the inclusion of group I muscle afferents which contaminate the joint and interosseal nerves, the analysis was restricted to fibres conducting at less than 75 m s-1 and/or displaying patterns of PAD which differed from those of group Ia and Ib muscle afferents in lower lumbar segments of anaesthetized cats. PAD was evoked by electrical stimulation of ipsilateral hindlimb nerves. 2. PAD of fibres in the posterior knee joint nerve was induced from group I (Ia and Ib) and group II muscle afferents and cutaneous afferents but not by stimulation of the joint or the interosseous nerves. The most effective stimuli were those applied to the superficial peroneal, sural, quadriceps and posterior biceps and semitendinosus nerves. 3. PAD of fibres in the interosseous nerve was also induced by stimulation of group I (Ia and Ib) and group II muscle afferents and cutaneous afferents and, in addition, by stimulation of joint and interosseous nerves. The most effective stimuli were those applied to the superficial peroneal, quadriceps, flexor digitorum longus and posterior biceps and semitendinosus nerves. 4. Individual fibres of the joint and the interosseous nerves were depolarized by only some of the conditioning stimuli. Even the most effective stimuli did not produce PAD in all of the fibres tested. Individual fibres of the joint and the interosseous nerves were depolarized by diverse combinations of afferents of different functional types and of different peripheral nerves. The differences in the sources of PAD were not associated with the conduction velocities and hence are unlikely to be related to differences in the receptor origin of the tested fibres. The diversity in the sources of PAD of individual fibres is interpreted as providing a high degree of differentiation in the control of transmission from receptors in joints and interosseal membranes.

Jankowska, E; Riddell, J S; McCrea, D A

1993-01-01

322

Synaptic Vesicle Transporter Expression Regulates Vesicle Phenotype and Quantal Size  

Microsoft Academic Search

While the transporters that accumulate classical neurotransmit- ters in synaptic vesicles have been identified, little is known about how their expression regulates synaptic transmission. We have used adenoviral-mediated transfection to increase expres- sion of the brain vesicular monoamine transporter VMAT2 and presynaptic amperometric recordings to characterize the effects on quantal release. In presynaptic axonal varicosities of ventral midbrain neurons in

Emmanuel N. Pothos; Kristin E. Larsen; David E. Krantz; Yong-jian Liu; John W. Haycock; Wanda Setlik; Michael D. Gershon; Robert H. Edwards; David Sulzer

2000-01-01

323

Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex.  

PubMed

Classic hallucinogens such as lysergic acid diethylamide are thought to elicit their psychotropic actions via serotonin receptors of the 5-hydroxytryptamine 2A subtype (5-HT(2A)R). One likely site for these effects is the prefrontal cortex (PFC). Previous studies have shown that activation of 5-HT(2A)Rs in this region results in a robust increase in spontaneous glutamatergic synaptic activity, and these results have led to the widely held idea that hallucinogens elicit their effect by modulating synaptic transmission within the PFC. Here, we combine cellular and molecular biological approaches, including single-cell 5-HT(2A)Rs inactivation and 5-HT(2A)R rescue over a 5-HT(2A)R knockout genetic background, to distinguish between competing hypotheses accounting for these effects. The results from these experiments do not support the idea that 5-HT(2A)Rs elicit the release of an excitatory retrograde messenger nor that they activate thalamocortical afferents, the two dominant hypotheses. Rather, they suggest that 5-HT(2A)Rs facilitate intrinsic networks within the PFC. Consistent with this idea, we locate a discrete subpopulation of pyramidal cells that is strongly excited by 5-HT(2A)R activation. PMID:17535909

Béïque, Jean-Claude; Imad, Mays; Mladenovic, Ljiljana; Gingrich, Jay A; Andrade, Rodrigo

2007-06-01

324

Piezo2 expression in corneal afferent neurons.  

PubMed

Recently, a novel class of mechanically sensitive channels has been identified and have been called Piezo channels. In this study, we explored Piezo channel expression in sensory neurons supplying the guinea pig corneal epithelium, which have well-defined modalities in this species. We hypothesized that a proportion of corneal afferent neurons express Piezo2, and that these neurons are neurochemically distinct from corneal polymodal nociceptors or cold-sensing neurons. We used a combination of retrograde tracing to identify corneal afferent neurons and double label in situ hybridization and/or immunohistochemistry to determine their molecular and/or neurochemical profile. We found that Piezo2 expression occurs in ?26% of trigeminal ganglion neurons and 30% of corneal afferent neurons. Piezo2 corneal afferent neurons are almost exclusively non-calcitonin gene-related peptide (CGRP)-immunoreactive (-IR), medium- to large-sized neurons that are NF200-IR, suggesting they are not corneal polymodal nociceptors. There was no coexpression of Piezo2 and transient receptor potential cation channel subfamily M member 8 (TRPM8) transcripts in any corneal afferent neurons, further suggesting that Piezo2 is not expressed in corneal cold-sensing neurons. We also noted that TRPM8-IR or CGRP-IR corneal afferent neurons are almost entirely small and lack NF200-IR. Piezo2 expression occurs in a neurochemically distinct subpopulation of corneal afferent neurons that are not polymodal nociceptors or cold-sensing neurons, and is likely confined to a subpopulation of pure mechano-nociceptors in the cornea. This provides the first evidence in an in vivo system that Piezo2 is a strong candidate for a channel that transduces noxious mechanical stimuli. J. Comp. Neurol. 522:2967-2979, 2014. © 2014 Wiley Periodicals, Inc. PMID:24549492

Bron, Romke; Wood, Rhiannon J; Brock, James A; Ivanusic, Jason J

2014-09-01

325

Reliable synaptic connections between pairs of excitatory layer 4 neurones within a single 'barrel' of developing rat somatosensory cortex  

PubMed Central

Dual whole-cell recordings were made from pairs of synaptically coupled excitatory neurones in the ‘barrel field’ in layer (L) 4 in slices of young (postnatal day 12–15) rat somatosensory cortex. The majority of interconnected excitatory neurones were spiny stellate cells with an asymmetrical dendritic arborisation largely confined to a single barrel. The remainder were star pyramidal cells with a prominent apical dendrite terminating in L2/3 without forming a tuft. Excitatory synaptic connections were examined between 131 pairs of spiny L4 neurones. Single presynaptic action potentials evoked unitary EPSPs with a peak amplitude of 1·59 ± 1·51 mV (mean ± s.d.), a latency of 0·92 ± 0·35 ms, a rise time of 1·53 ± 0·46 ms and a decay time constant of 17·8 ± 6·3 ms. At 34–36 °C, the coefficient of variation (c.v.) of the unitary EPSP amplitude was 0·37 ± 0·16 and the percentage of failures to evoke an EPSP was 5·3 ± 7·8%. The c.v. and failure rate decreased with increasing amplitude of the unitary EPSP. Postsynaptic glutamate receptors in spiny L4 neurones were of the AMPA and NMDA type. At ?60 mV in the presence of 1 mM Mg2+, NMDA receptors contributed 39·3 ± 12·5% to the EPSP integral. In Mg2+-free solution, the NMDA receptor/AMPA receptor ratio of the EPSC was 0·86 ± 0·64. The number of putative synaptic contacts established by the projection neurone with the target neurone varied between two and five with a mean of 3·4 ± 1·0 (n = 11). Synaptic contacts were exclusively found in the barrel in which the cell pair was located and were preferentially located on secondary to quarternary dendritic branches. Their mean geometric distance from the soma was 68·8 ± 37·4 ?m (range, 33·4-168·0 ?m). The number of synaptic contacts and mean EPSP amplitude showed no significant correlation. The results suggest that in L4 of the barrel cortex synaptic transmission between spiny neurones is largely restricted to a single barrel. The connections are very reliable, probably due to a high release probability, and have a high efficacy because of the compact structure of the dendrites and axons of spiny neurones. Intrabarrel connections thus function to amplify and distribute the afferent thalamic activity in the vertical directions of a cortical column.

Feldmeyer, Dirk; Egger, Veronica; Lubke, Joachim; Sakmann, Bert

1999-01-01

326

Differences in Synaptic GABA A Receptor Number Underlie Variation in GABA Mini Amplitude  

Microsoft Academic Search

In many neurons, responses to individual quanta of transmitter exhibit large variations in amplitude. The origin of this variability, although central to our understanding of synaptic transmission and plasticity, remains controversial. To examine the relationship between quantal amplitude and postsynaptic receptor number, we adopted a novel approach, combining patch-clamp recording of synaptic currents with quantitative immunogold localization of synaptic receptors.

Zoltan Nusser; Stuart Cull-Candy; Mark Farrant

1997-01-01

327

Vestibular afferent responses to microrotational stimuli  

NASA Technical Reports Server (NTRS)

Intracellular microelectrode recording/labeling techniques were used to investigate vestibular afferent responses in the bullfrog, to very small amplitude (less than 5 deg p-p) sinusoidal rotations in the vertical plane over the frequency range of 0.063-4 Hz. Robust responses to peak accelerations as low as 0.031 deg/sec per sec were obtained from units subsequently traced to either the central portion of the anterior canal crista or the striolar region of the utricle. All of these microrotationally sensitive afferent neurons had irregular resting discharge rates, and the majority had transfer ratios (relative to rotational velocity) of 1-40 spikes/sec per deg/sec. Individual utricular afferent velocity transfer ratios were nearly constant over the frequency range of 0.125-4 Hz. Canal units displayed decreasing response transfer ratios as stimulus frequencies increased. These findings indicate that, although utricular striolar and central crista afferent velocity transfer ratios to microrotations were very similar, utricular striolar afferent neurons were more faithful sensors of very small amplitude rotational velocity in the vertical plane.

Myers, Steven F.; Lewis, Edwin R.

1991-01-01

328

Enhanced Synaptic Inhibition Disrupts the Efferent Code of Cerebellar Purkinje Neurons in Leaner Cav2.1 Ca2+ Channel Mutant Mice  

PubMed Central

Cerebellar Purkinje cells (PCs) encode afferent information in the rate and temporal structure of their spike trains. Both spontaneous firing in these neurons and its modulation by synaptic inputs depend on Ca2+ current carried by Cav2.1 (P/Q) type channels. Previous studies have described how loss-of-function Cav2.1 mutations affect intrinsic excitability and excitatory transmission in PCs. This study examines the effects of the leaner mutation on fast GABAergic transmission and its modulation of spontaneous firing in PCs. The leaner mutation enhances spontaneous synaptic inhibition of PCs, leading to transitory reductions in PC firing rate and increased spike rate variability. Enhanced inhibition is paralleled by an increase in the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) measured under voltage clamp. These differences are abolished by tetrodotoxin, implicating effects of the mutation on spike-induced GABA release. Elevated sIPSC frequency in leaner PCs is not accompanied by increased mean firing rate in molecular layer interneurons, but IPSCs evoked in PCs by direct stimulation of these neurons exhibit larger amplitude, slower decay rate, and a higher burst probability compared to wild-type PCs. Ca2+ release from internal stores appears to be required for enhanced inhibition since differences in sIPSC frequency and amplitude in leaner and wild-type PCs are abolished by thapsigargin, an ER Ca2+ pump inhibitor. These findings represent the first account of the functional consequences of a loss-of-function P/Q channel mutation on PC firing properties through altered GABAergic transmission. Gain in synaptic inhibition shown here would compromise the fidelity of information coding in these neurons and may contribute to impaired cerebellar function resulting from loss-of function mutations in the CaV2.1 channel gene.

Ovsepian, Saak V.

2013-01-01

329

Inhibition of excitatory synaptic transmission in hippocampal neurons by levetiracetam involves Zn²?-dependent GABA type A receptor-mediated presynaptic modulation.  

PubMed

Levetiracetam (LEV) is an antiepileptic drug with a unique but as yet not fully resolved mechanism of action. Therefore, by use of a simplified rat-isolated nerve-bouton preparation, we have investigated how LEV modulates glutamatergic transmission from mossy fiber terminals to hippocampal CA3 neurons. Action potential-evoked excitatory postsynaptic currents (eEPSCs) were recorded using a conventional whole-cell patch-clamp recording configuration in voltage-clamp mode. The antiepileptic drug phenytoin decreased glutamatergic eEPSCs in a concentration-dependent fashion by inhibiting voltage-dependent Na? and Ca²? channel currents. In contrast, LEV had no effect on eEPSCs or voltage-dependent Na? or Ca²? channel currents. Activation of presynaptic GABA type A (GABA(A)) receptors by muscimol induced presynaptic inhibition of eEPSCs, resulting from depolarization block. Low concentrations of Zn²?, which had no effect on eEPSCs, voltage-dependent Na? or Ca²? channel currents, or glutamate receptor-mediated whole cell currents, reduced the muscimol-induced presynaptic inhibition. LEV applied in the continuous presence of 1 µM muscimol and 1 µM Zn²? reversed this Zn²? modulation on eEPSCs. The antagonizing effect of LEV on Zn²?-induced presynaptic GABA(A) receptor inhibition was also observed with the Zn²? chelators Ca-EDTA and RhodZin-3. Our results clearly show that LEV removes the Zn²?-induced suppression of GABA(A)-mediated presynaptic inhibition, resulting in a presynaptic decrease in glutamate-mediated excitatory transmission. Our results provide a novel mechanism by which LEV may inhibit neuronal activity. PMID:24259680

Wakita, Masahito; Kotani, Naoki; Kogure, Kyuya; Akaike, Norio

2014-02-01

330

Selective activation of primary afferent fibers evaluated by sine-wave electrical stimulation.  

PubMed

Transcutaneous sine-wave stimuli at frequencies of 2000, 250 and 5 Hz (Neurometer) are thought to selectively activate Abeta, Adelta and C afferent fibers, respectively. However, there are few reports to test the selectivity of these stimuli at the cellular level. In the present study, we analyzed action potentials (APs) generated by sine-wave stimuli applied to the dorsal root in acutely isolated rat dorsal root ganglion (DRG) preparations using intracellular recordings. We also measured excitatory synaptic responses evoked by transcutaneous stimuli in substantia gelatinosa (SG) neurons of the spinal dorsal horn, which receive inputs predominantly from C and Adelta fibers, using in vivo patch-clamp recordings. In behavioral studies, escape or vocalization behavior of rats was observed with both 250 and 5 Hz stimuli at intensity of approximately 0.8 mA (T5/ T250), whereas with 2000 Hz stimulation, much higher intensity (2.14 mA, T2000) was required. In DRG neurons, APs were generated at T5/T250 by 2000 Hz stimulation in Abeta, by 250 Hz stimulation both in Abeta and Adelta, and by 5 Hz stimulation in all three classes of DRG neurons. However, the AP frequencies elicited in Abeta and Adelta by 5 Hz stimulation were much less than those reported previously in physiological condition. With in vivo experiments large amplitude of EPSCs in SG neurons were elicited by 250 and 5 Hz stimuli at T5/ T250. These results suggest that 2000 Hz stimulation excites selectively Abeta fibers and 5 Hz stimulation activates noxious transmission mediated mainly through C fibers. Although 250 Hz stimulation activates both Adelta and Abeta fibers, tactile sensation would not be perceived when painful sensation is produced at the same time. Therefore, 250 Hz was effective stimulus frequency for activation of Adelta fibers initiating noxious sensation. Thus, the transcutaneous sine-wave stimulation can be applied to evaluate functional changes of sensory transmission by comparing thresholds with the three stimulus frequencies. PMID:15813963

Koga, Kohei; Furue, Hidemasa; Rashid, Md Harunor; Takaki, Atsushi; Katafuchi, Toshihiko; Yoshimura, Megumu

2005-01-01

331

LTD, LTP, and the sliding threshold for long-term synaptic plasticity.  

PubMed

LTD of synaptic transmission is a form of long-term synaptic plasticity with the potential to be as significant as LTP to both the activity-dependent development of neural circuitry and adult memory storage. In addition, interactions between LTP and LTD and the dynamic regulation of the gain of synaptic plasticity mechanisms are also very important. In particular, the computational ability of LTD to properly counterbalance LTP may be essential to maintaining synaptic strengths in the linear range, and to maximally sharpen the ability of synapses to compute and store frequency-based information about the phase relation between synapses. Experimental data confirm the presence of an activity-dependent "sliding threshold" with the expected properties. That is, when levels of neuronal activity are high, indicating circumstances increasing the likelihood of inducing LTP, compensatory changes cause the suppression of LTP and an enhanced likelihood of LTD. Conversely, we would predict that low levels of synaptic activity would shift the threshold in favor of greater LTP and less LTD, a hypothesis which has yet to be tested. The sliding threshold for LTP and LTD also has implications for underlying cellular mechanisms of both forms of long-term synaptic plasticity. If the thresholds for LTP and LTD are tightly and reciprocally co-regulated, that could imply that at least one component of LTD is a true depotentiation caused by reversal of a change mediating LTP. If so, the intuitively simplest hypothesis is that phosphorylation of AMPA glutamate receptors causes LTP of synaptic e.p.s.p.s, while dephosphorylation of the same site or sites causes depotentiation LTD. Of course, this hypothesis would refer only to a postsynaptic component of both LTP and LTD. There has been a recent report that, in neonatal rat hippocampus, a form of LTD that is expressed developmentally earlier than LTP appears to have a postsynaptic induction site, but is expressed as decreased presynaptic transmitter release (Bolshakov and Siegelbaum, 1994). Whether these properties will be retained as LTD matures is unknown, as is the likelihood that, if a component of LTP is expressed presynaptically, depotentiation of that presynaptic component can also occur. Equally unclear is the persistence of LTD relative to LTP. The few rigorous long-term anatomical studies available suggest that the latest phases of LTP may be expressed as changes in dendritic spine shapes and/or synaptic morphology. While heterosynaptic LTD has been reported to have a duration of weeks in vivo (Abraham et al., 1994), we do not know whether LTP-induced morphological changes that take many days to appear can be reversed in an activity-dependent manner. An important feature of the consolidation of memories may turn out to be the slow development of LTP that is resistant to reversal by LTD. While we still at an earlier stage in our understanding of the mechanisms underlying LTD compared to LTP, some things are becoming clear. LTD is induced by afferent neuronal activity that is relatively ineffective in exciting the postsynaptic cell--an "anti-hebbian" condition. This property, coupled with the hebbian properties of LTP and the dynamic nature of membrane conductances, necessarily confers upon synapses the ability to compute and store the results of a covariance function. However, the role of such a computation in processing and/or memory is unclear. In addition, LTD appears to require the activation of NMDA and metabotropic subtypes of glutamate receptors, release of Ca2+ from intracellular stores, and an increase in intracellular [Ca2+] that is lower than that necessary to induce LTP. The early evidence is consistent with some overlap of targets for modification by LTP and LTD, with some forms of LTD likely to be a reversal, or "depotentiation," of previous LTP, perhaps through dephosphorylation of AMPA receptors. PMID:8878740

Stanton, P K

1996-01-01

332

MAGUKs, Synaptic Development, and Synaptic Plasticity  

PubMed Central

MAGUKs are proteins that act as key scaffolds in surface complexes containing receptors, adhesion proteins, and various signaling molecules. These complexes evolved prior to the appearance of multicellular animals and play key roles in cell-cell intercommunication. A major example of this is the neuronal synapse, which contains several presynaptic and postsynaptic MAGUKs including PSD-95, SAP102, SAP97, PSD-93, CASK, and MAGIs. Here, they play roles in both synaptic development and in later synaptic plasticity events. During development, MAGUKs help to organize the postsynaptic density via associations with other scaffolding proteins, such as Shank, and the actin cytoskeleton. They affect the clustering of glutamate receptors and other receptors, and these associations change with development. MAGUKs are involved in long-term potentiation and depression (e.g., via their phosphorylation by kinases and phosphorylation of other proteins associated with MAGUKs). Importantly, synapse development and function are dependent on the kind of MAGUK present. For example, SAP102 shows high mobility and is present in early synaptic development. Later, much of SAP102 is replaced by PSD-95, a more stable synaptic MAGUK; this is associated with changes in glutamate receptor types that are characteristic of synaptic maturation.

Zheng, Chan-Ying; Seabold, Gail K.; Horak, Martin; Petralia, Ronald S.

2011-01-01

333

Pharmacological assays reveal age-related changes in synaptic transmission at the Caenorhabditis elegans neuromuscular junction that are modified by reduced insulin signalling.  

PubMed

Frailty is a feature of neuromuscular ageing. Here we provide insight into the relative contribution of pre- and postsynaptic dysfunction to neuromuscular ageing using the nematode Caenorhabditis elegans. Assays of C. elegans motility highlight a precipitous decline during ageing. We describe a novel deployment of pharmacological assays of C. elegans neuromuscular function to resolve pre- and postsynaptic dysfunction that underpin this decreased motility during ageing. The cholinergic agonist levamisole and the cholinesterase inhibitor aldicarb elicited whole worm contraction and allowed a direct comparison of neuromuscular integrity, from 1 to 16 days old: measurements could be made from aged worms that were otherwise almost completely immobile. The rapidity and magnitude of the drug-induced contraction provides a measure of neuromuscular signalling whilst the difference between levamisole and aldicarb highlights presynaptic effects. Presynaptic neuromuscular transmission increased between 1 and 5 days old in wild-type but not in the insulin/IGF1 receptor mutant daf-2 (e1370). Intriguingly, there was no evidence of a role for insulin-dependent effects in older worms. Notably in 16-day-old worms, which were virtually devoid of spontaneous movement, the maximal contraction produced by both drugs was unchanged. Taken together the data support a maturation of presynaptic function and/or upstream elements during early ageing that is lost after genetic reduction of insulin signalling. Furthermore, this experimental approach has demonstrated a counterintuitive phenomenon: in aged worms neuromuscular strength is maintained despite the absence of motility. PMID:23038730

Mulcahy, Ben; Holden-Dye, Lindy; O'Connor, Vincent

2013-02-01

334

Generator Potential Mechanisms in Mammalian Cold-Sensitive Afferents.  

National Technical Information Service (NTIS)

Studies have been performed on the afferent fibers innervating the scrotal skin of the rat to test the hypothesis that the generator potential mechanism underlying cold thermo-sensitivity of these afferent fibers is an electrogenic sodium pump. In intact ...

F. K. Pierau P. J. Torrey D. O. Carpenter

1975-01-01

335

The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing.  

PubMed

In terms of its sub-regional differentiation, the hippocampal CA1 region receives cortical information directly via the perforant (temporoammonic) path (pp-CA1 synapse) and indirectly via the tri-synaptic pathway where the last relay station is the Schaffer collateral-CA1 synapse (Sc-CA1 synapse). Research to date on pp-CA1 synapses has been conducted predominantly in vitro and never in awake animals, but these studies hint that information processing at this synapse might be distinct to processing at the Sc-CA1 synapse. Here, we characterized synaptic properties and synaptic plasticity at the pp-CA1 synapse of freely behaving adult rats. We observed that field excitatory postsynaptic potentials at the pp-CA1 synapse have longer onset latencies and a shorter time-to-peak compared to the Sc-CA1 synapse. LTP (>24 h) was successfully evoked by tetanic afferent stimulation of pp-CA1 synapses. Low frequency stimulation evoked synaptic depression at Sc-CA1 synapses, but did not elicit LTD at pp-CA1 synapses unless the Schaffer collateral afferents to the CA1 region had been severed. Paired-pulse responses also showed significant differences. Our data suggest that synaptic plasticity at the pp-CA1 synapse is distinct from the Sc-CA1 synapse and that this may reflect its specific role in hippocampal information processing. PMID:23986697

Aksoy-Aksel, Ayla; Manahan-Vaughan, Denise

2013-01-01

336

The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing  

PubMed Central

In terms of its sub-regional differentiation, the hippocampal CA1 region receives cortical information directly via the perforant (temporoammonic) path (pp-CA1 synapse) and indirectly via the tri-synaptic pathway where the last relay station is the Schaffer collateral-CA1 synapse (Sc-CA1 synapse). Research to date on pp-CA1 synapses has been conducted predominantly in vitro and never in awake animals, but these studies hint that information processing at this synapse might be distinct to processing at the Sc-CA1 synapse. Here, we characterized synaptic properties and synaptic plasticity at the pp-CA1 synapse of freely behaving adult rats. We observed that field excitatory postsynaptic potentials at the pp-CA1 synapse have longer onset latencies and a shorter time-to-peak compared to the Sc-CA1 synapse. LTP (>24 h) was successfully evoked by tetanic afferent stimulation of pp-CA1 synapses. Low frequency stimulation evoked synaptic depression at Sc-CA1 synapses, but did not elicit LTD at pp-CA1 synapses unless the Schaffer collateral afferents to the CA1 region had been severed. Paired-pulse responses also showed significant differences. Our data suggest that synaptic plasticity at the pp-CA1 synapse is distinct from the Sc-CA1 synapse and that this may reflect its specific role in hippocampal information processing.

Aksoy-Aksel, Ayla; Manahan-Vaughan, Denise

2013-01-01

337

Altered GABAA receptor-mediated synaptic transmission disrupts the firing of gonadotropin-releasing hormone neurons in male mice under conditions that mimic steroid abuse  

PubMed Central

Gonadotropin–releasing hormone (GnRH) neurons are the central regulators of reproduction. GABAergic transmission plays a critical role in pubertal activation of pulsatile GnRH secretion. Self-administration of excessive doses of anabolic androgenic steroids (AAS) disrupts reproductive function and may have critical repercussions for pubertal onset in adolescent users. Here, we demonstrate that chronic treatment of adolescent male mice with the AAS, 17?-methyltestosterone (17?MT), significantly decreased action potential frequency in GnRH neurons, reduced the serum gonadotropin levels, and decreased testes mass. AAS treatment did not induce significant changes in GABAA receptor subunit mRNA levels or alter the amplitude or decay kinetics of GABAA receptor-mediated spontaneous postsynaptic currents (sPSC) or tonic currents in GnRH neurons. However, AAS treatment significantly increased action potential frequency in neighboring medial preoptic area (mPOA) neurons and GABAA receptor-mediated sPSC frequency in GnRH neurons. In addition, physical isolation of the more lateral aspects of the mPOA from the medially-localized GnRH neurons abrogated the AAS-induced increase in GABAA receptor-mediated sPSC frequency and the decrease in action potential firing in the GnRH cells. Our results indicate that AAS act predominantly on steroid-sensitive presynaptic neurons within the mPOA to impart significant increases in GABAA receptor-mediated inhibitory tone onto downstream GnRH neurons resulting in diminished activity of these pivotal mediators of reproductive function. These AAS-induced changes in central GABAergic circuits of the forebrain may significantly contribute to the disruptive actions of these drugs on pubertal maturation and the development of reproductive competence in male steroid abusers.

Penatti, Carlos A A; Davis, Matthew C; Porter, Donna M; Henderson, Leslie P

2010-01-01

338

Imaging synaptic plasticity  

PubMed Central

Over the past decade, the use and development of optical imaging techniques has advanced our understanding of synaptic plasticity by offering the spatial and temporal resolution necessary to examine long-term changes at individual synapses. Here, we review the use of these techniques in recent studies of synaptic plasticity and, in particular, long-term potentiation in the hippocampus.

2011-01-01

339

Transneuronal tracing of central autonomic regions involved in cardiac sympathetic afferent reflex in rats.  

PubMed

Stimulation of cardiac afferents (CA) increased sympathetic outflow and blood pressure. The goal of the current study is to determine the central autonomic nuclei involved in the regulation of cardiac sympathetic afferent reflex (CSAR) which has been proved in previously functional studies. Neuroanatomical method and pseudorabies virus (PRV) transynaptic retrograde trace technique will be performed to investigate the relationship between kidney and heart and the temporal order of the most PRV-labeled neurons in the central nervous system. Recombinant PRV expressing enhanced green fluorescence protein (EGFP) was injected into the left kidney of rats as a specific trans-synaptic retrograde tracer in neurons. After 2, 3, 4, 5, 6, 7, 8 or 9days, brain, spinal cord and heart were collected for immunofluorescence staining. The temporal order of PRV labeled neurons was found in the ipsilateral intermediolateral nucleus (IML) of T8-T12 spinal segments on day 3; bilateral rostroventrolateral medulla (RVLM), paraventricular nucleus (PVN) and nucleus of the solitary tract (NTS) on day 4; and left and right ventricular walls and ventricular septum of the heart on day 9. In rats with renal denervation, no PRV-infected neurons or cardiomyocytes were found after PRV injection. In conclusion, PRV trans-synaptic retrograde trace confirms that CA, NTS, PVN, RVLM, IML and renal nerves do exist to be involved in the regulation of CSAR and there is a close relationship between heart and kidney. CA is mainly located in the left ventricular wall, right ventricular wall and ventricular septum. PMID:24819915

Gao, Juan; Zhang, Feng; Sun, Hai-Jian; Liu, Tong-Yan; Ding, Lei; Kang, Yu-Ming; Zhu, Guo-Qing; Zhou, Ye-Bo

2014-07-15

340

Unmyelinated tactile afferents signal touch and project to insular cortex  

Microsoft Academic Search

There is dual tactile innervation of the human hairy skin: in addition to fast-conducting myelinated afferent fibers, there is a system of slow-conducting unmyelinated (C) afferents that respond to light touch. In a unique patient lacking large myelinated afferents, we found that activation of C tactile (CT) afferents produced a faint sensation of pleasant touch. Functional magnetic resonance imaging (fMRI)

Y. Lamarre; H. Backlund; C. Morin; B. G. Wallin; G. Starck; S. Ekholm; I. Strigo; K. Worsley; Å. B. Vallbo; M. C. Bushnell; H. Olausson

2002-01-01

341

High-fidelity transmission of sensory information by single cerebellar mossy fibre boutons.  

PubMed

Understanding the transmission of sensory information at individual synaptic connections requires knowledge of the properties of presynaptic terminals and their patterns of firing evoked by sensory stimuli. Such information has been difficult to obtain because of the small size and inaccessibility of nerve terminals in the central nervous system. Here we show, by making direct patch-clamp recordings in vivo from cerebellar mossy fibre boutons-the primary source of synaptic input to the cerebellar cortex-that sensory stimulation can produce bursts of spikes in single boutons at very high instantaneous firing frequencies (more than 700 Hz). We show that the mossy fibre-granule cell synapse exhibits high-fidelity transmission at these frequencies, indicating that the rapid burst of excitatory postsynaptic currents underlying the sensory-evoked response of granule cells can be driven by such a presynaptic spike burst. We also demonstrate that a single mossy fibre can trigger action potential bursts in granule cells in vitro when driven with in vivo firing patterns. These findings suggest that the relay from mossy fibre to granule cell can act in a 'detonator' fashion, such that a single presynaptic afferent may be sufficient to transmit the sensory message. This endows the cerebellar mossy fibre system with remarkable sensitivity and high fidelity in the transmission of sensory information. PMID:18097412

Rancz, Ede A; Ishikawa, Taro; Duguid, Ian; Chadderton, Paul; Mahon, Séverine; Häusser, Michael

2007-12-20

342

The somatostatin analogue octreotide inhibits capsaicin-mediated activation of nociceptive primary afferent fibres in spinal cord lamina II (substantia gelatinosa).  

PubMed

Somatostatin (SST) in spinal cord has been linked with the inhibition of nociceptive neurotransmission in several experimental paradigms. The SST2 receptor (SSTR2) is the main SST receptor subtype in the superficial dorsal horn (DH) and is activated, besides to the naïve peptide, by the SST synthetic analogue octreotide (OCT). In the present work, we have studied the central effects of SSTR2 activation on capsaicin (CAP)-induced glutamate release in mouse DH. In neurons of the lamina II of DH, CAP (2 ?M) induced a strong increase of mEPSC frequency that was significantly reduced (70%) by OCT. SSTR2 involvement was assessed by using the specific antagonist CYN 154806. No differences were observed between frequency increase in CAP alone vs. CAP in the presence of CYN 154806+OCT. The effect of OCT was further investigated by studying c-fos expression in spinal cord slices. The CAP-induced increase in density of Fos immunoreactive nuclei in the superficial DH was strongly prevented by OCT. SSTR2a (a splicing variant of SSTR2) immunoreactivity was found in both pre- and post-synaptic compartments of laminae I-II synapses. By light and electron microscopy, SSTR2a was mainly localized onto non-peptidergic isolectin B4 (IB4)-positive primary afferent fibres (PAFs). A subset of them was also found to express the CAP receptor TRPV1. These data show that the SST analogue OCT inhibits CAP-mediated activation of non-peptidergic nociceptive PAFs in lamina II. Our data indicate that SSTR2a plays an important role in the pre-synaptic modulation of central excitatory nociceptive transmission in mouse. PMID:21109472

Bencivinni, Ileana; Ferrini, Francesco; Salio, Chiara; Beltramo, Massimiliano; Merighi, Adalberto

2011-07-01

343

Afferent discharges from venous pressoreceptors in liver  

Microsoft Academic Search

Increasing the perfusion pressure of the portal vein in isolated liver preparation in the guinea pig caused an increase in afferent discharge rate. Discharge patterns were compatible with those of the slowly adapting type. Increasing the portal venous pressure by means of intravenous injection of Locke's solution into the left jugular vein in the rabbit in vivo caused an increase

AKIRA NIIJIMA

344

Patterns of saccular afferent innervation in sciaenids.  

PubMed

In this study, saccular afferent arborization patterns in Atlantic croaker Micropogonias undulatus, red drum Sciaenops ocellatus and spot Leiostomus xanthurus were characterized. Leiostomus xanthurus showed the simplest configuration while M. undulatus displayed the most complex. In addition, hair-cell densities at sites sampled along the rostro-caudal axis of the saccular epithelia correlated with the observed patterns of arborization. PMID:23991887

Selckmann, G M; Ramcharitar, J

2013-09-01

345

5,6-EET Is Released upon Neuronal Activity and Induces Mechanical Pain Hypersensitivity via TRPA1 on Central Afferent Terminals  

PubMed Central

Epoxyeicosatrienoic acids (EETs) are cytochrome P450-epoxygenase-derived metabolites of arachidonic acid that act as endogenous signaling molecules in multiple biological systems. Here we have investigated the specific contribution of 5,6-EET to transient receptor potential (TRP) channel activation in nociceptor neurons and its consequence for nociceptive processing. We found that, during capsaicin-induced nociception, 5,6-EET levels increased in dorsal root ganglia (DRGs) and the dorsal spinal cord, and 5,6-EET is released from activated sensory neurons in vitro. 5,6-EET potently induced a calcium flux (100 nm) in cultured DRG neurons that was completely abolished when TRPA1 was deleted or inhibited. In spinal cord slices, 5,6-EET dose dependently enhanced the frequency, but not the amplitude, of spontaneous EPSCs (sEPSCs) in lamina II neurons that also responded to mustard oil (allyl isothiocyanate), indicating a presynaptic action. Furthermore, 5,6-EET-induced enhancement of sEPSC frequency was abolished in TRPA1-null mice, suggesting that 5,6-EET presynaptically facilitated spinal cord synaptic transmission by TRPA1. Finally, in vivo intrathecal injection of 5,6-EET caused mechanical allodynia in wild-type but not TRPA1-null mice. We conclude that 5,6-EET is synthesized on the acute activation of nociceptors and can produce mechanical hypersensitivity via TRPA1 at central afferent terminals in the spinal cord.

Sisignano, Marco; Park, Chul-Kyu; Angioni, Carlo; Zhang, Dong Dong; von Hehn, Christian; Cobos, Enrique J.; Ghasemlou, Nader; Xu, Zhen-Zhong; Kumaran, Vigneswara; Lu, Ruirui; Grant, Andrew; Fischer, Michael J. M.; Schmidtko, Achim; Reeh, Peter; Ji, Ru-Rong; Woolf, Clifford J.; Geisslinger, Gerd; Scholich, Klaus; Brenneis, Christian

2012-01-01

346

Coupling of energy metabolism and synaptic transmission at the transcriptional level: role of nuclear respiratory factor 1 in regulating both cytochrome c oxidase and NMDA glutamate receptor subunit genes.  

PubMed

Neuronal activity and energy metabolism are tightly coupled processes. Regions high in neuronal activity, especially of the glutamatergic type, have high levels of cytochrome c oxidase (COX). Perturbations in neuronal activity affect the expressions of COX and glutamatergic NMDA receptor subunit 1 (NR1). The present study sought to test our hypothesis that the coupling extends to the transcriptional level, whereby NR1 and possibly other NR subunits and COX are coregulated by the same transcription factor, nuclear respiratory factor 1 (NRF-1), which regulates all COX subunit genes. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation, promoter mutations, and real-time quantitative PCR, NRF-1 was found to functionally bind to the promoters of Grin 1 (NR1), Grin 2b (NR2b) and COX subunit genes, but not of Grin2a and Grin3a genes. These transcripts were upregulated by KCl and downregulated by tetrodotoxin (TTX) in cultured primary neurons. However, silencing of NRF-1 with small interference RNA blocked the upregulation of Grin1, Grin2b, and COX induced by KCl, and overexpression of NRF-1 rescued these transcripts that were suppressed by TTX. NRF-1 binding sites on Grin1 and Grin2b genes are also highly conserved among mice, rats, and humans. Thus, NRF-1 is an essential transcription factor critical in the coregulation of NR1, NR2b, and COX, and coupling exists at the transcriptional level to ensure coordinated expressions of proteins important for synaptic transmission and energy metabolism. PMID:19144849

Dhar, Shilpa S; Wong-Riley, Margaret T T

2009-01-14

347

Caudal ventrolateral medulla mediates baroreceptor afferent inputs to subfornical organ angiotensin II responsive neurons.  

PubMed

Although anatomical data indicates that the caudal ventrolateral medulla (CVLM) projects directly to the subfornical organ (SFO), little is known about the afferent information relayed through the CVLM to SFO. Experiments were done in the anesthetized rat to investigate whether CVLM neurons mediate baroreceptor afferent information to SFO and whether this afferent information alters the response of SFO neurons to systemic injections of angiotensin II (ANG II). Extracellular single unit recordings were made from 78 spontaneously discharging single units in SFO. Of these, 32 (41%) responded to microinjection of L-glutamate (L-Glu; 0.25M; 10nl) into CVLM (27/32 were inhibited and 5/32 were excited). All 32 units also were excited by systemic injections of ANG II (250ng/0.1ml, ia). However, only those units inhibited by CVLM (n=27) were found to be inhibited by the reflex activation of baroreceptors following systemic injections of phenylephrine (2?g/kg, iv). Activation of CVLM or arterial baroreceptors in conjunction with ANG II resulted in an attenuation of the SFO unit's response to ANG II. Finally, microinjections (100nl) of the synaptic blocker CoCl(2) or the non-specific glutamate receptor antagonist kynurenic acid into CVLM attenuated (10/13 units tested) the SFO neuron's response to activation of baroreceptors, but not the unit's response evoked by systemic ANG II. Taken together, these data suggest that baroreceptor afferent information relayed through CVLM functions to modulate of the activity of neurons within SFO to extracellular signals of body fluid balance. PMID:23142269

Ciriello, John

2013-01-23

348

Presynaptic CaV2.1 calcium channels carrying familial hemiplegic migraine mutation R192Q allow faster recovery from synaptic depression in mouse calyx of Held  

PubMed Central

CaV2.1 Ca2+ channels have a dominant and specific role in initiating fast synaptic transmission at central excitatory synapses, through a close association between release sites and calcium sensors. Familial hemiplegic migraine type 1 (FHM-1) is an autosomal-dominant subtype of migraine with aura, caused by missense mutations in the CACNA1A gene that encodes the ?1A pore-forming subunit of CaV2.1 channel. We used knock-in (KI) transgenic mice harboring the FHM-1 mutation R192Q to study the consequences of this mutation in neurotransmission at the giant synapse of the auditory system formed by the presynaptic calyx of Held terminal and the postsynaptic neurons of the medial nucleus of the trapezoid body (MNTB). Although synaptic transmission seems unaffected by low-frequency stimulation in physiological Ca2+ concentration, we observed that with low Ca2+ concentrations (<1 mM) excitatory postsynaptic currents (EPSCs) showed increased amplitudes in R192Q KI mice compared with wild type (WT), meaning significant differences in the nonlinear calcium dependence of nerve-evoked transmitter release. In addition, when EPSCs were evoked by broadened presynaptic action potentials (achieved by inhibition of K+ channels) via Cav2.1-triggered exocytosis, R192Q KI mice exhibited further enhancement of EPSC amplitude and charge compared with WT mice. Repetitive stimulation of afferent axons to the MNTB at different frequencies caused short-term depression of EPSCs that recovered significantly faster in R192Q KI mice than in WT mice. Faster recovery in R192Q KI mice was prevented by the calcium chelator EGTA-AM, pointing to enlarged residual calcium as a key factor in accelerating the replenishment of synaptic vesicles.

Inchauspe, Carlota Gonzalez; Urbano, Francisco J.; Di Guilmi, Mariano N.; Ferrari, Michel D.; van den Maagdenberg, Arn M. J. M.; Forsythe, Ian D.

2012-01-01

349

Synapse geometry and receptor dynamics modulate synaptic strength.  

PubMed

Synaptic transmission relies on several processes, such as the location of a released vesicle, the number and type of receptors, trafficking between the postsynaptic density (PSD) and extrasynaptic compartment, as well as the synapse organization. To study the impact of these parameters on excitatory synaptic transmission, we present a computational model for the fast AMPA-receptor mediated synaptic current. We show that in addition to the vesicular release probability, due to variations in their release locations and the AMPAR distribution, the postsynaptic current amplitude has a large variance, making a synapse an intrinsic unreliable device. We use our model to examine our experimental data recorded from CA1 mice hippocampal slices to study the differences between mEPSC and evoked EPSC variance. The synaptic current but not the coefficient of variation is maximal when the active zone where vesicles are released is apposed to the PSD. Moreover, we find that for certain type of synapses, receptor trafficking can affect the magnitude of synaptic depression. Finally, we demonstrate that perisynaptic microdomains located outside the PSD impacts synaptic transmission by regulating the number of desensitized receptors and their trafficking to the PSD. We conclude that geometrical modifications, reorganization of the PSD or perisynaptic microdomains modulate synaptic strength, as the mechanisms underlying long-term plasticity. PMID:21984900

Freche, Dominik; Pannasch, Ulrike; Rouach, Nathalie; Holcman, David

2011-01-01

350

Synapse Geometry and Receptor Dynamics Modulate Synaptic Strength  

PubMed Central

Synaptic transmission relies on several processes, such as the location of a released vesicle, the number and type of receptors, trafficking between the postsynaptic density (PSD) and extrasynaptic compartment, as well as the synapse organization. To study the impact of these parameters on excitatory synaptic transmission, we present a computational model for the fast AMPA-receptor mediated synaptic current. We show that in addition to the vesicular release probability, due to variations in their release locations and the AMPAR distribution, the postsynaptic current amplitude has a large variance, making a synapse an intrinsic unreliable device. We use our model to examine our experimental data recorded from CA1 mice hippocampal slices to study the differences between mEPSC and evoked EPSC variance. The synaptic current but not the coefficient of variation is maximal when the active zone where vesicles are released is apposed to the PSD. Moreover, we find that for certain type of synapses, receptor trafficking can affect the magnitude of synaptic depression. Finally, we demonstrate that perisynaptic microdomains located outside the PSD impacts synaptic transmission by regulating the number of desensitized receptors and their trafficking to the PSD. We conclude that geometrical modifications, reorganization of the PSD or perisynaptic microdomains modulate synaptic strength, as the mechanisms underlying long-term plasticity.

Freche, Dominik; Pannasch, Ulrike; Rouach, Nathalie; Holcman, David

2011-01-01

351

The synaptic function of LRRK2.  

PubMed

Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most frequent genetic lesions so far found in familial as well as sporadic forms of PD (Parkinson's disease), a neurodegenerative disease characterized by the dysfunction and degeneration of dopaminergic and other neuronal types. The molecular and cellular mechanisms underlying LRRK2 action remain poorly defined. Synaptic dysfunction has been increasingly recognized as an early event in the pathogenesis of major neurological disorders. Using Drosophila as a model system, we have shown that LRRK2 controls synaptic morphogenesis. Loss of dLRRK (Drosophila LRRK2) results in synaptic overgrowth at the Drosophila neuromuscular junction synapse, whereas overexpression of wild-type dLRRK, hLRRK2 (human LRRK2) or the pathogenic hLRRK2-G2019S mutant has the opposite effect. Alteration of LRRK2 activity also affects synaptic transmission in a complex manner. LRRK2 exerts its effects on synaptic morphology by interacting with distinct downstream effectors at the pre- and post-synaptic compartments. At the postsynapse, LRRK2 functionally interacts with 4E-BP (eukaryotic initiation factor 4E-binding protein) and the microRNA machinery, both of which negatively regulate protein synthesis. At the presynapse, LRRK2 phosphorylates and negatively regulates the microtubule-binding protein Futsch and functionally interacts with the mitochondrial transport machinery. These results implicate compartment-specific synaptic dysfunction caused by altered protein synthesis, cytoskeletal dynamics and mitochondrial transport in LRRK2 pathogenesis and offer a new paradigm for understanding and ultimately treating LRRK2-related PD. PMID:22988863

Lee, Seongsoo; Imai, Yuzuru; Gehrke, Stephan; Liu, Song; Lu, Bingwei

2012-10-01

352

Ceramidase Regulates Synaptic Vesicle Exocytosis and Trafficking  

PubMed Central

A screen for Drosophila synaptic dysfunction mutants identified slug-a-bed (slab). The slab gene encodes ceramidase, a central enzyme in sphingolipid metabolism and regulation. Sphingolipids are major constituents of lipid rafts, membrane domains with roles in vesicle trafficking, and signaling pathways. Null slab mutants arrest as fully developed embryos with severely reduced movement. The SLAB protein is widely expressed in different tissues but enriched in neurons at all stages of development. Targeted neuronal expression of slab rescues mutant lethality, demonstrating the essential neuronal function of the protein. C5-ceramide applied to living preparations is rapidly accumulated at neuromuscular junction (NMJ) synapses dependent on the SLAB expression level, indicating that synaptic sphingolipid trafficking and distribution is regulated by SLAB function. Evoked synaptic currents at slab mutant NMJs are reduced by 50–70%, whereas postsynaptic glutamate-gated currents are normal, demonstrating a specific presynaptic impairment. Hypertonic saline-evoked synaptic vesicle fusion is similarly impaired by 50–70%, demonstrating a loss of readily releasable vesicles. In addition, FM1-43 dye uptake is reduced in slab mutant presynaptic terminals, indicating a smaller cycling vesicle pool. Ultrastructural analyses of mutants reveal a normal vesicle distribution clustered and docked at active zones, but fewer vesicles in reserve regions, and a twofold to threefold increased incidence of vesicles linked together and tethered at the plasma membrane. These results indicate that SLAB ceramidase function controls presynaptic terminal sphingolipid composition to regulate vesicle fusion and trafficking, and thus the strength and reliability of synaptic transmission.

Rohrbough, Jeffrey; Rushton, Emma; Palanker, Laura; Woodruff, Elvin; Matthies, Heinrich J. G.; Acharya, Usha; Acharya, Jairaj K.; Broadie, Kendal

2009-01-01

353

Neurotransmitters and synaptic components in the Merkel cell-neurite complex, a gentle touch receptor  

PubMed Central

Merkel cells are an enigmatic group of rare cells found in the skin of vertebrates. Most make contacts with somatosensory afferents to form Merkel cell-neurite complexes, which are gentle-touch receptors that initiate slowly adapting type I responses. The function of Merkel cells within the complex remains debated despite decades of research. Numerous anatomical studies demonstrate that Merkel cells form synaptic-like contacts with sensory afferent terminals. Moreover, recent molecular analysis reveals that Merkel cells express dozens of presynaptic molecules that are essential for synaptic vesicle release in neurons. Merkel cells also produce a host of neuro-active substances that can act as fast excitatory neurotransmitters or neuromodulators. Here, we review the major neurotransmitters found in Merkel cells and discuss these findings in relation to the potential function of Merkel cells in touch reception.

Maksimovic, Srdjan; Baba, Yoshichika; Lumpkin, Ellen A.

2013-01-01

354

Calcium-Fluxing Glutamate Receptors Associated With Primary Gustatory Afferent Terminals In Goldfish (Carassius auratus)  

PubMed Central

Presynaptic ionotropic glutamate receptors modulate transmission at primary afferent synapses in several glutamatergic systems. In order to test whether primary gustatory afferent fibers express Ca++ permeable AMPA/kainate receptors, we utilized kainate-stimulated uptake of Co++ along with immunocytochemistry for the Ca++-binding proteins (CaBPs), calbindin and calretinin to investigate the primary gustatory afferents in goldfish (Carassius auratus). In goldfish, the primary gustatory nucleus (equivalent to the gustatory portion of the nucleus of the solitary tract) includes the vagal lobe, which is a large, laminated structure protruding dorsally from the medulla. Kainate-stimulated uptake of Co++ (a measure of Ca++-fluxing glutamate receptors) shows punctate staining distributed in the distinct laminar pattern matching the layers of termination of the primary gustatory afferent fibers. In addition, CaBP immunocytochemistry, which correlates highly with expression of Ca++ permeable AMPA/kainate receptors, shows a laminar pattern of distribution similar to that found with kainite-stimulated cobalt uptake. Nearly all neurons of the vagal gustatory ganglion show Co++ uptake and are immunopositive for CaBPs. Transection of the vagus nerve proximal to the ganglion results in loss of such punctate Co++ uptake and of punctate CaBP staining as soon as 4 days post-lesion. These results are consonant with the presence of Ca++ fluxing glutamate receptors on the presynaptic terminals of primary gustatory terminals, providing an avenue for modulation of primary gustatory input.

Huesa, Gema; Ikenaga, Takanori; Bottger, Barbel; Finger, Thomas E.

2008-01-01

355

Ginger and Its Pungent Constituents Non-Competitively Inhibit Serotonin Currents on Visceral Afferent Neurons  

PubMed Central

Nausea and emesis are a major side effect and obstacle for chemotherapy in cancer patients. Employ of antiemetic drugs help to suppress chemotherapy-induced emesis in some patients but not all patients. Ginger, an herbal medicine, has been traditionally used to treat various kinds of diseases including gastrointestinal symptoms. Ginger is effective in alleviating nausea and emesis, particularly, for cytotoxic chemotherapy drug-induced emesis. Ginger-mediated antiemetic effect has been attributed to its pungent constituents-mediated inhibition of serotonin (5-HT) receptor activity but its cellular mechanism of action is still unclear. Emetogenic chemotherapy drugs increase 5-HT concentration and activate visceral vagal afferent nerve activity. Thus, 5-HT mediated vagal afferent activation is essential to provoke emesis during chemotherapy. In this experiment, water extract of ginger and its three major pungent constituent's effect on 5-HT-evoked responses were tested on acutely dispersed visceral afferent neurons with patch-clamp methods. The ginger extract has similar effects to antiemetic drug ondansetron by blocking 5-HT-evoked responses. Pungent constituents of the ginger, [6]-shogaol, [6]-gingerol, and zingerone inhibited 5-HT responses in a dose dependent manner. The order of inhibitory potency for these compounds were [6]-shogaol>[6]-gingerol>zingerone. Unlike well-known competitive 5-HT3 receptor antagonist ondansetron, all tested ginger constituents acted as non-competitive antagonist. Our results imply that ginger and its pungent constituents exert antiemetic effects by blocking 5-HT-induced emetic signal transmission in vagal afferent neurons.

Jin, Zhenhua; Lee, Goeun; Kim, Sojin; Park, Cheung-Seog; Park, Yong Seek

2014-01-01

356

Distinct target cell-dependent forms of short-term plasticity of the central visceral afferent synapses of the rat  

Microsoft Academic Search

BACKGROUND: The visceral afferents from various cervico-abdominal sensory receptors project to the dorsal vagal complex (DVC), which is composed of the nucleus of the solitary tract (NTS), the area postrema and the dorsal motor nucleus of the vagus nerve (DMX), via the vagus and glossopharyngeal nerves and then the solitary tract (TS) in the brainstem. While the excitatory transmission at

Kiyofumi Yamamoto; Jun Noguchi; Chiaki Yamada; Ayako M Watabe; Fusao Kato

2010-01-01

357

Neuroinflammation and synaptic loss.  

PubMed

Neuroinflammation plays a critical role in the progression of many neurodegenerative, neuropsychiatric and viral diseases. In neuroinflammation, activated microglia and astrocytes release cytokines and chemokines as well as nitric oxide, which in turn activate many signal transduction pathways. The cytokines, interleukin-1 beta and tumor necrosis factor alpha, regulate transcription of a number of genes within the brain, which can lead to the formation of pro-inflammatory products of the arachidonic acid cascade. Formation of pro-inflammatory agents and associated cytotoxic products during neuroinflammation can be detrimental to neurons by altering synaptic proteins. Neuroinflammation as well as excitotoxic insults reduce synaptic markers such as synaptophysin and drebrin. Neurodegenerative, neuropsychiatric illnesses and viral infections are accompanied by loss of both pre- and post-synaptic proteins. These synaptic changes may contribute to the progressive cognitive decline and behavioral changes associated with these illnesses. PMID:22311128

Rao, Jagadeesh S; Kellom, Matthew; Kim, Hyung-Wook; Rapoport, Stanley I; Reese, Edmund A

2012-05-01

358

Simulation studies of vestibular macular afferent-discharge patterns using a new, quasi-3-D finite volume method  

NASA Technical Reports Server (NTRS)

A quasi-three-dimensional finite-volume numerical simulator was developed to study passive voltage spread in vestibular macular afferents. The method, borrowed from computational fluid dynamics, discretizes events transpiring in small volumes over time. The afferent simulated had three calyces with processes. The number of processes and synapses, and direction and timing of synapse activation, were varied. Simultaneous synapse activation resulted in shortest latency, while directional activation (proximal to distal and distal to proximal) yielded most regular discharges. Color-coded visualizations showed that the simulator discretized events and demonstrated that discharge produced a distal spread of voltage from the spike initiator into the ending. The simulations indicate that directional input, morphology, and timing of synapse activation can affect discharge properties, as must also distal spread of voltage from the spike initiator. The finite volume method has generality and can be applied to more complex neurons to explore discrete synaptic effects in four dimensions.

Ross, M. D.; Linton, S. W.; Parnas, B. R.

2000-01-01

359

Cyclooxygenase-2 in Synaptic Signaling  

PubMed Central

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme converting arachidonic acid to prostaglandins and a key player in neuroinflammation, has been implicated in the pathogenesis of neurodegenerative diseases such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases, and in traumatic brain injury- and ischemia-induced neuronal damage, and epileptogenesis. Accumulated information suggests that the contribution of COX-2 to neuropathology is associated with its involvement in synaptic modification. Inhibition or elevation of COX-2 has been shown to suppress or enhance excitatory glutamatergic neurotransmission and long-term potentiation (LTP). These events are mainly mediated via PGE2, the predominant reaction product of COX-2, and the PGE2 subtype 2 receptor (EP2)-protein kinase A pathway. Recent evidence shows that endogenous cannabinoids are substrates for COX-2 and can be oxygenated by COX-2 to form new classes of prostaglandins (prostaglandin