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Sample records for state-dependent presynaptic inhibition

  1. In search of lost presynaptic inhibition.

    PubMed

    Rudomin, Pablo

    2009-06-01

    This chapter presents an historical review on the development of some of the main findings on presynaptic inhibition. Particular attention is given to recent studies pertaining the differential GABAa control of the synaptic effectiveness of muscle, cutaneous and articular afferents, to some of the problems arising with the identification of the interneurons mediating the GABAergic depolarization of primary afferents (PAD) of muscle afferents, on the influence of the spontaneous activity of discrete sets of dorsal horn neurons on the pathways mediating PAD of muscle and cutaneous afferents, and to the unmasking of the cutaneous-evoked responses in the lumbosacral spinal cord and associated changes in tonic PAD that follow acute and chronic section of cutaneous nerves. The concluding remarks are addressed to several issues that need to be considered to have a better understanding of the functional role of presynaptic inhibition and PAD on motor performance and sensory processing and on their possible contribution to the shaping of a higher coherence between the cortically programmed and the executed movements.

  2. Presynaptic inhibition in the vertebrate spinal cord revisited.

    PubMed

    Rudomin, P; Schmidt, R F

    1999-11-01

    The present review examines the experimental evidence supporting the existence of central mechanisms able to modulate the synaptic effectiveness of sensory fibers ending in the spinal cord of vertebrates. The first section covers work on the mode of operation and the synaptic mechanisms of presynaptic inhibition, in particular of the presynaptic control involving axo-axonic synapses made by GABAergic interneurons with the terminal arborizations of the afferent fibers. This includes reviewing of the ionic mechanisms involved in the generation of primary afferent depolarization (PAD) by GABAergic synapses, the ultrastructural basis underlying the generation of PAD, the relationship between PAD and presynaptic inhibition, the conduction of action potentials in the terminal arborizations of the afferent fibers, and the modeling of the presynaptic inhibitory synapse. The second section of the review deals with the functional organization of presynaptic inhibition. This includes the segmental and descending presynaptic control of the synaptic effectiveness of group-I and group-II muscle afferents, the evidence dealing with the local character of PAD as well as the differential inhibition of PAD in selected collaterals of individual muscle-spindle afferents by cutaneous and descending inputs. This section also examines observations on the presynaptic modulation of large cutaneous afferents, including the modulation of the synaptic effectiveness of thin myelinated and unmyelinated cutaneous fibers and of visceral afferents, as well as the presynaptic control of the synaptic actions of interneurons and descending tract neurons. The third section deals with the changes in PAD occurring during sleep and fictive locomotion in higher vertebrates and with the changes of presynaptic inhibition in humans during the execution of a variety of voluntary movements. In the final section, we examine the non-synaptic presynaptic modulation of transmitter release, including the

  3. Optogenetic Visualization of Presynaptic Tonic Inhibition of Cerebellar Parallel Fibers

    PubMed Central

    Berglund, Ken; Wen, Lei; Dunbar, Robert L.; Feng, Guoping

    2016-01-01

    Tonic inhibition was imaged in cerebellar granule cells of transgenic mice expressing the optogenetic chloride indicator, Clomeleon. Blockade of GABAA receptors substantially reduced chloride concentration in granule cells due to block of tonic inhibition. This indicates that tonic inhibition is a significant contributor to the resting chloride concentration of these cells. Tonic inhibition was observed not only in granule cell bodies, but also in their axons, the parallel fibers (PFs). This presynaptic tonic inhibition could be observed in slices both at room and physiological temperatures, as well as in vivo, and has many of the same properties as tonic inhibition measured in granule cell bodies. GABA application revealed that PFs possess at least two types of GABAA receptor: one high-affinity receptor that is activated by ambient GABA and causes a chloride influx that mediates tonic inhibition, and a second with a low affinity for GABA that causes a chloride efflux that excites PFs. Presynaptic tonic inhibition regulates glutamate release from PFs because GABAA receptor blockade enhanced both the frequency of spontaneous EPSCs and the amplitude of evoked EPSCs at the PF-Purkinje cell synapse. We conclude that tonic inhibition of PFs could play an important role in regulating information flow though cerebellar synaptic circuits. Such cross talk between phasic and tonic signaling could be a general mechanism for fine tuning of synaptic circuits. SIGNIFICANCE STATEMENT This paper demonstrates that an unconventional form of signaling, known as tonic inhibition, is found in presynaptic terminals and affects conventional synaptic communication. Our results establish the basic characteristics and mechanisms of presynaptic tonic inhibition and show that it occurs in vivo as well as in isolated brain tissue. PMID:27225762

  4. GABAB receptor-mediated presynaptic inhibition in guinea-pig hippocampus is caused by reduction of presynaptic Ca2+ influx.

    PubMed Central

    Wu, L G; Saggau, P

    1995-01-01

    1. The hypothesis that activation of GABAB receptors inhibits evoked synaptic transmission by reducing the presynaptic Ca2+ influx was tested using a recently developed technique for simultaneously recording the presynaptic Ca2+ transient ([Ca2+]t) and the field excitatory postsynaptic potential (fEPSP) evoked by a single electrical stimulus at CA3 to CA1 synapses of guinea-pig hippocampus. 2. The GABAB receptor agonist baclofen reversibly blocked, in a dose-dependant manner, both the fEPSP and the presynaptic [Ca2+]t with similar time courses. During application of baclofen, the fEPSP was proportional to about the fourth power of the presynaptic [Ca2+]t, and the presynaptic fibre volley and the resting Ca2+ level did not change. These results are similar to those we previously observed following application of several voltage-dependent Ca2+ channel blockers, suggesting that baclofen inhibits the fEPSP by blocking the presynaptic Ca2+ influx. 3. The inhibition by baclofen of both the fEPSP and the presynaptic [Ca2+]t was blocked by the GABAB receptor antagonist CGP 35348, consistent with the causal relationship between the GABAB receptor-mediated presynaptic inhibition of the [Ca2+]t and the fEPSP. 4. The inhibition by baclofen of the [Ca2+]t was partially occluded by application of the voltage-dependent Ca2+ channel blocker omega-conotoxin-GVIA (omega-CgTX-GVIA), but not omega-agatoxin-IVA (omega-AgaTX-IVA), suggesting that baclofen reduces the presynaptic [Ca2+]t by blocking Ca2+ channels including the omega-CgTX-GVIA-sensitive type. 5. We conclude that baclofen inhibits evoked transmitter release by reducing presynaptic Ca2+ influx.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7562607

  5. Static otolithic drive alters presynaptic inhibition in soleus motor pool.

    PubMed

    Fox, Apollonia; Koceja, David

    2017-02-01

    The vestibular system has both direct and indirect connections to the soleus motor pool via the vestibulospinal and reticulospinal tracts. The exact nature of how this vestibular information is integrated within the spinal cord is largely unknown. The purpose of this study was to identify whether changes in static otolithic drive altered the amount of presynaptic inhibition in the soleus H-reflex pathway. Changes in static otolithic drive were investigated in sixteen healthy participants using a tilt table. Two presynaptic pathways (common peroneal and femoral) to the soleus H-reflex were tested in three weight conditions (supine, non-weight bearing, and weight bearing). The dependent variable was the peak-to-peak amplitude of the soleus H-reflex. Inhibition to the soleus motor pool through the common peroneal nerve pathway differed significantly during weight conditions and tilt. During tilt and non-weight bearing there was greater inhibition of the soleus H-reflex compared to supine, however, this effect was reversed during tilt and weight bearing. Facilitation from the femoral nerve pathway was reduced by tilt compared to supine, but this reduction was unaffected by weight condition. This supports a role of the vestibular system as providing complex, task-dependent presynaptic input to motoneurons in the lower limbs.

  6. Relationships between presynaptic inhibition and static postural sway in subjects with and without diabetic neuropathy.

    PubMed

    Chun, Jihyun; Hong, Junggi

    2015-09-01

    [Purpose] Diabetic peripheral neuropathy can often lead to balance impairment. The spinal reflex is a mechanism that is reportedly important for balance, but it has not been investigated in diabetic peripheral neuropathy patients. Moreover, inhibitory or facilitatory behavior of the spinal reflex-known as presynaptic inhibition-is essential for controlling postural sway. The purpose of this study was to compare the differences in as presynaptic inhibition and balance in subjects with and without diabetic peripheral neuropathy to determine the influence of presynaptic inhibition on balance in diabetic peripheral neuropathy patients. [Subjects and Methods] Presynaptic inhibition and postural sway were tested in eight patients (mean age, 58±6 years) and eight normal subjects (mean age, 59±7 years). The mean percent difference in conditioned reflex amplitude relative to the unconditioned reflex amplitude was assessed to calculate as presynaptic inhibition. The single-leg balance index was measured using a computerized balance-measuring device. [Results] The diabetic peripheral neuropathy group showed lower presynaptic inhibition (47±30% vs. 75±22%) and decreased balance (0.65±0.24 vs. 0.38±0.06) as compared with the normal group. No significant correlation was found between as presynaptic inhibition and balance score (R=0.37). [Conclusion] Although the decreased as presynaptic inhibition observed in diabetic peripheral neuropathy patients may suggest central nervous system involvement, further research is necessary to explore the role of presynaptic inhibition in decreased balance in diabetic peripheral neuropathy patients.

  7. Presynaptic inhibition of synaptic transmission in the rat hippocampus by activation of muscarinic receptors: involvement of presynaptic calcium influx

    PubMed Central

    Qian, Jing; Saggau, Peter

    1997-01-01

    Modulation of presynaptic voltage-dependent calcium channels (VDCCs) by muscarinic receptors at the CA3–CA1 synapse of rat hippocampal slices was investigated by using the calcium indicator fura-2. Stimulation-evoked presynaptic calcium transients ([Capre]t) and field excitatory postsynaptic potentials (fe.p.s.ps) were simultaneously recorded. The relationship between presynaptic calcium influx and synaptic transmission was studied. Activation of muscarinic receptors inhibited [Capre]t, thereby reducing synaptic transmission. Carbachol (CCh, 10 μM) inhibited [Capre]t by 35% and reduced fe.p.s.p. by 85%. The inhibition was completely antagonized by 1 μM atropine. An approximate 4th power relationship was found between presynaptic calcium influx and postsynaptic responses. Application of the N-type VDCC-blocking peptide toxin ω-conotoxin GVIA (ω-CTx GVIA, 1 μM) inhibited [Capre]t and fe.p.s.ps by 21% and 49%, respectively, while the P/Q-type VDCC blocker ω-agatoxin IVA (ω-Aga IVA, 1 μM) reduced [Capre]t and fe.p.s.ps by 35% and 85%, respectively. Muscarinic receptor activation differentially inhibited distinct presynaptic VDCCs. ω-CTx GVIA-sensitive calcium channels were inhibited by muscarinic receptors, while ω-Aga IVA-sensitive channels were not. The percentage inhibition of ω-CTx GVIA-sensitive [Capre]t was about 63%. Muscarinic receptors inhibited presynaptic VDCCs in a way similar to adenosine (Ad) receptors. The percentage inhibition of ω-CTx GVIA-sensitive [Capre]t by Ad (100 μM) was about 59%. There was no significant inhibition of ω-Aga IVA-sensitive channels by Ad. The inhibitions of [Capre]t by CCh and Ad were mutually occlusive. These results indicate that inhibition of synaptic transmission by muscarinic receptors is mainly the consequence of a reduction of the [Capre]t due to inhibition of presynaptic VDCCs. PMID:9351508

  8. Presynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction

    PubMed Central

    Chen, Jeremy Tsung-chieh; Guo, Da; Campanelli, Dario; Frattini, Flavia; Mayer, Florian; Zhou, Luming; Kuner, Rohini; Heppenstall, Paul A.; Knipper, Marlies; Hu, Jing

    2014-01-01

    The gate control theory proposes the importance of both pre- and post-synaptic inhibition in processing pain signal in the spinal cord. However, although postsynaptic disinhibition caused by brain-derived neurotrophic factor (BDNF) has been proved as a crucial mechanism underlying neuropathic pain, the function of presynaptic inhibition in acute and neuropathic pain remains elusive. Here we show that a transient shift in the reversal potential (EGABA) together with a decline in the conductance of presynaptic GABAA receptor result in a reduction of presynaptic inhibition after nerve injury. BDNF mimics, whereas blockade of BDNF signalling reverses, the alteration in GABAA receptor function and the neuropathic pain syndrome. Finally, genetic disruption of presynaptic inhibition leads to spontaneous development of behavioural hypersensitivity, which cannot be further sensitized by nerve lesions or BDNF. Our results reveal a novel effect of BDNF on presynaptic GABAergic inhibition after nerve injury and may represent new strategy for treating neuropathic pain. PMID:25354791

  9. Contrasting effects of presynaptic alpha2-adrenergic autoinhibition and pharmacologic augmentation of presynaptic inhibition on sympathetic heart rate control.

    PubMed

    Miyamoto, Tadayoshi; Kawada, Toru; Yanagiya, Yusuke; Akiyama, Tsuyoshi; Kamiya, Atsunori; Mizuno, Masaki; Takaki, Hiroshi; Sunagawa, Kenji; Sugimachi, Masaru

    2008-11-01

    Presynaptic alpha2-adrenergic receptors are known to exert feedback inhibition on norepinephrine release from the sympathetic nerve terminals. To elucidate the dynamic characteristics of the inhibition, we stimulated the right cardiac sympathetic nerve according to a binary white noise signal while measuring heart rate (HR) in anesthetized rabbits (n = 6). We estimated the transfer function from cardiac sympathetic nerve stimulation to HR and the corresponding step response of HR, with and without the blockade of presynaptic inhibition by yohimbine (1 mg/kg followed by 0.1 mg.kg(-1).h(-1) iv). We also examined the effect of the alpha2-adrenergic receptor agonist clonidine (0.3 and 1.5 mg.kg(-1).h(-1) iv) in different rabbits (n = 5). Yohimbine increased the maximum step response (from 7.2 +/- 0.8 to 12.2 +/- 1.7 beats/min, means +/- SE, P < 0.05) without significantly affecting the initial slope (0.93 +/- 0.23 vs. 0.94 +/- 0.22 beats.min(-1).s(-1)). Higher dose but not lower dose clonidine significantly decreased the maximum step response (from 6.3 +/- 0.8 to 6.8 +/- 1.0 and 2.8 +/- 0.5 beats/min, P < 0.05) and also reduced the initial slope (from 0.56 +/- 0.07 to 0.51 +/- 0.04 and 0.22 +/- 0.06 beats.min(-1).s(-1), P < 0.05). Our findings indicate that presynaptic alpha2-adrenergic autoinhibition limits the maximum response without significantly compromising the rapidity of effector response. In contrast, pharmacologic augmentation of the presynaptic inhibition not only attenuates the maximum response but also results in a sluggish effector response.

  10. Reliability of presynaptic inhibition in patients with diabetic peripheral neuropathy.

    PubMed

    Palmer, Shannon J; Hong, Junggi

    2012-09-01

    There has been rising interest in evaluating spinal reflex activity within the clinical population, however no study has yet investigated the reliability of presynaptic inhibition (PI) on patients with diabetic peripheral neuropathy (DPN). Because neuropathy is closely related to central nervous system modification, it is important to understand the mechanism of spinal reflex activity in the DPN population. Therefore, the purpose of the study was to evaluate the reliability of PI in patients with DPN. Eight participants (58.24 ± 6.38 yrs.) diagnosed with either type I or type II diabetes and peripheral neuropathy were recruited for the study. Each subject's H-reflex was measured using an EMG to elicit and record a series of 10 paired reflex depression trials. Reliability was measured by calculating Intra Class Correlation Coefficients (ICCs) with a 95% confidence interval. The results showed excellent reliability in both intraday (0.94) and interday (0.88) reliability. Therefore, analyzing PI in the central nervous system allows for an accurate evaluation of spinal cord circuitry in a non-invasive manner.

  11. Kainate receptor-mediated presynaptic inhibition at the mouse hippocampal mossy fibre synapse

    PubMed Central

    Kamiya, Haruyuki; Ozawa, Seiji

    2000-01-01

    The presynaptic action of kainate (KA) receptor activation at the mossy fibre-CA3 synapse was examined using fluorescence measurement of presynaptic Ca2+ influx as well as electrophysiological recordings in mouse hippocampal slices. Bath application of a low concentration (0·2 μM) of KA reversibly increased the amplitude of presynaptic volley evoked by stimulation of mossy fibres to 146 ± 6 % of control (n = 6), whereas it reduced the field excitatory postsynaptic potential (EPSPs) to 30 ± 4 %. The potentiating effect of KA on the presynaptic volleys was also observed in Ca2+-free solution, and was partly antagonized by (2S,4R)-4-methylglutamic acid (SYM 2081, 1 μM), which selectively desensitizes KA receptors. The antidromic population spike of dentate granule cells evoked by stimulation of mossy fibres was increased by application of 0·2 μM KA to 160 ± 10 % of control (n = 6). Whole-cell current-clamp recordings revealed that the stimulus threshold for generating antidromic spikes recorded from a single granule cell was lowered by KA application. Application of KA (0·2 μM) suppressed presynaptic Ca2+ influx to 78 ± 4 % of control (n = 6), whereas the amplitude of the presynaptic volley was increased. KA at 0·2 μM reversibly suppressed excitatory postsynaptic currents (EPSCs) evoked by mossy fibre simulation to 38 ± 9 % of control (n = 5). These results suggest that KA receptor activation enhances the excitability of mossy fibres, probably via axonal depolarization, and reduces action potential-induced Ca2+ influx, thereby inhibiting mossy fibre EPSCs presynaptically. This novel presynaptic inhibitory action of KA at the mossy fibre-CA3 synapse may regulate the excitability of highly interconnected CA3 networks. PMID:10718745

  12. Early postnatal development of GABAergic presynaptic inhibition of Ia proprioceptive afferent connections in mouse spinal cord.

    PubMed

    Sonner, Patrick M; Ladle, David R

    2013-04-01

    Sensory feedback is critical for normal locomotion and adaptation to external perturbations during movement. Feedback provided by group Ia afferents influences motor output both directly through monosynaptic connections and indirectly through spinal interneuronal circuits. For example, the circuit responsible for reciprocal inhibition, which acts to prevent co-contraction of antagonist flexor and extensor muscles, is driven by Ia afferent feedback. Additionally, circuits mediating presynaptic inhibition can limit Ia afferent synaptic transmission onto central neuronal targets in a task-specific manner. These circuits can also be activated by stimulation of proprioceptive afferents. Rodent locomotion rapidly matures during postnatal development; therefore, we assayed the functional status of reciprocal and presynaptic inhibitory circuits of mice at birth and compared responses with observations made after 1 wk of postnatal development. Using extracellular physiological techniques from isolated and hemisected spinal cord preparations, we demonstrate that Ia afferent-evoked reciprocal inhibition is as effective at blocking antagonist motor neuron activation at birth as at 1 wk postnatally. In contrast, at birth conditioning stimulation of muscle nerve afferents failed to evoke presynaptic inhibition sufficient to block functional transmission at synapses between Ia afferents and motor neurons, even though dorsal root potentials could be evoked by stimulating the neighboring dorsal root. Presynaptic inhibition at this synapse was readily observed, however, at the end of the first postnatal week. These results indicate Ia afferent feedback from the periphery to central spinal circuits is only weakly gated at birth, which may provide enhanced sensitivity to peripheral feedback during early postnatal experiences.

  13. Paired Associative Stimulation Induces Change in Presynaptic Inhibition of Ia Terminals in Wrist Flexors in Humans

    PubMed Central

    Russmann, Heike; Shamim, Ejaz A.; Meunier, Sabine; Hallett, Mark

    2010-01-01

    Enhancements in the strength of corticospinal projections to muscles are induced in conscious humans by paired associative stimulation (PAS) to the motor cortex. Although most of the previous studies support the hypothesis that the increase of the amplitude of motor evoked potentials (MEPs) by PAS involves long-term potentiation (LTP)-like mechanism in cortical synapses, changes in spinal excitability after PAS have been reported, suggestive of parallel modifications in both cortical and spinal excitability. In a first series of experiments (experiment 1), we confirmed that both flexor carpi radialis (FCR) MEPs and FCR H reflex recruitment curves are enhanced by PAS. To elucidate the mechanism responsible for this change in the H reflex amplitude, we tested, using the same subjects, the hypothesis that enhanced H reflexes are caused by a down-regulation of the efficacy of mechanisms controlling Ia afferent discharge, including presynaptic Ia inhibition and postactivation depression. To address this question, amounts of both presynaptic Ia inhibition of FCR Ia terminals (D1and D2 inhibitions methods; experiment 2) and postactivation depression (experiment 3) were determined before and after PAS. Results showed that PAS induces a significant decrease of presynaptic Ia inhibition of FCR terminals, which was concomitant with the facilitation of the H reflex. Postactivation depression was unaffected by PAS. It is argued that enhancement of segmental excitation by PAS relies on a selective effect of PAS on the interneurons controlling presynaptic inhibition of Ia terminals. PMID:20538768

  14. Muscarinic presynaptic inhibition of neostriatal glutamatergic afferents is mediated by Q-type Ca2+ channels.

    PubMed

    Barral, J; Galarraga, E; Bargas, J

    1999-07-01

    Cholinergic presynaptic inhibition was investigated on neostriatal glutamatergic transmission. Paired pulse facilitation (PPF) of orthodromic population spikes (PS) were used to construct a concentration-response relationship for muscarine on presynaptic inhibition. Muscarine had an effect proportional to its extracellular concentration with an EC50 (mean +/- standard estimation error) of: 2.5 +/- 1.5 nM, and a maximal effect (saturation) of 245 +/- 16%. Several peptidic toxins against some voltage-gated Ca2+-channels increased PPF indicating that the Ca2+-channels they block participate in transmitter release. However, neither 1 microM omega-conotoxin GVIA, a specific blocker of N-type Ca2+-channels, nor 10-30 nM omega-agatoxinTK, a selective blocker of P-type Ca2+-channels, were able to occlude muscarine's effect on presynaptic inhibition. Nevertheless, 100-400 nM omega-agatoxinTK occluded muscarine's action on PPF in a dose-dependent manner. These results are consistent with Q-type Ca2+-channels mediating muscarinic presynaptic inhibition of neostriatal afferents.

  15. Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice

    PubMed Central

    Borgkvist, Anders; Avegno, Elizabeth M.; Wong, Minerva Y.; Kheirbek, Mazen A.; Sonders, Mark S.; Hen, Rene; Sulzer, David

    2015-01-01

    SUMMARY Degeneration of dopamine (DA) neurons in Parkinson’s disease (PD) causes hypokinesia, but DA replacement therapy can elicit exaggerated voluntary and involuntary behaviors that have been attributed to enhanced DA receptor sensitivity in striatal projection neurons. Here we reveal that in hemiparkinsonian mice, striatal D1 receptor-expressing medium spiny neurons (MSNs) directly projecting to the substantia nigra reticulata (SNr) lose tonic presynaptic inhibition by GABAB receptors. The absence of presynaptic GABAB response potentiates evoked GABA release from MSN efferents to the SNr and drives motor sensitization. This alternative mechanism of sensitization suggests a synaptic target for PD pharmacotherapy. PMID:26335644

  16. Acetylcholine-Induced Inhibition of Presynaptic Calcium Signals and Transmitter Release in the Frog Neuromuscular Junction

    PubMed Central

    Khaziev, Eduard; Samigullin, Dmitry; Zhilyakov, Nikita; Fatikhov, Nijaz; Bukharaeva, Ellya; Verkhratsky, Alexei; Nikolsky, Evgeny

    2016-01-01

    Acetylcholine (ACh), released from axonal terminals of motor neurons in neuromuscular junctions regulates the efficacy of neurotransmission through activation of presynaptic nicotinic and muscarinic autoreceptors. Receptor-mediated presynaptic regulation could reflect either direct action on exocytotic machinery or modulation of Ca2+ entry and resulting intra-terminal Ca2+ dynamics. We have measured free intra-terminal cytosolic Ca2+ ([Ca2+]i) using Oregon-Green 488 microfluorimetry, in parallel with voltage-clamp recordings of spontaneous (mEPC) and evoked (EPC) postsynaptic currents in post-junctional skeletal muscle fiber. Activation of presynaptic muscarinic and nicotinic receptors with exogenous acetylcholine and its non-hydrolized analog carbachol reduced amplitude of the intra-terminal [Ca2+]i transients and decreased quantal content (calculated by dividing the area under EPC curve by the area under mEPC curve). Pharmacological analysis revealed the role of muscarinic receptors of M2 subtype as well as d-tubocurarine-sensitive nicotinic receptor in presynaptic modulation of [Ca2+]i transients. Modulation of synaptic transmission efficacy by ACh receptors was completely eliminated by pharmacological inhibition of N-type Ca2+ channels. We conclude that ACh receptor-mediated reduction of Ca2+ entry into the nerve terminal through N-type Ca2+ channels represents one of possible mechanism of presynaptic modulation in frog neuromuscular junction. PMID:28018246

  17. Release-dependent feedback inhibition by a presynaptically localized ligand-gated anion channel

    PubMed Central

    Takayanagi-Kiya, Seika; Zhou, Keming; Jin, Yishi

    2016-01-01

    Presynaptic ligand-gated ion channels (LGICs) have long been proposed to affect neurotransmitter release and to tune the neural circuit activity. However, the understanding of their in vivo physiological action remains limited, partly due to the complexity in channel types and scarcity of genetic models. Here we report that C. elegans LGC-46, a member of the Cys-loop acetylcholine (ACh)-gated chloride (ACC) channel family, localizes to presynaptic terminals of cholinergic motor neurons and regulates synaptic vesicle (SV) release kinetics upon evoked release of acetylcholine. Loss of lgc-46 prolongs evoked release, without altering spontaneous activity. Conversely, a gain-of-function mutation of lgc-46 shortens evoked release to reduce synaptic transmission. This inhibition of presynaptic release requires the anion selectivity of LGC-46, and can ameliorate cholinergic over-excitation in a C. elegans model of excitation-inhibition imbalance. These data demonstrate a novel mechanism of presynaptic negative feedback in which an anion-selective LGIC acts as an auto-receptor to inhibit SV release. DOI: http://dx.doi.org/10.7554/eLife.21734.001 PMID:27782882

  18. The effect of the ankle joint angle in the level of soleus Ia afferent presynaptic inhibition.

    PubMed

    Patikas, D A; Kotzamanidis, C; Robertson, C T; Koceja, D M

    2004-12-01

    The factors that are responsible for the relationship between motoneuron excitability and muscle length may have both mechanical and/or neurophysiologic origins. The aim of the study was to investigate the changes in the level of presynaptic inhibition, as measured with a soleus H-reflex conditioning protocol, and muscle length. Ten healthy volunteers were measured at three different ankle angles: 30 degrees plantar flexion, neutral position (0 degrees) and 15 degrees dorsiflexion. At each position the soleus H-reflex and the maximum M-wave were measured while the limb was relaxed. The H-reflex was conditioned by a stimulation of the common peroneal nerve, 100 ms prior to the tibial nerve stimulation. The results revealed that the level of presynaptic inhibition was higher at the neutral position in comparison to the dorsiflexed or plantarflexed positions. Additionally, the HMAX/MMAX ratio was significantly decreased when the joint position was set at dorsiflexion. Further, there was a significant correlation, independent of ankle joint angle, between presynaptic inhibition levels and the HMAX/MMAX ratio. The above findings support the concept that peripheral feedback from passive, static modifications in the joint angle and consequently in muscle length, can modify the input/output threshold of the motoneurons on a presynaptic level.

  19. GCP II (NAALADase) Inhibition Suppresses Mossy Fiber-CA3 Synaptic Neurotransmission by a Presynaptic Mechanism

    PubMed Central

    Garrido Sanabria, Emilio R.; Wozniak, Krystyna M.; Slusher, Barbara S.; Keller, Asaf

    2009-01-01

    We tested the hypothesis that endogenous N-acetylaspartylglutamate (NAAG) presynaptically inhibits glutamate release at mossy fiber-CA3 synapses. For this purpose, we made use of 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), an inhibitor of glutamate carboxypeptidase II [GCP II; also known as N-acetylated alpha-linked acidic dipeptidase (NAALADase)], the enzyme that hydrolyzes NAAG into N-acetylaspartate and glutamate. Application of 2-MPPA (1–20 μM) had no effect on intrinsic membrane properties of CA3 pyramidal neurons recorded in vitro in whole cell current- or voltage-clamp mode. Bath application of 10 μM 2-MPPA suppressed evoked excitatory postsynaptic current (EPSC) amplitudes. Attenuation of EPSC amplitudes was accompanied by a significant increase in paired-pulse facilitation (50-ms interpulse intervals), suggesting that a presynaptic mechanism is involved. The group II metabotropic glutamate receptor (mGluR) antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-y l) propanoic acid (LY341495) prevented the 2-MPPA-dependent suppression of EPSC amplitudes. 2-MPPA reduced the frequencies of TTX-insensitive miniature EPSCs (mEPSC), without affecting their amplitudes, further supporting a presynaptic action for GCP II inhibition. 2-MPPA-induced reduction of mEPSC frequencies was prevented by LY341495, reinforcing the role of presynaptic group II mGluR. Because GCP II inhibition is thought to increase NAAG levels, these results suggest that NAAG suppresses synaptic transmission at mossy fiber-CA3 synapses through presynaptic activation of group II mGluRs. PMID:12917384

  20. Gender differences in the effects of presynaptic and postsynaptic dopamine agonists on latent inhibition in rats.

    PubMed

    Wang, Ying-Chou; He, Bo-Han; Chen, Chih-Chung; Huang, Andrew Chih Wei; Yeh, Yu-Chi

    2012-04-04

    The present study investigated gender differences in the effects of presynaptic and postsynaptic DA agonists on latent inhibition in the passive avoidance paradigm. During the preexposure phase, 32 male and 32 female Wistar rats were exposed to a passive avoidance box (or a different context) and received drug injections in three trials: the control group received an injection of 10% ascorbic acid in a different context. The experimental groups received injections of 10% ascorbic acid (latent inhibition [LI] group), 1mg/kg of the postsynaptic DA D(1)/D(2) agonist apomorphine (APO group), and 1.5mg/kg of the presynaptic DA agonist methamphetamine (METH group) in a passive avoidance box. All experimental groups were placed in the light compartment of the passive avoidance box and were allowed to enter into the dark compartment to receive a footshock (1mA, 2s) in five trials over 5 days. The latency to enter into the dark compartment was recorded in these five trials. The latent inhibition occurred in the female LI group but not in the male LI group. Regardless of gender, the APO group exhibited an increase in latent inhibition. Male rats in the METH group exhibited a decrease in latent inhibition, but female rats in the METH group exhibited an increase in latent inhibition, indicating that the METH group exhibited sexual dimorphism. The gender factor interacted only with the METH group and not the LI or APO group. The present paper discusses whether gender, the postsynaptic DA D(1)/D(2) agonist APO, and presynaptic DA agonist METH may be related to schizophrenia.

  1. Presynaptic inhibition of muscle spindle and tendon organ afferents in the mammalian spinal cord.

    PubMed

    Rudomin, P

    1990-12-01

    More than 30 years ago, Frank and Fuortes proposed that the synaptic effectiveness of muscle spindle afferents associated with spinal motoneurones could be diminished by the activation of nerves from flexor muscles. Since that time, research has focused on disclosing the mode of operation and the spinal pathways involved in this presynaptic inhibitory control. Initially, it was assumed that the same last-order interneurones mediated presynaptic inhibition of both muscle spindle and tendon organ afferent fibres. More recent evidence indicates that the synaptic effectiveness of these two groups of afferents is controlled by separate sets of GABAergic interneurones synapsing directly with the intraspinal terminals of the afferent fibres. This unique arrangement allows for selective control of the information on muscle length or muscle tension, despite the convergence of muscle spindle and tendon organ afferents on second-order interneurones.

  2. Presynaptic inhibition and antidromic spikes in primary afferents of the crayfish: a computational and experimental analysis.

    PubMed

    Cattaert, D; Libersat, F; El Manira A, A

    2001-02-01

    Primary afferent depolarizations (PADs) are associated with presynaptic inhibition and antidromic discharges in both vertebrates and invertebrates. In the present study, we have elaborated a realistic compartment model of a primary afferent from the coxobasipodite chordotonal organ of the crayfish based on anatomical and electrophysiological data. The model was used to test the validity of shunting and sodium channel inactivation hypotheses to account for presynaptic inhibition. Previous studies had demonstrated that GABA activates chloride channels located on the main branch close to the first branching point. We therefore focused the analysis on the effect of GABA synapses on the propagation of action potentials in the first axonal branch. Given the large diameters of the sensory axons in the region in which PADs were likely to be produced and recorded, the model indicates that a relatively large increase in chloride conductance (up to 300 nS) is needed to significantly reduce the amplitude of sensory spikes. The role of the spatial organization of GABA synapses in the sensory arborization was analyzed, demonstrating that the most effective location for GABA synapses is in the area of transition from active to passive conduction. This transition is likely to occur on the main branch a few hundred micrometers distal to the first branching point. As a result of this spatial organization, antidromic spikes generated by large-amplitude PADs are prevented from propagating distally.

  3. Persistence of PAD and presynaptic inhibition of muscle spindle afferents after peripheral nerve crush.

    PubMed

    Enríquez-Denton, M; Manjarrez, E; Rudomin, P

    2004-11-19

    Two to twelve weeks after crushing a muscle nerve, still before the damaged afferents reinnervate the muscle receptors, conditioning stimulation of group I fibers from flexor muscles depolarizes the damaged afferents [M. Enriquez, I. Jimenez, P. Rudomin, Changes in PAD patterns of group I muscle afferents after a peripheral nerve crush. Exp. Brain Res., 107 (1996), 405-420]. It is not known, however, if this primary afferent depolarization (PAD) is indeed related to presynaptic inhibition. We now show in the cat that 2-12 weeks after crushing the medial gastrocnemius nerve (MG), conditioning stimulation of group I fibers from flexors increases the excitability of the intraspinal terminals of both the intact lateral gastrocnemius plus soleus (LGS) and of the previously damaged MG fibers ending in the motor pool, because of PAD. The PAD is associated with the depression of the pre- and postsynaptic components of the extracellular field potentials (EFPs) evoked in the motor pool by stimulation of either the intact LGS or of the previously damaged MG nerves. These observations indicate, in contrast to what has been reported for crushed cutaneous afferents [K.W. Horch, J.W. Lisney, Changes in primary afferent depolarization of sensory neurones during peripheral nerve regeneration in the cat, J. Physiol., 313 (1981), 287-299], that shortly after damaging their peripheral axons, the synaptic efficacy of group I spindle afferents remains under central control. Presynaptic inhibitory mechanisms could be utilized to adjust the central actions of muscle afferents not fully recovered from peripheral lesions.

  4. Endocannabinoids gate state-dependent plasticity of synaptic inhibition in feeding circuits.

    PubMed

    Crosby, Karen M; Inoue, Wataru; Pittman, Quentin J; Bains, Jaideep S

    2011-08-11

    Changes in food availability alter the output of hypothalamic nuclei that underlie energy homeostasis. Here, we asked whether food deprivation impacts the ability of GABA synapses in the dorsomedial hypothalamus (DMH), an important integrator of satiety signals, to undergo activity-dependent changes. GABA synapses in DMH slices from satiated rats exhibit endocannabinoid-mediated long-term depression (LTD(GABA)) in response to high-frequency stimulation of afferents. When CB1Rs are blocked, however, the same stimulation elicits long-term potentiation (LTP(GABA)), which manifests presynaptically and requires heterosynaptic recruitment of NMDARs and nitric oxide (NO). Interestingly, NO signaling is required for eCB-mediated LTD(GABA). Twenty-four hour food deprivation results in a CORT-mediated loss of CB1R signaling and, consequently, GABA synapses only exhibit LTP(GABA). These observations indicate that CB1R signaling promotes LTD(GABA) and gates LTP(GABA). Furthermore, the satiety state of an animal, through regulation of eCB signaling, determines the polarity of activity-dependent plasticity at GABA synapses in the DMH.

  5. Depletion of glucose causes presynaptic inhibition of neuronal transmission in the rat dorsolateral septal nucleus.

    PubMed

    Akasu, T; Tsurusaki, M; Shoji, S

    1996-10-01

    The role of glucose in synaptic transmission was examined in the rat dorsolateral septal nucleus (DLSN) with single-microelectrode voltage-clamp and slice-patch technique. Removal of glucose from the oxygenated Krebs solution caused an outward current associated with an increased membrane conductance. The current-voltage relationship (I-V curve) showed that the hypoglycemia-induced outward current was reversed in polarity at the equilibrium potential for K+. Exposure of DLSN neurons to the glucose-free solution for 5-20 min depressed the excitatory postsynaptic current (EPSC), the inhibitory postsynaptic current (IPSC), and the late hyperpolarizing current (LHC). Replacement of glucose with 2-deoxy-D-glucose (2DG), an antimetabolic substrate, mimicked the deprivation of glucose. Mannoheptulose (10 mM) and dinitrophenol, inhibitors of glucose metabolism, also depressed the PSCs, even in the presence of 10 mM glucose. Glucose-free perfusion did not significantly depress the glutamate-induced inward current, indicating that the inhibition of the EPSC by the glucose-free perfusion was presynaptic. gamma-Aminobutyric acid (GABA)-induced outward currents were depressed by the glucose-free solution. Intracellular dialysis of DLSN neurons with a patch-pipette solution containing 5 mM ATP attenuated the hypoglycemia-induced outward current. Glucose-free superfusion consistently inhibited the IPSC and the LHC without changing the GABA-induced outward current in ATP-treated DLSN neurons. It is suggested that glucose metabolism directly regulates the release of both excitatory amino acids and GABA from the presynaptic nerve terminals.

  6. 5-HT2 presynaptic receptors mediate inhibition of glutamate release from cerebellar mossy fibre terminals.

    PubMed

    Maura, G; Carbone, R; Guido, M; Pestarino, M; Raiteri, M

    1991-09-17

    'Giant' synaptosomes originating from mossy fibre terminals and having sedimentation properties different from those of standard synaptosomes were obtained from rat cerebellum. Exposure of superfused giant synaptosomes to 15 mM KCl caused the release of endogenous glutamate in a largely (about 80%) calcium-dependent manner. The K(+)-evoked overflow of glutamate was inhibited in a concentration-dependent manner by 5-hydroxytryptamine (5-HT) and by the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), but not by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The effects of 5-HT and DOI were quite potent, already reaching significant inhibition (about 25%) at 10 nM. The 5-HT2 receptor antagonist ketanserin counteracted the inhibitory effect of 5-HT. In cerebellar slices, ketanserin increased on its own the calcium-dependent K(+)-evoked release of glutamate and this effect was not prevented by tetrodotoxin (TTX). The results support the idea that cerebellar mossy fibres use glutamate as a transmitter and show that the release of glutamate can be inhibited via presynaptic heteroreceptors of the 5-HT2 type probably localized on the mossy fibre terminals.

  7. Inhibition of GABA release by presynaptic ionotropic GABA receptors in hippocampal CA3.

    PubMed

    Axmacher, Nikolai; Draguhn, Andreas

    2004-02-09

    Vesicular transmitter release can be regulated by transmitter-gated ion channels at presynaptic axon terminals. The central inhibitory transmitter GABA acts on such presynaptic ionotropic receptors in various cells, including inhibitory interneurons. Here we report that GABA-mediated postsynaptic inhibitory currents in CA3 pyramidal cells of rat hippocampal slices are suppressed by agonists of GABAA receptors. The effect is present for both stimulus-induced and miniature IPSCs, indicating a reduction in the probability of vesicular release by presynaptic, action-potential-independent mechanisms. We conclude that the release of GABA from hippocampal CA3 interneurons is regulated by a negative feedback via presynaptic ionotropic GABA autoreceptors.

  8. Melanocortin 4 receptor activation inhibits presynaptic N-type calcium channels in amygdaloid complex neurons.

    PubMed

    Agosti, Francina; López Soto, Eduardo J; Cabral, Agustina; Castrogiovanni, Daniel; Schioth, Helgi B; Perelló, Mario; Raingo, Jesica

    2014-09-01

    The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor involved in food intake and energy expenditure regulation. MC4R activation modifies neuronal activity but the molecular mechanisms by which this regulation occurs remain unclear. Here, we tested the hypothesis that MC4R activation regulates the activity of voltage-gated calcium channels and, as a consequence, synaptic activity. We also tested whether the proposed effect occurs in the amygdala, a brain area known to mediate the anorexigenic actions of MC4R signaling. Using the patch-clamp technique, we found that the activation of MC4R with its agonist melanotan II specifically inhibited 34.5 ± 1.5% of N-type calcium currents in transiently transfected HEK293 cells. This inhibition was concentration-dependent, voltage-independent and occluded by the Gαs pathway inhibitor cholera toxin. Moreover, we found that melanotan II specifically inhibited 25.9 ± 2.0% of native N-type calcium currents and 55.4 ± 14.4% of evoked inhibitory postsynaptic currents in mouse cultured amygdala neurons. In vivo, we found that the MC4R agonist RO27-3225 increased the marker of cellular activity c-Fos in several components of the amygdala, whereas the N-type channel blocker ω conotoxin GVIA increased c-Fos expression exclusively in the central subdivision of the amygdala. Thus, MC4R specifically inhibited the presynaptic N-type channel subtype, and this inhibition may be important for the effects of melanocortin in the central subdivision of the amygdala.

  9. Pre-synaptic GABA receptors inhibit glutamate release through GIRK channels in rat cerebral cortex.

    PubMed

    Ladera, Carolina; del Carmen Godino, María; José Cabañero, María; Torres, Magdalena; Watanabe, Masahiko; Luján, Rafael; Sánchez-Prieto, José

    2008-12-01

    Neuronal G protein-gated inwardly rectifying potassium (GIRK) channels mediate the slow inhibitory effects of many neurotransmitters post-synaptically. However, no evidence exists that supports that GIRK channels play any role in the inhibition of glutamate release by GABA(B) receptors. In this study, we show for the first time that GABA(B) receptors operate through two mechanisms in nerve terminals from the cerebral cortex. As shown previously, GABA(B) receptors reduces glutamate release and the Ca(2+) influx mediated by N-type Ca(2+) channels in a mode insensitive to the GIRK channel blocker tertiapin-Q and consistent with direct inhibition of this voltage-gated Ca(2+) channel. However, by means of weak stimulation protocols, we reveal that GABA(B) receptors also reduce glutamate release mediated by P/Q-type Ca(2+) channels, and that these responses are reversed by the GIRK channel blocker tertiapin-Q. Consistent with the functional interaction between GABA(B) receptors and GIRK channels at nerve terminals we demonstrate by immunogold electron immunohistochemistry that pre-synaptic boutons of asymmetric synapses co-express GABA(B) receptors and GIRK channels, thus suggesting that the functional interaction of these two proteins, found at the post-synaptic level, also occurs at glutamatergic nerve terminals.

  10. Network state-dependent inhibition of identified hippocampal CA3 axo-axonic cells in vivo.

    PubMed

    Viney, Tim J; Lasztoczi, Balint; Katona, Linda; Crump, Michael G; Tukker, John J; Klausberger, Thomas; Somogyi, Peter

    2013-12-01

    Hippocampal sharp waves are population discharges initiated by an unknown mechanism in pyramidal cell networks of CA3. Axo-axonic cells (AACs) regulate action potential generation through GABAergic synapses on the axon initial segment. We found that CA3 AACs in anesthetized rats and AACs in freely moving rats stopped firing during sharp waves, when pyramidal cells fire most. AACs fired strongly and rhythmically around the peak of theta oscillations, when pyramidal cells fire at low probability. Distinguishing AACs from other parvalbumin-expressing interneurons by their lack of detectable SATB1 transcription factor immunoreactivity, we discovered a somatic GABAergic input originating from the medial septum that preferentially targets AACs. We recorded septo-hippocampal GABAergic cells that were activated during hippocampal sharp waves and projected to CA3. We hypothesize that inhibition of AACs, and the resulting subcellular redistribution of inhibition from the axon initial segment to other pyramidal cell domains, is a necessary condition for the emergence of sharp waves promoting memory consolidation.

  11. Presynaptic inhibition of optogenetically identified VGluT3+ sensory fibres by opioids and baclofen.

    PubMed

    Honsek, Silke D; Seal, Rebecca P; Sandkühler, Jürgen

    2015-02-01

    Distinct subsets of sensory nerve fibres are involved in mediating mechanical and thermal pain hypersensitivity. They may also differentially respond to analgesics. Heat-sensitive C-fibres, for example, are thought to respond to μ-opioid receptor (MOR) activation while mechanoreceptive fibres are supposedly sensitive to δ-opioid receptor (DOR) or GABAB receptor (GABABR) activation. The suggested differential distribution of inhibitory neurotransmitter receptors on different subsets of sensory fibres is, however, heavily debated. In this study, we quantitatively compared the degree of presynaptic inhibition exerted by opioids and the GABABR agonist baclofen on (1) vesicular glutamate transporter subtype 3-positive (VGluT3) non-nociceptive primary afferent fibres and (2) putative nociceptive C-fibres. To investigate VGluT3 sensory fibres, we evoked excitatory postsynaptic currents with blue light at the level of the dorsal root ganglion (DRG) in spinal cord slices of mice, expressing channelrhodopsin-2. Putative nociceptive C-fibres were explored in VGluT3-knockout mice through electrical stimulation. The MOR agonist DAMGO strongly inhibited both VGluT3 and VGluT3 C-fibres innervating lamina I neurons but generally had less influence on fibres innervating lamina II neurons. The DOR agonist SNC80 did not have any pronounced effect on synaptic transmission in any fibre type tested. Baclofen, in striking contrast, powerfully inhibited all fibre populations investigated. In summary, we report optogenetic stimulation of DRG neurons in spinal slices as a capable approach for the subtype-selective investigation of primary afferent nerve fibres. Overall, pharmacological accessibility of different subtypes of sensory fibres considerably overlaps, indicating that MOR, DOR, and GABABR expressions are not substantially segregated between heat and mechanosensitive fibres.

  12. Inhibition of intramolecular electron transfer in ascorbate oxidase by Ag+: redox state dependent binding.

    PubMed

    Santagostini, Laura; Gullotti, Michele; Hazzard, James T; Maritano, Silvana; Tollin, Gordon; Marchesini, Augusto

    2005-02-01

    Intramolecular electron transfer within zucchini squash ascorbate oxidase is inhibited in a novel manner in the presence of an equimolar concentration of Ag(+). At pH 5.5 in acetate buffer reduction of the enzyme by laser flash photolytically generated 5-deazariboflavin semiquinone occurs at the Type I Cu with a rate constant of 5 x 10(8) M(-1)s(-1). Subsequent to this initial reduction step, equilibration of the reducing equivalent between the Type I Cu and the trinuclear Type II, III copper cluster (TNC) occurs with rate constant of 430 s(-1). The 41% of the reduced Type I Cu is oxidized by this intramolecular electron transfer reaction. When these reactions are performed in the presence of Ag(+) equimolar to dimeric AO, the bimolecular reduction of the enzyme by the 5-deazariboflavin semiquinone is not affected. As in the case of the native enzyme, intramolecular electron transfer between the Type I Cu and the TNC occurs, which continues until 25% of the reducing equivalent has been transferred. At that point, the reducing equivalent is observed to more slowly return to the Type I Cu, resulting a second reduction phase whose rate constant (100 s(-1)) is protein and Ag(+) concentration independent. The data suggest that partial reduction of the TNC results in Ag(+) binding to the enzyme which causes the apparent midpoint potential of the TNC as a whole to decrease thereby reversing the direction of electron flow. These results are consistent with the inhibitory effect of Ag(+) on the steady-state activity of ascorbate oxidase [S. Maritano, E. Malusa, A. Marchesini, presented at The Meeting on Metalloproteins, SERC Daresbury Laboratory, Warrington, England, 1992; A. Marchesini, XIX Convegno Nazionale SICA, Italian Society of Agricultural Chemistry, Reggio Calabria, Italy, September 2001.].

  13. Blockade of the dorsal hippocampal dopamine D1 receptors inhibits the scopolamine-induced state-dependent learning in rats.

    PubMed

    Piri, M; Rostampour, M; Nasehi, M; Zarrindast, M R

    2013-11-12

    In the present study, we investigated the possible role of the dorsal hippocampal (CA1) dopamine D1 receptors on scopolamine-induced amnesia as well as scopolamine state-dependent memory in adult male Wistar rats. Animals were bilaterally implanted with chronic cannulae in the CA1 regions of the dorsal hippocampus, trained in a step-through type inhibitory avoidance task, and tested 24h after training for their step-through latency. Results indicated that pre-training or pre-test intra-CA1 administration of scopolamine (1.5 and 3 μg/rat) dose-dependently reduced the step-through latency, showing an amnestic response. The pre-training scopolamine-induced amnesia (3 μg/rat) was reversed by the pre-test administration of scopolamine, indicating a state-dependent effect. Similarly, the pre-test administration of dopamine D1 receptor agonist, 1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF38393; 1, 2 and 4 μg/rat, intra-CA1), could significantly reverse the scopolamine-induced amnesia. Interestingly, administration of an ineffective dose of scopolamine (0.25 μg/rat, intra-CA1) before different doses of SKF38393, blocked the reversal effect of SKF38393 on the pre-training scopolamine-induced amnesia. Moreover, while the pre-test intra-CA1 injection of the dopamine D1 receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0.1 and 0.5 μg/rat, intra-CA1), resulted in apparent memory impairment, microinjection of the same doses of this agent inhibited the scopolamine-induced state-dependent memory. These results indicate that the CA1 dopamine D1 receptors may potentially play an important role in scopolamine-induced amnesia as well as the scopolamine state-dependent memory. Furthermore, our results propose that dopamine D1 receptor agonist, SKF38393 reverses the scopolamine-induced amnesia via acetylcholine release and possibly through the activation of muscarinic

  14. Presynaptic Inhibition of Glutamate Transmission by Alpha-2 Receptors in the VTA

    PubMed Central

    Jiménez-Rivera, Carlos A.; Figueroa, Johnny; Vázquez, Rafael; Vélez, María; Schwarz, David; Velásquez-Martinez, María C.; Arencibia-Albite, Francisco

    2013-01-01

    The ventral tegmental area (VTA) forms part of the mesocorticolimbic system and plays a pivotal role in reward and reinforcing actions of drugs of abuse. Glutamate transmission within the VTA controls important aspects of goal-directed behavior and motivation. Noradrenergic receptors also present in the VTA have important functions in the modulation of neuronal activity. Here we studied the effects of alpha-2 noradrenergic receptor activation in the alteration of glutamate neurotransmission in VTA dopaminergic neurons from male Sprague-Dawley rats. We used whole cell patch clamp recordings from putative VTA dopaminergic neurons and measured excitatory postsynaptic currents. Clonidine (40 μM) and UK 13,408 (40 μM), both alpha-2 receptor agonists, reduced (~ 40%) the amplitude of glutamate-induced excitatory postsynaptic currents. After clonidine administration, there was a dose-dependent reduction over the concentration range of 15–40 μM. Using yohimbine (20μM) and two other alpha-2 adrenergic receptor antagonists, idaxozan (40 μM) and atipemazole (20μM), we demonstrated that the inhibitory action is specifically mediated by alpha-2 receptors. Moreover, by inhibiting protein kinases with H-7 (75 μM), Rp-adenosine 3′,5′-cyclic (11 μM) and chelerythrine (1 μM) it was shown that the clonidine-induced inhibition seems to involve a selective activation of the protein kinase C intracellular pathway. An increased paired-pulse ratios and changes in spontaneous and miniature excitatory postsynaptic currents frequencies but not amplitudes indicated that the alpha-2 agonist’s effect was presynaptically mediated. It is suggested that the suppression of glutamate excitatory inputs onto VTA dopaminergic neurons might be relevant in the regulation of reward and drug seeking behaviors. PMID:22564071

  15. Age-related influence of vision and proprioception on Ia presynaptic inhibition in soleus muscle during upright stance.

    PubMed

    Baudry, Stéphane; Duchateau, Jacques

    2012-11-01

    This study investigated the modulation of Ia afferent input in young and elderly adults during quiet upright stance in normal and modified visual and proprioceptive conditions. The surface EMG of leg muscles, recruitment curve of the soleus (SOL) Hoffmann (H) reflex and presynaptic inhibition of Ia afferents from SOL, assessed with the D1 inhibition and single motor unit methods, were recorded when young and elderly adults stood with eyes open or closed on two surfaces (rigid vs. foam) placed over a force platform. The results showed that elderly adults had a longer path length for the centre of pressure and larger antero-posterior body sway across balance conditions (P < 0.05). Muscle EMG activities were greater in elderly compared with young adults (P < 0.05), whereas the H(max) expressed as a percentage of the H(max) was lower (P = 0.048) in elderly (38 ± 16%) than young adults (58 ± 16%). The conditioned H reflex/test H reflex ratio (D1 inhibition method) increased with eye closure and when standing on foam (P < 0.05), with greater increases for elderly adults (P = 0.019). These changes were accompanied by a reduced peak motor unit discharge probability when standing on rigid and foam surfaces (P 0.001), with a greater effect for elderly adults (P = 0.026). Based on these latter results, the increased conditioned H reflex/test H reflex ratio in similar sensory conditions is likely to reflect occlusion at the level of presynaptic inhibitory interneurones. Together, these findings indicate that elderly adults exhibit greater modulation of Ia presynaptic inhibition than young adults with variation in the sensory conditions during upright standing.

  16. Robust presynaptic serotonin 5-HT1B receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment

    PubMed Central

    Ding, Shengyuan; Li, Li

    2015-01-01

    The striatonigral projection is a striatal output pathway critical to motor control, cognition, and emotion regulation. Its axon terminals in the substantia nigra pars reticulata (SNr) express a high level of serotonin (5-HT) type 1B receptors (5-HT1BRs), whereas the SNr also receives an intense 5-HT innervation that expresses 5-HT transporters, providing an anatomic substrate for 5-HT and selective 5-HT reuptake inhibitor (SSRI)-based antidepressant treatment to regulate the striatonigral output. In this article we show that 5-HT, by activating presynaptic 5-HT1BRs on the striatonigral axon terminals, potently inhibited the striatonigral GABA output, as reflected in the reduction of the striatonigral inhibitory postsynaptic currents in SNr GABA neurons. Functionally, 5-HT1BR agonism reduced the striatonigral GABA output-induced pause of the spontaneous high-frequency firing in SNr GABA neurons. Equally important, chronic SSRI treatment with fluoxetine enhanced this presynaptic 5-HT1BR-mediated pause reduction in SNr GABA neurons. Taken together, these results indicate that activation of the 5-HT1BRs on the striatonigral axon terminals can limit the motor-promoting GABA output. Furthermore, in contrast to the desensitization of 5-HT1 autoreceptors, chronic SSRI-based antidepressant treatment sensitizes this presynaptic 5-HT1BR-mediated effect in the SNr, a novel cellular mechanism that alters the striatonigral information transfer, potentially contributing to the behavioral effects of chronic SSRI treatment. PMID:25787955

  17. Differential effects of acidosis, high potassium concentrations, and metabolic inhibition on noradrenaline release and its presynaptic muscarinic regulation.

    PubMed

    Haunstetter, Armin; Schulze Icking, Babette; Backs, Johannes; Krüger, Carsten; Haass, Markus

    2002-03-01

    It was the aim of the present study to characterize the effect of single components of ischaemia, such as inhibition of aerobic and anaerobic energy production by combined anoxic and glucose-free perfusion (metabolic inhibition), high extracellular potassium concentrations (hyperkalaemia), and acidosis, on (1). the stimulated release of noradrenaline from the in situ perfused guinea-pig heart and (2). its presynaptic modulation by the muscarinic agonist carbachol. The release of endogenous noradrenaline from efferent cardiac sympathetic nerve endings was induced by electrical stimulation of the left stellate ganglion (1 min, 5 V, 12 Hz) and quantified in the coronary venous effluent by high-performance liquid chromatography. Under control conditions, two consecutive electrical stimulations (S1, S2) elicited a similar noradrenaline overflow (S2/S1: 0.98 plus minus 0.05). After 10 min of global myocardial ischaemia overflow of endogenous noradrenaline was significantly reduced (S2/S1: 0.18 plus minus 0.03; P< 0.05). When studied separately, metabolic inhibition, hyperkalaemia (16 mM), and acidosis (pH 6.0) each markedly attenuated stimulated noradrenaline overflow (S2/S1: 0.65 plus minus 0.05, 0.43 plus minus 0.14, and 0.37 plus minus 0.09, respectively; P< 0.05). The muscarinic agonist carbachol (10 microM) inhibited stimulated noradrenaline release under normoxic conditions (S2/S1: 0.41 plus minus 0.07; P< 0.05). However, after 10 min of global myocardial ischaemia the inhibitory effect of carbachol on noradrenaline overflow was completely lost. Single components of ischaemia had a differential effect on presynaptic muscarinic modulation. Whereas hyperkalaemia (8-16 mM) did not affect muscarinic inhibition of noradrenaline release, carbachol lost its inhibitory effect during acidosis and metabolic inhibition. In conclusion, hyperkalaemia, metabolic inhibition, and severe acidosis each contribute to reduced overflow of noradrenaline after 10 min of myocardial

  18. Pre-synaptic adenosine A2A receptors control cannabinoid CB1 receptor-mediated inhibition of striatal glutamatergic neurotransmission.

    PubMed

    Martire, Alberto; Tebano, Maria Teresa; Chiodi, Valentina; Ferreira, Samira G; Cunha, Rodrigo A; Köfalvi, Attila; Popoli, Patrizia

    2011-01-01

    An interaction between adenosine A(2A) receptors (A(2A) Rs) and cannabinoid CB(1) receptors (CB(1) Rs) has been consistently reported to occur in the striatum, although the precise mechanisms are not completely understood. As both receptors control striatal glutamatergic transmission, we now probed the putative interaction between pre-synaptic CB(1) R and A(2A) R in the striatum. In extracellular field potentials recordings in corticostriatal slices from Wistar rats, A(2A) R activation by CGS21680 inhibited CB(1) R-mediated effects (depression of synaptic response and increase in paired-pulse facilitation). Moreover, in superfused rat striatal nerve terminals, A(2A) R activation prevented, while A(2A) R inhibition facilitated, the CB(1) R-mediated inhibition of 4-aminopyridine-evoked glutamate release. In summary, the present study provides converging neurochemical and electrophysiological support for the occurrence of a tight control of CB(1) R function by A(2A) Rs in glutamatergic terminals of the striatum. In view of the key role of glutamate to trigger the recruitment of striatal circuits, this pre-synaptic interaction between CB(1) R and A(2A) R may be of relevance for the pathogenesis and the treatment of neuropsychiatric disorders affecting the basal ganglia.

  19. Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein by presynaptic histamine H3 receptors.

    PubMed

    Molderings, G J; Weissenborn, G; Schlicker, E; Likungu, J; Göthert, M

    1992-07-01

    The human saphenous vein was used to examine whether presynaptic histamine receptors can modulate noradrenaline release and, if so, to determine their pharmacological characteristics. Strips of this blood vessel were incubated with [3H]noradrenaline and subsequently superfused with physiological salt solution containing desipramine and corticosterone. Electrically (2 Hz) evoked 3H overflow was inhibited by histamine and the H3 receptor agonist R-(-)-alpha-methylhistamine. Histamine-induced inhibition of electrically evoked tritium overflow was not affected by alpha 2-adrenoceptor blockade by rauwolscine. S-(+)-alpha-methylhistamine (up to 10 mumol/l) as well as the histamine H1 and H2 receptor agonists 2-(2-thiazolyl)ethylamine (up to 3 mumol/l) and dimaprit (up to 30 mumol/l), respectively, were ineffective. The selective histamine H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine. The histamine H2 and H1 receptor antagonists ranitidine and pheniramine, respectively, did not affect the histamine-induced inhibition of evoked tritium overflow. The present results are compatible with the suggestion that the sympathetic nerves of the human saphenous vein are endowed with inhibitory presynaptic histamine receptors of the H3 class.

  20. Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1.

    PubMed

    Schmitz, Sabine K; King, Cillian; Kortleven, Christian; Huson, Vincent; Kroon, Tim; Kevenaar, Josta T; Schut, Desiree; Saarloos, Ingrid; Hoetjes, Joost P; de Wit, Heidi; Stiedl, Oliver; Spijker, Sabine; Li, Ka Wan; Mansvelder, Huibert D; Smit, August B; Cornelisse, Lennart Niels; Verhage, Matthijs; Toonen, Ruud F

    2016-06-01

    Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by extracellular signal-regulated kinase (ERK) that mediates CB1R- and mGluR2/3-induced secretion inhibition. This pathway is triggered by a variety of events, from foot shock-induced stress to intense neuronal activity, and induces phosphorylation of the presynaptic protein Munc18-1. Mimicking constitutive phosphorylation of Munc18-1 results in a drastic decrease in synaptic transmission. ERK-mediated phosphorylation of Munc18-1 ultimately leads to degradation by the ubiquitin-proteasome system. Conversely, preventing ERK-dependent Munc18-1 phosphorylation increases synaptic strength. CB1R- and mGluR2/3-induced synaptic inhibition and depolarization-induced suppression of excitation (DSE) are reduced upon ERK/MEK pathway inhibition and further reduced when ERK-dependent Munc18-1 phosphorylation is blocked. Thus, ERK-dependent Munc18-1 phosphorylation provides a major negative feedback loop to control synaptic strength upon activation of presynaptic receptors and during intense neuronal activity.

  1. Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABAB and mGlu2/3 receptors

    PubMed Central

    Kupferschmidt, David A; Lovinger, David M

    2015-01-01

    Cortical inputs to the dorsolateral striatum (DLS) are dynamically regulated during skill learning and habit formation, and are dysregulated in disorders characterized by impaired action control. Therefore, a mechanistic investigation of the processes regulating corticostriatal transmission is key to understanding DLS-associated circuit function, behaviour and pathology. Presynaptic GABAB and group II metabotropic glutamate (mGlu2/3) receptors exert marked inhibitory control over corticostriatal glutamate release in the DLS, yet the signalling pathways through which they do so are unclear. We developed a novel approach using the genetically encoded calcium (Ca2+) indicator GCaMP6 to assess presynaptic Ca2+ in corticostriatal projections to the DLS. Using simultaneous photometric presynaptic Ca2+ and striatal field potential recordings, we report that relative to P/Q-type Ca2+ channels, N-type channels preferentially contributed to evoked presynaptic Ca2+ influx in motor cortex projections to, and excitatory transmission in, the DLS. Activation of GABAB or mGlu2/3 receptors inhibited both evoked presynaptic Ca2+ transients and striatal field potentials. mGlu2/3 receptor-mediated depression did not require functional N-type Ca2+ channels, but was attenuated by blockade of P/Q-type channels. These findings reveal presynaptic mechanisms of inhibitory modulation of corticostriatal function that probably contribute to the selection and shaping of behavioural repertoires. Key points Plastic changes at cortical inputs to the dorsolateral striatum (DLS) underlie skill learning and habit formation, so characterizing the mechanisms by which these inputs are regulated is important for understanding the neural basis of action control. We developed a novel approach using the genetically encoded calcium (Ca2+) indicator GCaMP6 and brain slice photometry to assess evoked presynaptic Ca2+ transients in cortical inputs to the DLS and study their regulation by GABAB and mGlu2

  2. Ontogenesis of presynaptic GABAB receptor-mediated inhibition in the CA3 region of the rat hippocampus.

    PubMed

    Caillard, O; McLean, H A; Ben-Ari, Y; Gaïarsa, J L

    1998-03-01

    although GABAB receptor-dependent and -independent mechanisms of presynaptic inhibition are present onGABAergic terminals and functional, they do not operate at the level of monosynaptic GABAergic synaptic transmission at early stages of development. Absence of presynaptic autoinhibition of GABA release seems to be due to the small amount of transmitter that can access presynaptic regulatory sites.

  3. Rosiglitazone Suppresses In Vitro Seizures in Hippocampal Slice by Inhibiting Presynaptic Glutamate Release in a Model of Temporal Lobe Epilepsy

    PubMed Central

    Wong, Shi-Bing; Cheng, Sin-Jhong; Hung, Wei-Chen; Lee, Wang-Tso; Min, Ming-Yuan

    2015-01-01

    Peroxisomal proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor whose agonist, rosiglitazone has a neuroprotective effect to hippocampal neurons in pilocarpine-induced seizures. Hippocampal slice preparations treated in Mg2+ free medium can induce ictal and interictal-like epileptiform discharges, which is regarded as an in vitro model of N-methyl-D-aspartate (NMDA) receptor-mediated temporal lobe epilepsy (TLE). We applied rosiglitazone in hippocampal slices treated in Mg2+ free medium. The effects of rosiglitazone on hippocampal CA1-Schaffer collateral synaptic transmission were tested. We also examined the neuroprotective effect of rosiglitazone toward NMDA excitotoxicity on cultured hippocampal slices. Application of 10μM rosiglitazone significantly suppressed amplitude and frequency of epileptiform discharges in CA1 neurons. Pretreatment with the PPARγ antagonist GW9662 did not block the effect of rosiglitazone on suppressing discharge frequency, but reverse the effect on suppressing discharge amplitude. Application of rosiglitazone suppressed synaptic transmission in the CA1-Schaffer collateral pathway. By miniature excitatory-potential synaptic current (mEPSC) analysis, rosiglitazone significantly suppressed presynaptic neurotransmitter release. This phenomenon can be reversed by pretreating PPARγ antagonist GW9662. Also, rosiglitazone protected cultured hippocampal slices from NMDA-induced excitotoxicity. The protective effect of 10μM rosiglitazone was partially antagonized by concomitant high dose GW9662 treatment, indicating that this effect is partially mediated by PPARγ receptors. In conclusion, rosiglitazone suppressed NMDA receptor-mediated epileptiform discharges by inhibition of presynaptic neurotransmitter release. Rosiglitazone protected hippocampal slice from NMDA excitotoxicity partially by PPARγ activation. We suggest that rosiglitazone could be a potential agent to treat patients with TLE. PMID:26659605

  4. Inosine induces presynaptic inhibition of acetylcholine release by activation of A3 adenosine receptors at the mouse neuromuscular junction

    PubMed Central

    Cinalli, A R; Guarracino, J F; Fernandez, V; Roquel, L I; Losavio, A S

    2013-01-01

    Background and Purpose The role of inosine at the mammalian neuromuscular junction (NMJ) has not been clearly defined. Moreover, inosine was classically considered to be the inactive metabolite of adenosine. Hence, we investigated the effect of inosine on spontaneous and evoked ACh release, the mechanism underlying its modulatory action and the receptor type and signal transduction pathway involved. Experimental Approach End-plate potentials (EPPs) and miniature end-plate potentials (MEPPs) were recorded from the mouse phrenic-nerve diaphragm preparations using conventional intracellular electrophysiological techniques. Key Results Inosine (100 μM) reduced MEPP frequency and the amplitude and quantal content of EPPs; effects inhibited by the selective A3 receptor antagonist MRS-1191. Immunohistochemical assays confirmed the presence of A3 receptors at mammalian NMJ. The voltage-gated calcium channel (VGCC) blocker Cd2+, the removal of extracellular Ca2+ and the L-type and P/Q-type VGCC antagonists, nitrendipine and ω-agatoxin IVA, respectively, all prevented inosine-induced inhibition. In the absence of endogenous adenosine, inosine decreased the hypertonic response. The effects of inosine on ACh release were prevented by the Gi/o protein inhibitor N-ethylmaleimide, PKC antagonist chelerytrine and calmodulin antagonist W-7, but not by PKA antagonists, H-89 and KT-5720, or the inhibitor of CaMKII KN-62. Conclusion and Implications Our results suggest that, at motor nerve terminals, inosine induces presynaptic inhibition of spontaneous and evoked ACh release by activating A3 receptors through a mechanism that involves L-type and P/Q-type VGCCs and the secretory machinery downstream of calcium influx. A3 receptors appear to be coupled to Gi/o protein. PKC and calmodulin may be involved in these effects of inosine. PMID:23731236

  5. Presynaptic modulation of spinal reflexes.

    PubMed

    Rudomin, P; Quevedo, J; Eguibar, J R

    1993-12-01

    Recent evidence suggests that independent sets of interneurons mediate presynaptic inhibition of primary and secondary muscle spindles and of tendon organ afferents. There is also evidence that the information which flows through different intraspinal collaterals of a single muscle spindle or tendon organ afferent fiber is selectively affected by electrical stimulation of the motor cortex. These studies suggest that presynaptic inhibition plays an important role in the selection of the sensory signals required for the execution of a specific motor task.

  6. Pre-Synaptic Inhibition of Afferent Feedback in the Macaque Spinal Cord Does Not Modulate with Cycles of Peripheral Oscillations Around 10 Hz

    PubMed Central

    Galán, Ferran; Baker, Stuart N.

    2015-01-01

    Spinal interneurons are partially phase-locked to physiological tremor around 10 Hz. The phase of spinal interneuron activity is approximately opposite to descending drive to motoneurons, leading to partial phase cancellation and tremor reduction. Pre-synaptic inhibition of afferent feedback modulates during voluntary movements, but it is not known whether it tracks more rapid fluctuations in motor output such as during tremor. In this study, dorsal root potentials (DRPs) were recorded from the C8 and T1 roots in two macaque monkeys following intra-spinal micro-stimulation (random inter-stimulus interval 1.5–2.5 s, 30–100 μA), whilst the animals performed an index finger flexion task which elicited peripheral oscillations around 10 Hz. Forty one responses were identified with latency < 5 ms; these were narrow (mean width 0.59 ms), and likely resulted from antidromic activation of afferents following stimulation near terminals. Significant modulation during task performance occurred in 16/41 responses, reflecting terminal excitability changes generated by pre-synaptic inhibition (Wall's excitability test). Stimuli falling during large-amplitude 8–12 Hz oscillations in finger acceleration were extracted, and sub-averages of DRPs constructed for stimuli delivered at different oscillation phases. Although some apparent phase-dependent modulation was seen, this was not above the level expected by chance. We conclude that, although terminal excitability reflecting pre-synaptic inhibition of afferents modulates over the timescale of a voluntary movement, it does not follow more rapid changes in motor output. This suggests that pre-synaptic inhibition is not part of the spinal systems for tremor reduction described previously, and that it plays a role in overall—but not moment-by-moment—regulation of feedback gain. PMID:26635536

  7. Okadaic acid-induced inhibition of B-50 dephosphorylation by presynaptic membrane-associated protein phosphatases.

    PubMed

    Han, Y F; Dokas, L A

    1991-10-01

    The neuronal tissue-specific protein kinase C (PKC) substrate B-50 can be dephosphorylated by endogenous protein phosphatases (PPs) in synaptic plasma membranes (SPMs). The present study characterizes membrane-associated B-50 phosphatase activity by using okadaic acid (OA) and purified 32P-labeled substrates. At a low concentration of [gamma-32P]ATP, PKC-mediated [32P]phosphate incorporation into B-50 in SPMs reached a maximal value at 30 s, followed by dephosphorylation. OA, added 30 s after the initiation of phosphorylation, partially prevented the dephosphorylation of B-50 at 2 nM, a dose that inhibits PP-2A. At the higher concentration of 1 microM, a dose of OA that inhibits PP-1 as well as PP-2A, a nearly complete blockade of B-50 dephosphorylation was seen. Heat-stable PP inhibitor-2 (I-2) also inhibited dephosphorylation of B-50. The effects of OA and I-2 on B-50 phosphatase activity were additive. Endogenous PP-1- and PP-2A-like activities in SPMs were also demonstrated by their capabilities of dephosphorylating [32P]phosphorylase a and [32P]casein. With these exogenous substrates, sensitivities of the membrane-bound phosphatases to OA and I-2 were found to be similar to those of purified forms of these enzymes. These results indicate that PP-1- and PP-2A-like enzymes are the major B-50 phosphatases in SPMs.

  8. Activation of Presynaptic GABAB(1a,2) Receptors Inhibits Synaptic Transmission at Mammalian Inhibitory Cholinergic Olivocochlear–Hair Cell Synapses

    PubMed Central

    Wedemeyer, Carolina; Zorrilla de San Martín, Javier; Ballestero, Jimena; Gómez-Casati, María Eugenia; Torbidoni, Ana Vanesa; Fuchs, Paul A.; Bettler, Bernhard; Elgoyhen, Ana Belén

    2013-01-01

    The synapse between olivocochlear (OC) neurons and cochlear mechanosensory hair cells is cholinergic, fast, and inhibitory. The inhibitory sign of this cholinergic synapse is accounted for by the activation of Ca2+-permeable postsynaptic α9α10 nicotinic receptors coupled to the opening of hyperpolarizing Ca2+-activated small-conductance type 2 (SK2)K+ channels. Acetylcholine (ACh) release at this synapse is supported by both P/Q- and N-type voltage-gated calcium channels (VGCCs). Although the OC synapse is cholinergic, an abundant OC GABA innervation is present along the mammalian cochlea. The role of this neurotransmitter at the OC efferent innervation, however, is for the most part unknown. We show that GABA fails to evoke fast postsynaptic inhibitory currents in apical developing inner and outer hair cells. However, electrical stimulation of OC efferent fibers activates presynaptic GABAB(1a,2) receptors [GABAB(1a,2)Rs] that downregulate the amount of ACh released at the OC–hair cell synapse, by inhibiting P/Q-type VGCCs. We confirmed the expression of GABABRs at OC terminals contacting the hair cells by coimmunostaining for GFP and synaptophysin in transgenic mice expressing GABAB1–GFP fusion proteins. Moreover, coimmunostaining with antibodies against the GABA synthetic enzyme glutamic acid decarboxylase and synaptophysin support the idea that GABA is directly synthesized at OC terminals contacting the hair cells during development. Thus, we demonstrate for the first time a physiological role for GABA in cochlear synaptic function. In addition, our data suggest that the GABAB1a isoform selectively inhibits release at efferent cholinergic synapses. PMID:24068816

  9. Inhibition of noradrenaline release in the rat brain cortex via presynaptic H3 receptors.

    PubMed

    Schlicker, E; Fink, K; Hinterthaner, M; Göthert, M

    1989-12-01

    The effects of histamine and related drugs on the evoked tritium overflow from superfused rat brain cortex slices preincubated with 3H-noradrenaline were determined. Tritium overflow was stimulated electrically (3 Hz; slices superfused with normal physiological salt solution) or by introduction of CaCl2 1.3 mmol/l (slices superfused with Ca2(+)-free medium containing K+ 20 mmol/l). Histamine slightly decreased the electrically evoked 3H overflow in slices superfused in the presence of desipramine. The degree of inhibition obtained with histamine was doubled when both desipramine and phentolamine were present in the superfusion medium (pIC15 6.46). Under the latter condition, the evoked overflow was inhibited by the H3 receptor agonist R-(-)-alpha-methylhistamine and its S-(+) enantiomer (pIC15 7.36 and 5.09, respectively), but was not affected by the H2 receptor agonist dimaprit and the H1 receptor agonist 2-thiazolylethylamine (both at up to 32 mumols/l). The concentration-response curve of histamine was shifted to the right by the H3 receptor antagonists thioperamide, impromidine and burimamide (apparent pA2 8.37, 6.86 and 7.05, respectively), by the H2 receptor antagonist ranitidine (apparent pA2 4.27) and was not affected by the H1 receptor antagonist dimetindene (32 mumols/l). The inhibitory effect of R-(-)-alpha-methylhistamine on the evoked overflow was also counteracted by thioperamide. Given alone, none of the five histamine receptor antagonists affected the evoked overflow. In the absence of desipramine plus phentolamine, impromidine and burimamide facilitated the electrically evoked 3H overflow whereas thioperamide had no effect. The facilitatory effects of impromidine and burimamide were abolished by phentolamine, but not affected by desipramine.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Circuit motifs for contrast-adaptive differentiation in early sensory systems: the role of presynaptic inhibition and short-term plasticity.

    PubMed

    Zhang, Danke; Wu, Si; Rasch, Malte J

    2015-01-01

    In natural signals, such as the luminance value across of a visual scene, abrupt changes in intensity value are often more relevant to an organism than intensity values at other positions and times. Thus to reduce redundancy, sensory systems are specialized to detect the times and amplitudes of informative abrupt changes in the input stream rather than coding the intensity values at all times. In theory, a system that responds transiently to fast changes is called a differentiator. In principle, several different neural circuit mechanisms exist that are capable of responding transiently to abrupt input changes. However, it is unclear which circuit would be best suited for early sensory systems, where the dynamic range of the natural input signals can be very wide. We here compare the properties of different simple neural circuit motifs for implementing signal differentiation. We found that a circuit motif based on presynaptic inhibition (PI) is unique in a sense that the vesicle resources in the presynaptic site can be stably maintained over a wide range of stimulus intensities, making PI a biophysically plausible mechanism to implement a differentiator with a very wide dynamical range. Moreover, by additionally considering short-term plasticity (STP), differentiation becomes contrast adaptive in the PI-circuit but not in other potential neural circuit motifs. Numerical simulations show that the behavior of the adaptive PI-circuit is consistent with experimental observations suggesting that adaptive presynaptic inhibition might be a good candidate neural mechanism to achieve differentiation in early sensory systems.

  11. Circuit Motifs for Contrast-Adaptive Differentiation in Early Sensory Systems: The Role of Presynaptic Inhibition and Short-Term Plasticity

    PubMed Central

    Zhang, Danke; Wu, Si; Rasch, Malte J.

    2015-01-01

    In natural signals, such as the luminance value across of a visual scene, abrupt changes in intensity value are often more relevant to an organism than intensity values at other positions and times. Thus to reduce redundancy, sensory systems are specialized to detect the times and amplitudes of informative abrupt changes in the input stream rather than coding the intensity values at all times. In theory, a system that responds transiently to fast changes is called a differentiator. In principle, several different neural circuit mechanisms exist that are capable of responding transiently to abrupt input changes. However, it is unclear which circuit would be best suited for early sensory systems, where the dynamic range of the natural input signals can be very wide. We here compare the properties of different simple neural circuit motifs for implementing signal differentiation. We found that a circuit motif based on presynaptic inhibition (PI) is unique in a sense that the vesicle resources in the presynaptic site can be stably maintained over a wide range of stimulus intensities, making PI a biophysically plausible mechanism to implement a differentiator with a very wide dynamical range. Moreover, by additionally considering short-term plasticity (STP), differentiation becomes contrast adaptive in the PI-circuit but not in other potential neural circuit motifs. Numerical simulations show that the behavior of the adaptive PI-circuit is consistent with experimental observations suggesting that adaptive presynaptic inhibition might be a good candidate neural mechanism to achieve differentiation in early sensory systems. PMID:25723493

  12. Temporal redistribution of inhibition over neuronal subcellular domains underlies state-dependent rhythmic change of excitability in the hippocampus.

    PubMed

    Somogyi, Peter; Katona, Linda; Klausberger, Thomas; Lasztóczi, Bálint; Viney, Tim J

    2014-02-05

    The behaviour-contingent rhythmic synchronization of neuronal activity is reported by local field potential oscillations in the theta, gamma and sharp wave-related ripple (SWR) frequency ranges. In the hippocampus, pyramidal cell assemblies representing temporal sequences are coordinated by GABAergic interneurons selectively innervating specific postsynaptic domains, and discharging phase locked to network oscillations. We compare the cellular network dynamics in the CA1 and CA3 areas recorded with or without anaesthesia. All parts of pyramidal cells, except the axon initial segment, receive GABA from multiple interneuron types, each with distinct firing dynamics. The axon initial segment is exclusively innervated by axo-axonic cells, preferentially firing after the peak of the pyramidal layer theta cycle, when pyramidal cells are least active. Axo-axonic cells are inhibited during SWRs, when many pyramidal cells fire synchronously. This dual inverse correlation demonstrates the key inhibitory role of axo-axonic cells. Parvalbumin-expressing basket cells fire phase locked to field gamma activity in both CA1 and CA3, and also strongly increase firing during SWRs, together with dendrite-innervating bistratified cells, phasing pyramidal cell discharge. Subcellular domain-specific GABAergic innervation probably developed for the coordination of multiple glutamatergic inputs on different parts of pyramidal cells through the temporally distinct activity of GABAergic interneurons, which differentially change their firing during different network states.

  13. Activation of histamine H3 receptors produces presynaptic inhibition of neurally evoked cat nictitating membrane responses in vivo.

    PubMed

    Koss, M C; Hey, J A

    1992-08-01

    This study was undertaken in order to determine the potential role of prejunctional histamine H3 receptors in an in vivo adrenergic model system. Frequency-dependent nictitating membrane responses were elicited by sympathetic nerve stimulation in anesthetized cats. Systemic administration of the selective histamine H3 receptor agonist, (R)-alpha-methylhistamine (R alpha MeHA) produced a dose-related depression of amplitude of the evoked nictitating membrane responses with a threshold of about 10 micrograms/kg and maximal effect (50% depression at the lowest frequency; 0.5 Hz) seen at 100-300 micrograms/kg. Responses obtained with low frequency stimulation were more sensitive to depression by R alpha MeHA than were responses evoked with higher frequencies of stimulation. Larger doses of R alpha MeHA given to the same animals, failed to produce additional inhibition. R alpha MeHA depressed the amplitude of nictitating membrane responses evoked by either pre- or postganglionic nerve stimulation to an equivalent degree. This depressant action of R alpha MeHA was antagonized by pretreatment with the specific histamine H3 antagonist, thioperamide (3 mg/kg), but not by combined pretreatment with histamine H1 and H2 blockers chlorpheniramine (300 micrograms/kg) and cimetidine (5 mg/kg). Intravenous administration of adrenaline (1-30 micrograms/kg) also produced graded nictitating membrane responses that were not altered by subsequent administration of R alpha MeHA. These results suggest that histamine H3 receptors are involved in the modulation of neurally evoked noradrenaline release in the cat nictitating membrane by an inhibitory presynaptic action.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Ciproxifan, a histamine H3 receptor antagonist and inverse agonist, presynaptically inhibits glutamate release in rat hippocampus.

    PubMed

    Lu, Cheng-Wei; Lin, Tzu-Yu; Chang, Chia-Ying; Huang, Shu-Kuei; Wang, Su-Jane

    2017-03-15

    Ciproxifan is an H3 receptor antagonist and inverse agonist with antipsychotic effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus. In a synaptosomal preparation, ciproxifan reduced 4-aminopyridine (4-AP)-evoked Ca(2+)-dependent glutamate release and cytosolic Ca(2+) concentration elevation but did not affect the membrane potential. The inhibitory effect of ciproxifan on 4-AP-evoked glutamate release was prevented by the Gi/Go-protein inhibitor pertussis toxin and Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was not affected by the intracellular Ca(2+)-release inhibitors dantrolene and CGP37157. Furthermore, the phospholipase A2 (PLA2) inhibitor OBAA, prostaglandin E2 (PGE2), PGE2 subtype 2 (EP2) receptor antagonist PF04418948, and extracellular signal-regulated kinase (ERK) inhibitor FR180204 eliminated the inhibitory effect of ciproxifan on glutamate release. Ciproxifan reduced the 4-AP-evoked phosphorylation of ERK and synapsin I, a presynaptic target of ERK. The ciproxifan-mediated inhibition of glutamate release was prevented in synaptosomes from synapsin I-deficient mice. Moreover, ciproxifan reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that ciproxifan, acting through the blockade of Gi/Go protein-coupled H3 receptors present on hippocampal nerve terminals, reduces voltage-dependent Ca(2+) entry by diminishing PLA2/PGE2/EP2 receptor pathway, which subsequently suppresses the ERK/synapsin I cascade to decrease the evoked glutamate release.

  15. Human presynaptic receptors.

    PubMed

    Schlicker, Eberhard; Feuerstein, Thomas

    2017-04-01

    Presynaptic receptors are sites at which transmitters, locally formed mediators or hormones inhibit or facilitate the release of a given transmitter from its axon terminals. The interest in the identification of presynaptic receptors has faded in recent years and it may therefore be justified to give an overview of their occurrence in the autonomic and central nervous system; this review will focus on presynaptic receptors in human tissues. Autoreceptors are presynaptic receptors at which a given transmitter restrains its further release, though in some instances may also increase its release. Inhibitory autoreceptors represent a typical example of a negative feedback; they are tonically activated by the respective endogenous transmitter and/or are constitutively active. Autoreceptors also play a role under pathophysiological conditions, e.g. by limiting the massive noradrenaline release occurring during congestive heart failure. They can be used for therapeutic purposes; e.g., the α2-adrenoceptor antagonist mirtazapine is used as an antidepressant and the inverse histamine H3 receptor agonist pitolisant has been marketed as a new drug for the treatment of narcolepsy in 2016. Heteroreceptors are presynaptic receptors at which transmitters from adjacent neurons, locally formed mediators (e.g. endocannabinoids) or hormones (e.g. adrenaline) can inhibit or facilitate transmitter release; they may be subject to an endogenous tone. The constipating effect of the sympathetic nervous system or of the antihypertensive drug clonidine is related to the activation of inhibitory α2-adrenoceptors on postganglionic parasympathetic neurons. Part of the stimulating effect of adrenaline on the sympathetic nervous system during stress is related to its facilitatory effect on noradrenaline release via β2-adrenoceptors.

  16. Effects of stimulation of group I afferents from flexor muscles on heterosynaptic facilitation of monosynaptic reflexes produced by Ia and descending inputs: a test for presynaptic inhibition.

    PubMed

    Rudomin, P; Jiménez, I; Enriquez, M

    1991-01-01

    1. In the chloralose anesthetized cat, conditioning stimulation of group I flexor afferents depresses the monosynaptic potentials generated by Ia afferents in single spinal motoneurons or in populations of motoneurons without affecting the monosynaptic potentials produced by stimulation of descending fibers in the ipsilateral ventromedial fasciculus (VMF). 2. Heterosynaptic facilitation of monosynaptic reflexes was used to test changes in the presynaptic effectiveness of excitatory inputs with direct connections with motoneurons. We found that the heterosynaptic facilitation of Ia origin was reduced by conditioning stimulation of group I afferents from flexors, without affecting the heterosynaptic facilitation produced by stimulation of the VMF. 3. These results confirm and expand previous observations showing that the synaptic effectiveness of descending fibers synapsing with motoneurons is not subjected to a presynaptic control mechanism of the type acting on Ia fiber terminals, and provide further basis for the use of changes in heterosynaptic facilitation of monosynaptic reflexes of Ia origin as an estimate of changes in presynaptic inhibition of Ia fibers (Hultborn et al. 1987a).

  17. Presynaptic G protein-coupled receptors dynamically modify vesicle fusion, synaptic cleft glutamate concentrations and motor behavior

    PubMed Central

    Gerachshenko, Tatyana; Schwartz, Eric; Bleckert, Adam; Photowala, Huzefa; Seymour, Andrew; Alford, Simon

    2009-01-01

    Understanding how neuromodulators regulate behavior requires investigating their effects on functional neural systems, but also their underlying cellular mechanisms. Utilizing extensively characterized lamprey motor circuits, and the unique access to reticulospinal presynaptic terminals in the intact spinal cord that initiate these behaviours, we have investigated effects of presynaptic G protein-coupled receptors on locomotion from the systems level, to the molecular control of vesicle fusion. 5-HT inhibits neurotransmitter release via a Gβγ interaction with the SNARE complex that promotes kiss-and-run vesicle fusion. In the lamprey spinal cord we demonstrate that while presynaptic 5-HT receptors inhibit evoked neurotransmitter release from reticulospinal command neurons, their activation does not abolish locomotion, but rather modulates locomotor rhythms. Liberation of presynaptic Gβγ causes substantial inhibition of AMPA receptor-mediated synaptic responses, but leaves NMDA receptor-mediated components of neurotransmission largely intact. Because Gβγ binding to the SNARE complex is displaced by Ca2+-synaptotagmin binding, 5-HT-mediated inhibition displays Ca2+ sensitivity. We show that as Ca2+ accumulates presynaptically during physiological bouts of activity, 5-HT/Gβγ-mediated presynaptic inhibition is relieved leading to a frequency-dependent increase in synaptic concentrations of glutamate. This frequency dependent phenomenon mirrors a shift in the vesicle fusion mode and a recovery of AMPA receptor-mediated EPSCs from inhibition without a modification of NMDA receptor EPSCs. We conclude that activation of presynaptic 5-HT GPCRs state-dependently alters vesicle fusion properties to shift the weight of NMDA vs AMPA receptor-mediated responses at excitatory synapses. We have therefore identified a novel mechanism in which modification of vesicle fusion modes may profoundly alter locomotor behaviour. PMID:19692597

  18. Pre- and postsynaptic excitation and inhibition at octopus optic lobe photoreceptor terminals; implications for the function of the 'presynaptic bags'.

    PubMed

    Piscopo, Stefania; Moccia, Francesco; Di Cristo, Carlo; Caputi, Luigi; Di Cosmo, Anna; Brown, Euan R

    2007-10-01

    Synaptic transmission was examined in the plexiform zone of Octopus vulgaris optic lobes using field-potential recording from optic lobe slices. Stimulation of the optic nerve produced pre- and postsynaptic field potentials. Transmission was abolished in calcium-free seawater, L- glutamate or the AMPA/Kainate receptor blocker CNQX (EC(50), 40 microm), leaving an intact presynaptic field potential. ACh markedly reduced or blocked and d-tubocurarine augmented both pre- and postsynaptic field potentials, while alpha-bungarotoxin and atropine were without effect. Paired-pulse stimulation showed short-term depression of pre- and postsynaptic components with a half-time of recovery of approximately 500 ms. The depression was partially relieved in the presence of d-tubocurarine (half-time of recovery, 350 ms). No long-term changes in synaptic strength were induced by repetitive stimulation. A polyclonal antibody raised against a squid glutamate receptor produced positive staining in the third radial layer of the plexiform zone. No positive staining was observed in the other layers. Taking into account previous morphological data and our results, we propose that the excitatory terminations of the photoreceptors are in the innermost layer of the plexiform zone where the transmitter is likely to be glutamate and postsynaptic receptors are AMPA/kainate-like. Thus, the function of the terminal bags is to provide a location for a presynaptic cholinergic inhibitory shunt. The results imply that this arrangement provides a temporal filter for visual processing and enhances the perception of moving vs. stationary objects.

  19. Prenatal melamine exposure impairs spatial cognition and hippocampal synaptic plasticity by presynaptic and postsynaptic inhibition of glutamatergic transmission in adolescent offspring.

    PubMed

    An, Lei; Sun, Wei

    2017-03-05

    Our previous studies showed that prenatal melamine exposure (PME) could impair spatial cognition and hippocampal long-term potentiation (LTP). More importantly, the synaptic dysfunction induced by PME was associated with the probability of presynaptic glutamate release. Considering the crucial role of the other form of synaptic plasticity, long-term depression (LTD), in some types of learning and memory process, the aim of present study was to investigate if the hippocampal LTD and cognitive flexibility were affected. And then we attempted to explore the underlying mechanism. The animal model was produced by melamine exposure throughout gestational period with 400mg/kg bodyweight, the male offspring rats were used in the study. Morris water maze (MWM) test was performed, and then LTD was recorded from Schaffer collaterals to CA1 region in the hippocampus. Behavioral test showed that learning, reference memory and re-acquisition learning abilities were impaired significantly by PME. The field excitatory postsynaptic potentials (fEPSPs) slopes of LTD were significantly higher after PME. Furthermore, the data of whole-cell patch-clamp experiments showed that PME markedly diminished the frequencies of spontaneous EPSCs (sEPSCs) and simultaneously reduced the amplitude of sEPSCs. In conclusion, PME inhibited glutamate transmission presynaptically and postsynaptically which could contribute importantly to the depressed hippocampal synaptic plasticity and further induced cognitive deficits in MWM tests.

  20. RGS2 determines short-term synaptic plasticity in hippocampal neurons by regulating Gi/o-mediated inhibition of presynaptic Ca2+ channels.

    PubMed

    Han, Jing; Mark, Melanie D; Li, Xiang; Xie, Mian; Waka, Sayumi; Rettig, Jens; Herlitze, Stefan

    2006-09-07

    RGS2, one of the small members of the regulator of G protein signaling (RGS) family, is highly expressed in brain and regulates G(i/o) as well as G(q)-coupled receptor pathways. RGS2 modulates anxiety, aggression, and blood pressure in mice, suggesting that RGS2 regulates synaptic circuits underlying animal physiology and behavior. How RGS2 in brain influences synaptic activity is unknown. We therefore analyzed the synaptic function of RGS2 in hippocampal neurons by comparing electrophysiological recordings from RGS2 knockout and wild-type mice. Our study provides a general mechanism of the action of the RGS family containing RGS2 by demonstrating that RGS2 increases synaptic vesicle release by downregulating the G(i/o)-mediated presynaptic Ca(2+) channel inhibition and therefore provides an explanation of how regulation of RGS2 expression can modulate the function of neuronal circuits underlying behavior.

  1. Near-Infrared Spectroscopy – Electroencephalography-Based Brain-State-Dependent Electrotherapy: A Computational Approach Based on Excitation–Inhibition Balance Hypothesis

    PubMed Central

    Dagar, Snigdha; Chowdhury, Shubhajit Roy; Bapi, Raju Surampudi; Dutta, Anirban; Roy, Dipanjan

    2016-01-01

    Stroke is the leading cause of severe chronic disability and the second cause of death worldwide with 15 million new cases and 50 million stroke survivors. The poststroke chronic disability may be ameliorated with early neuro rehabilitation where non-invasive brain stimulation (NIBS) techniques can be used as an adjuvant treatment to hasten the effects. However, the heterogeneity in the lesioned brain will require individualized NIBS intervention where innovative neuroimaging technologies of portable electroencephalography (EEG) and functional-near-infrared spectroscopy (fNIRS) can be leveraged for Brain State Dependent Electrotherapy (BSDE). In this hypothesis and theory article, we propose a computational approach based on excitation–inhibition (E–I) balance hypothesis to objectively quantify the poststroke individual brain state using online fNIRS–EEG joint imaging. One of the key events that occurs following Stroke is the imbalance in local E–I (that is the ratio of Glutamate/GABA), which may be targeted with NIBS using a computational pipeline that includes individual “forward models” to predict current flow patterns through the lesioned brain or brain target region. The current flow will polarize the neurons, which can be captured with E–I-based brain models. Furthermore, E–I balance hypothesis can be used to find the consequences of cellular polarization on neuronal information processing, which can then be implicated in changes in function. We first review the evidence that shows how this local imbalance between E–I leading to functional dysfunction can be restored in targeted sites with NIBS (motor cortex and somatosensory cortex) resulting in large-scale plastic reorganization over the cortex, and probably facilitating recovery of functions. Second, we show evidence how BSDE based on E–I balance hypothesis may target a specific brain site or network as an adjuvant treatment. Hence, computational neural mass model-based integration of

  2. Near-Infrared Spectroscopy - Electroencephalography-Based Brain-State-Dependent Electrotherapy: A Computational Approach Based on Excitation-Inhibition Balance Hypothesis.

    PubMed

    Dagar, Snigdha; Chowdhury, Shubhajit Roy; Bapi, Raju Surampudi; Dutta, Anirban; Roy, Dipanjan

    2016-01-01

    Stroke is the leading cause of severe chronic disability and the second cause of death worldwide with 15 million new cases and 50 million stroke survivors. The poststroke chronic disability may be ameliorated with early neuro rehabilitation where non-invasive brain stimulation (NIBS) techniques can be used as an adjuvant treatment to hasten the effects. However, the heterogeneity in the lesioned brain will require individualized NIBS intervention where innovative neuroimaging technologies of portable electroencephalography (EEG) and functional-near-infrared spectroscopy (fNIRS) can be leveraged for Brain State Dependent Electrotherapy (BSDE). In this hypothesis and theory article, we propose a computational approach based on excitation-inhibition (E-I) balance hypothesis to objectively quantify the poststroke individual brain state using online fNIRS-EEG joint imaging. One of the key events that occurs following Stroke is the imbalance in local E-I (that is the ratio of Glutamate/GABA), which may be targeted with NIBS using a computational pipeline that includes individual "forward models" to predict current flow patterns through the lesioned brain or brain target region. The current flow will polarize the neurons, which can be captured with E-I-based brain models. Furthermore, E-I balance hypothesis can be used to find the consequences of cellular polarization on neuronal information processing, which can then be implicated in changes in function. We first review the evidence that shows how this local imbalance between E-I leading to functional dysfunction can be restored in targeted sites with NIBS (motor cortex and somatosensory cortex) resulting in large-scale plastic reorganization over the cortex, and probably facilitating recovery of functions. Second, we show evidence how BSDE based on E-I balance hypothesis may target a specific brain site or network as an adjuvant treatment. Hence, computational neural mass model-based integration of neurostimulation with

  3. Acamprosate enhances N-methyl-D-apartate receptor-mediated neurotransmission but inhibits presynaptic GABA(B) receptors in nucleus accumbens neurons.

    PubMed

    Berton, F; Francesconi, W G; Madamba, S G; Zieglgänsberger, W; Siggins, G R

    1998-02-01

    Acamprosate (calcium acetylhomotaurine) is used therapeutically in Europe to reduce relapse in weaned alcoholics. However, the mechanisms of acamprosate action in the central nervous system are still obscure, although early studies suggested an action on GABA receptors. The nucleus accumbens (NAcc) is a brain region thought to underlie ethanol reinforcement. Recent studies from our laboratory have demonstrated that ethanol inhibits both N-methyl-D-aspartate (NMDA) and non-NMDA types of glutamatergic synaptic transmission in the NAcc. In the present study, we used voltage- and current-clamp intracellular recording of NAcc core neurons in a slice preparation to examine acamprosate actions on resting membrane properties and pharmacologically isolated synaptic responses. We isolated NMDA and non-NMDA receptor-mediated excitatory postsynaptic potentials or currents (EPSP/Cs) with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonovalerate (d-APV), respectively. Bicuculline was also included to block GABA(A) receptors. Superfusion of acamprosate (5, 50, and 300 microM) did not alter the resting membrane properties of NAcc neurons. However, 300 microM acamprosate significantly increased the NMDA receptor-mediated components of EPSP/Cs (NMDA-EPSP/Cs) with recovery on washout. In contrast, 300 microM acamprosate had no significant effect on the non-NMDA receptor component of the EPSP/Cs (non-NMDA-EPSP/Cs). To test acamprosate actions on the GABA system, we superfused 60 microM d-APV and 20 microM CNQX to block glutamatergic transmission and evoked monosynaptic GABA(A) receptor-mediated synaptic responses within the NAcc. Acamprosate (300 microM) did not change these monosynaptic GABA(A)-IPSCs. We also used a paired-pulse paradigm to test whether acamprosate could act on presynaptic GABA(B) autoreceptors, in the presence of d-APV and CNQX to block glutamatergic transmission. Like 0.5 microM CGP 34358 (a GABA[B] receptor blocker), acamprosate significantly

  4. Presynaptic inhibition of gamma-aminobutyric acidB-mediated synaptic current by adenosine recorded in vitro in midbrain dopamine neurons.

    PubMed

    Wu, Y N; Mercuri, N B; Johnson, S W

    1995-05-01

    Adenosine receptor antagonists such as caffeine cause dopamine-dependent behavioral arousal and hyperlocomotion in rodents. In the present study, we used the whole-cell recording technique in the rat brain slice to investigate effects of adenosine on dopamine neurons and their synaptic inputs in the substantia nigra zona compacta and ventral tegmental area. Adenosine was most potent for inhibiting the amplitude of the inhibitory postsynaptic current (IPSC) mediated by gamma-aminobutyric acid (GABA)B receptors (EC50 = 47 +/- 3 microM) compared with inhibition of the GABAA-mediated IPSC (117 +/- 51 microM) and the excitatory amino acid-mediated excitatory postsynaptic current (119 +/- 36 microM). Adenosine failed to inhibit current evoked by exogenous GABA or baclofen, suggesting that adenosine acted presynaptically to reduce GABA release from nerve terminals. Adenosine inhibited the GABAB-mediated IPSC by acting at the adenosine A1 receptor, because its effect was blocked by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM), as well as by the methylxanthines caffeine (1 mM) and theophylline (300 microM). The rank-order of potency of adenosine agonists [N6-cyclohexyladenosine > R-(-)-N6-(2-phenylisopropyl)-adenosine = N6- cyclohexyladenosine > 5'-N-ethylcarboxamidoadenosine > 2-chloroadenosine] also was consistent with activation of the adenosine A1 receptor, whereas the selective adenosine A2A agonist CGS 21680 [2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine] had no effect on the GABAB IPSC. None of the adenosine agonists or antagonists affected holding current or membrane conductance.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Presynaptic autoinhibition of central noradrenaline release in vitro: operational characteristics and effects of drugs acting at alpha-2 adrenoceptors in the presence of uptake inhibition

    SciTech Connect

    Valenta, B.; Drobny, H.; Singer, E.A.

    1988-06-01

    Functional characteristics of autoinhibition of central noradrenaline release were studied in the presence of uptake inhibition. Slices of rat cerebral cortex were incubated with (3H)noradrenaline, superfused and field-stimulated with 1 to 16 monophasic rectangular pulses at frequencies of 0.02 to 40 Hz. 1) Substances acting at presynaptic alpha-2 adrenoceptors were identified as antagonists, agonists or partial agonists by comparing their effects on 3H-overflow evoked by a single pulse or by two consecutive pulses at 1 Hz. 2) When 1 to 16 pulses were delivered at 0.02, 0.08, 0.3 and 1 Hz to stimulate outflow of tritium, a frequency-dependent suppression of responses to the second and the following pulses was observed. In the presence of the alpha-2 adrenoceptor antagonist idazoxan (10(-6) M), comparable amounts of tritium were released by the first stimulus and each of the following stimuli at 0.02 Hz. In contrast, at 0.08, 0.3 and 1 Hz the amount of 3H-overflow evoked by the first pulse was not reached in response to the following pulses. Clonidine (10(-6) M) diminished markedly the response to the first as well as to the following stimuli, irrespective of the frequency of stimulation. 3) Using two consecutive pulses delivered with decreasing pulse intervals, an apparent reduction or complete abolition of autoinhibition was observed at intervals of less than 100 msec, indicated by reduction or loss of the facilitatory effects of alpha-2 adrenoceptor antagonists. The present results provide detailed insights in operational characteristics of alpha-2 adrenoceptor-mediated autoinhibition and the effects of drugs on this regulatory mechism.

  6. Nitrous oxide directly inhibits action potential-dependent neurotransmission from single presynaptic boutons adhering to rat hippocampal CA3 neurons.

    PubMed

    Wakita, Masahito; Kotani, Naoki; Yamaga, Toshitaka; Akaike, Norio

    2015-09-01

    We evaluated the effects of N2O on synaptic transmission using a preparation of mechanically dissociated rat hippocampal CA3 neurons that allowed assays of single bouton responses evoked from native functional nerve endings. We studied the effects of N2O on GABAA, glutamate, AMPA and NMDA receptor-mediated currents (IGABA, IGlu, IAMPA and INMDA) elicited by exogenous application of GABA, glutamate, (S)-AMPA, and NMDA and spontaneous, miniature, and evoked GABAergic inhibitory and glutamatergic excitatory postsynaptic current (sIPSC, mIPSC, eIPSC, sEPSC, mEPSC and eEPSC) in mechanically dissociated CA3 neurons. eIPSC and eEPSC were evoked by focal electrical stimulation of a single bouton. Administration of 70% N2O altered neither IGABA nor the frequency and amplitude of both sIPSCs and mIPSCs. In contrast, N2O decreased the amplitude of eIPSCs, while increasing failure rates (Rf) and paired-pulse ratios (PPR) in a concentration-dependent manner. On the other hand, N2O decreased IGlu, IAMPA and INMDA. Again N2O did not change the frequency and amplitude of either sEPSCs of mEPSCs. N2O also decreased amplitudes of eEPSCs with increased Rf and PPR. The decay phases of all synaptic responses were unchanged. The present results indicated that N2O inhibits the activation of AMPA/KA and NMDA receptors and also that N2O preferentially depress the action potential-dependent GABA and glutamate releases but had little effects on spontaneous and miniature releases.

  7. Dual pools of actin at presynaptic terminals.

    PubMed

    Bleckert, Adam; Photowala, Huzefa; Alford, Simon

    2012-06-01

    We investigated actin's function in vesicle recycling and exocytosis at lamprey synapses and show that FM1-43 puncta and phalloidin-labeled filamentous actin (F-actin) structures are colocalized, yet recycling vesicles are not contained within F-actin clusters. Additionally, phalloidin also labels a plasma membrane-associated cortical actin. Injection of fluorescent G-actin revealed activity-independent dynamic actin incorporation into presynaptic synaptic vesicle clusters but not into cortical actin. Latrunculin-A, which sequesters G-actin, dispersed vesicle-associated actin structures and prevented subsequent labeled G-actin and phalloidin accumulation at presynaptic puncta, yet cortical phalloidin labeling persisted. Dispersal of presynaptic F-actin structures by latrunculin-A did not disrupt vesicle clustering or recycling or alter the amplitude or kinetics of excitatory postsynaptic currents (EPSCs). However, it slightly enhanced release during repetitive stimulation. While dispersal of presynaptic actin puncta with latrunculin-A failed to disperse synaptic vesicles or inhibit synaptic transmission, presynaptic phalloidin injection blocked exocytosis and reduced endocytosis measured by action potential-evoked FM1-43 staining. Furthermore, phalloidin stabilization of only cortical actin following pretreatment with latrunculin-A was sufficient to inhibit synaptic transmission. Conversely, treatment of axons with jasplakinolide, which induces F-actin accumulation but disrupts F-actin structures in vivo, resulted in increased synaptic transmission accompanied by a loss of phalloidin labeling of cortical actin but no loss of actin labeling within vesicle clusters. Marked synaptic deficits seen with phalloidin stabilization of cortical F-actin, in contrast to the minimal effects of disruption of a synaptic vesicle-associated F-actin, led us to conclude that two structurally and functionally distinct pools of actin exist at presynaptic sites.

  8. Cyfip1 Regulates Presynaptic Activity during Development

    PubMed Central

    Hsiao, Kuangfu; Harony-Nicolas, Hala; Buxbaum, Joseph D.

    2016-01-01

    Copy number variations encompassing the gene encoding Cyfip1 have been associated with a variety of human diseases, including autism and schizophrenia. Here we show that juvenile mice hemizygous for Cyfip1 have altered presynaptic function, enhanced protein translation, and increased levels of F-actin. In developing hippocampus, reduced Cyfip1 levels serve to decrease paired pulse facilitation and increase miniature EPSC frequency without a change in amplitude. Higher-resolution examination shows these changes to be caused primarily by an increase in presynaptic terminal size and enhanced vesicle release probability. Short hairpin-mediated knockdown of Cyfip1 coupled with expression of mutant Cyfip1 proteins indicates that the presynaptic alterations are caused by dysregulation of the WAVE regulatory complex. Such dysregulation occurs downstream of Rac1 as acute exposure to Rac1 inhibitors rescues presynaptic responses in culture and in hippocampal slices. The data serve to highlight an early and essential role for Cyfip1 in the generation of normally functioning synapses and suggest a means by which changes in Cyfip1 levels could impact the generation of neural networks and contribute to abnormal and maladaptive behaviors. SIGNIFICANCE STATEMENT Several developmental brain disorders have been associated with gene duplications and deletions that serve to increase or decrease levels of encoded proteins. Cyfip1 is one such protein, but the role it plays in brain development is poorly understood. We asked whether decreased Cyfip1 levels altered the function of developing synapses. The data show that synapses with reduced Cyfip1 are larger and release neurotransmitter more rapidly. These effects are due to Cyfip1's role in actin polymerization and are reversed by expression of a Cyfip1 mutant protein retaining actin regulatory function or by inhibiting Rac1. Thus, Cyfip1 has a more prominent early role regulating presynaptic activity during a stage of development when

  9. Presynaptic Calcium Signalling in Cerebellar Mossy Fibres

    PubMed Central

    Thomsen, Louiza B.; Jörntell, Henrik; Midtgaard, Jens

    2009-01-01

    Whole-cell recordings were obtained from mossy fibre terminals in adult turtles in order to characterize the basic membrane properties. Calcium imaging of presynaptic calcium signals was carried out in order to analyse calcium dynamics and presynaptic GABA B inhibition. A tetrodotoxin (TTX)-sensitive fast Na+ spike faithfully followed repetitive depolarizing pulses with little change in spike duration or amplitude, while a strong outward rectification dominated responses to long-lasting depolarizations. High-threshold calcium spikes were uncovered following addition of potassium channel blockers. Calcium imaging using Calcium-Green dextran revealed a stimulus-evoked all-or-none TTX-sensitive calcium signal in simple and complex rosettes. All compartments of a complex rosette were activated during electrical activation of the mossy fibre, while individual simple and complex rosettes along an axon appeared to be isolated from one another in terms of calcium signalling. CGP55845 application showed that GABA B receptors mediated presynaptic inhibition of the calcium signal over the entire firing frequency range of mossy fibres. A paired-pulse depression of the calcium signal lasting more than 1 s affected burst firing in mossy fibres; this paired-pulse depression was reduced by GABA B antagonists. While our results indicated that a presynaptic rosette electrophysiologically functioned as a unit, topical GABA application showed that calcium signals in the branches of complex rosettes could be modulated locally, suggesting that cerebellar glomeruli may be dynamically sub-compartmentalized due to ongoing inhibition mediated by Golgi cells. This could provide a fine-grained control of mossy fibre-granule cell information transfer and synaptic plasticity within a mossy fibre rosette. PMID:20162034

  10. Presynaptic BK type Ca(2+)-activated K(+) channels are involved in prostanoid TP receptor-mediated inhibition of noradrenaline release from the rat gastric sympathetic nerves.

    PubMed

    Nakamura, Kumiko; Yokotani, Kunihiko

    2010-03-10

    Previously, we reported that prostanoid TP receptor mediates the inhibition of electrically evoked noradrenaline release from gastric sympathetic nerves in rats. Prostanoid TP receptor has been shown to activate phospholipase C (PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-triphosphate (IP(3)) and diacylglycerol; IP(3) triggers the release of Ca(2+) from intracellular stores and diacylglycerol activates protein kinase C. In the present study, therefore, we examined whether these PLC-mediated mechanisms are involved in the TP receptor-mediated inhibition of gastric noradrenaline release using an isolated, vascularly perfused rat stomach. U-46619 (9,11-dideoxy-9alpha,11alpha-methanoepoxy PGF(2alpha)) (a prostanoid TP receptor agonist)-induced inhibition of noradrenaline release from the stomach was reduced by U-73122 [1-[6-[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]-amino]hexyl]-1H-pyrrole-2,5-dine] (a PLC inhibitor) and ET-18-OCH(3) (1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine) (a phosphatidylinositol-specific PLC inhibitor), respectively. 2-APB (2-aminoethyldiphenyl borate) (a putative IP(3) receptor antagonist) also abolished the U-46619-induced inhibition of noradrenaline release, but Ro 31-8220 [2-{1-[3-(amidinothio)propyl]-1H-indol-3-yl}-3-(1-methylindol-3-yl)-maleimide] (a protein kinase C inhibitor) had no effect. Furthermore, a small dose of tetraethylammonium and charybdotoxin [blockers of BK type Ca(2+)-activated K(+) channel] abolished the U-46619-induced inhibition, but apamin (a blocker of SK-type Ca(2+)-activated K(+) channel) had no effect. These results suggest that BK type Ca(2+)-activated K(+) channels are involved in prostanoid TP receptor-mediated inhibition of electrically evoked noradrenaline release from the gastric sympathetic nerve terminals in rats.

  11. Presynaptic long-term plasticity

    PubMed Central

    Yang, Ying; Calakos, Nicole

    2013-01-01

    Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now apparent that there is a vast array of mechanisms for long-term synaptic plasticity that involve modifications to either or both the presynaptic terminal and postsynaptic site. In this article, we discuss current and evolving approaches to identify presynaptic mechanisms as well as discuss their limitations. We next provide examples of the diverse circuits in which presynaptic forms of long-term synaptic plasticity have been described and discuss the potential contribution this form of plasticity might add to circuit function. Finally, we examine the present evidence for the molecular pathways and cellular events underlying presynaptic long-term synaptic plasticity. PMID:24146648

  12. Involvement of presynaptic voltage-dependent Kv3 channel in endothelin-1-induced inhibition of noradrenaline release from rat gastric sympathetic nerves.

    PubMed

    Nakamura, Kumiko; Shimizu, Takahiro; Tanaka, Kenjiro; Taniuchi, Keisuke; Yokotani, Kunihiko

    2012-11-05

    We previously reported that two types of K(+) channels, the BK type Ca(2+)-activated K(+) channel coupled with phospholipase C (PLC) and the voltage-dependent K(+) channel (Kv channel), are, respectively, involved in the prostanoid TP receptor- and muscarinic M(2) receptor-mediated inhibition of noradrenaline (NA) release from rat gastric sympathetic nerves. In the present study, therefore, we examined whether these K(+) channels are involved in endothelin-1-induced inhibition of NA release, using an isolated, vascularly perfused rat stomach. The gastric sympathetic postganglionic nerves around the left gastric artery were electrically stimulated twice at 2.5 Hz for 1 min, and endothelin-1 was added during the second stimulation. Endothelin-1 (1, 2 and 10 nM) dose-dependently inhibited gastric NA release. Endothelin-1 (2 nM)-induced inhibition of NA release was neither attenuated by PLC inhibitors [U-73122 (3 μM) and ET-18-OCH(3) (3 μM)] nor by Ca(2+)-activated K(+) channel blockers [charybdotoxin (0.1 μM) (a blocker of BK type K(+) channel) and apamin (0.3 μM) (a blocker of SK type K(+) channel)]. The endothelin-1-induced inhibitory response was also not attenuated by α-dendrotoxin (0.1 μM) (a selective inhibitor of Kv1 channel), but abolished by 4-aminopyridine (20 μM) (a selectively inhibitory dose for Kv3 channel). These results suggest the involvement of a voltage-dependent Kv3 channel in the endothelin-1-induced inhibition of NA release from the gastric sympathetic nerves in rats.

  13. A Presynaptic Gain Control Mechanism Fine-Tunes Olfactory Behavior

    PubMed Central

    Root, Cory M.; Masuyama, Kaoru; Green, David S.; Enell, Lina E.; Nässel, Dick R.; Lee, Chi-Hon; Wang, Jing W.

    2008-01-01

    Early sensory processing can play a critical role in sensing environmental cues. We have investigated the physiological and behavioral function of gain control at the first synapse of olfactory processing in Drosophila. We report that olfactory receptor neurons (ORNs) express the GABAB receptor (GABABR) and its expression expands the dynamic range of ORN synaptic transmission that is preserved in projection neuron responses. Strikingly, we find that different ORN channels have unique baseline levels of GABABR expression. ORNs that sense the aversive odorant CO2 do not express GABABRs nor exhibit any presynaptic inhibition. In contrast, pheromone-sensing ORNs express a high level of GABABRs and exhibit strong presynaptic inhibition. Furthermore, a behavioral significance of presynaptic inhibition was revealed by a courtship behavior in which pheromone-dependent mate localization is impaired in flies that lack GABABRs in specific ORNs. Together, these findings indicate that different olfactory receptor channels may employ heterogeneous presynaptic gain control as a mechanism to allow an animal’s innate behavioral responses to match its ecological needs. PMID:18667158

  14. Synthetic Aβ oligomers (Aβ(1-42) globulomer) modulate presynaptic calcium currents: prevention of Aβ-induced synaptic deficits by calcium channel blockers.

    PubMed

    Hermann, David; Mezler, Mario; Müller, Michaela K; Wicke, Karsten; Gross, Gerhard; Draguhn, Andreas; Bruehl, Claus; Nimmrich, Volker

    2013-02-28

    Alzheimer's disease is accompanied by increased brain levels of soluble amyloid-β (Aβ) oligomers. It has been suggested that oligomers directly impair synaptic function, thereby causing cognitive deficits in Alzheimer's disease patients. Recently, it has been shown that synthetic Aβ oligomers directly modulate P/Q-type calcium channels, possibly leading to excitotoxic cascades and subsequent synaptic decline. Using whole-cell recordings we studied the modulation of recombinant presynaptic calcium channels in HEK293 cells after application of a stable Aβ oligomer preparation (Aβ1-42 globulomer). Aβ globulomer shifted the half-activation voltage of P/Q-type and N-type calcium channels to more hyperpolarized values (by 11.5 and 7.5 mV). Application of non-aggregated Aβ peptides had no effect. We then analyzed the potential of calcium channel blockers to prevent Aβ globulomer-induced synaptic decline in hippocampal slice cultures. Specific block of P/Q-type or N-type calcium channels with peptide toxins completely reversed Aβ globulomer-induced deficits in glutamatergic neurotransmission. Two state-dependent low molecular weight P/Q-type and N-type calcium channel blockers also protected neurons from Aβ-induced alterations. On the contrary, inhibition of L-type calcium channels failed to reverse the deficit. Our data show that Aβ globulomer directly modulates recombinant P/Q-type and N-type calcium channels in HEK293 cells. Block of presynaptic calcium channels with both state-dependent and state-independent modulators can reverse Aβ-induced functional deficits in synaptic transmission. These findings indicate that presynaptic calcium channel blockers may be a therapeutic strategy for the treatment of Alzheimer's disease.

  15. Presynaptic modulation by somatostatin in the neostriatum.

    PubMed

    Lopez-Huerta, Violeta Gisselle; Tecuapetla, Fatuel; Guzman, Jaime N; Bargas, Jose; Galarraga, Elvira

    2008-08-01

    Medium spiny projection neurons (MSNs) are the main neuronal population in the neostriatum. MSNs are inhibitory and GABAergic. MSNs connect with other MSNs via local axon collaterals that produce lateral inhibition, which is thought to select cell assemblies for motor action. MSNs also receive inhibitory inputs from GABAergic local interneurons. This work shows, through the use of the paired pulse protocol, that somatostatin (SST) acts presynaptically to regulate GABA release from the terminals interconnecting MSNs. This SST action is reversible and not mediated through the release of dopamine. It is blocked by the SST receptor (SSTR) antagonist ciclosomatostatin (cicloSST). In contrast, SST does not regulate inhibition coming from interneurons. Because, SST is released by a class of local interneuron, it is concluded that this neuron helps to regulate the selection of motor acts.

  16. 3,4-Diaminopyridine masks the inhibition of noradrenaline release from chick sympathetic neurons via presynaptic alpha 2-adrenoceptors: insights into the role of N- and L-type calcium channels.

    PubMed

    Dolezal, V; Huang, H Y; Schobert, A; Hertting, G

    1996-05-20

    antagonised this effect. UK 14304 did not measurably inhibit the stimulation-evoked rise of intraterminal [Ca2+]i in the presence of 3,4-diaminopyridine but it produced an inhibition by 26% if nifedipine had been applied together with 3,4-diaminopyridine. Our observations show that, under control conditions, the stimulated release of [3H]noradrenaline is mainly associated with the opening of N-type channels, while in the presence of 3,4-diaminopyridine the contribution of L-type channels becomes more important. The alpha 2-adrenoceptor stimulation by UK 14304 inhibits the release of [3H]noradrenaline but, in the presence of 3,4-diaminopyridine, the inhibition of release can only be observed if the massive influx through L-type calcium channels is prevented. These data suggest that presynaptic alpha 2-adrenoceptors of chick sympathetic neurons preferentially influence the N-type calcium channels.

  17. Macroautophagy can press a brake on presynaptic neurotransmission.

    PubMed

    Torres, Ciara A; Sulzer, David

    2012-10-01

    The mechanistic target of rapamycin (MTOR) has been implicated in regulating synaptic plasticity and neurodegeneration, but MTOR's role in modulating presynaptic function through autophagy is unexplored. We studied presynaptic function in ventral dopamine neurons, a system from which neurotransmitter release can be measured directly by cyclic voltammetry. We generated mutant mice that were specifically deficient for macroautophagy in dopaminergic neurons by deleting the Atg7 gene in cells that express the dopamine uptake transporter. Dopamine axonal profiles in the mutant dorsal striatum were ~one third larger in the mutant mice, released ~50% more stimulus-evoked dopamine release, and exhibited more rapid presynaptic recovery than controls. Rapamycin reduced dopamine neuron axon profile size by ~30% in control mice, but had no effect on macroautophagy deficient axons. Acute rapamycin decreased dopaminergic synaptic vesicle density by ~25% and inhibited evoked dopamine release by ~25% in control mice, but not in the Atg7 deficient mutants. Thus, both basal and induced macroautophagy can provide a brake on presynaptic activity in vivo, perhaps by regulating the turnover of synaptic vesicles, and further regulates terminal volume and the kinetics of transmitter release.

  18. High-content imaging of presynaptic assembly

    PubMed Central

    Poon, Vivian Y.; Goh, Chiatzun; Voorhoeve, P. Mathijs; Fivaz, Marc

    2014-01-01

    Presynaptic assembly involves the specialization of a patch of axonal membrane into a complex structure that supports synaptic vesicle exocytosis and neurotransmitter release. In mammalian neurons, presynaptic assembly is widely studied in a co-culture assay, where a synaptogenic cue expressed at the surface of a heterologous cell induces presynaptic differentiation in a contacting axon. This assay has led to the discovery of numerous synaptogenic proteins, but has not been used to probe neuronal mechanisms regulating presynaptic induction. The identification of regulatory pathways that fine-tune presynaptic assembly is hindered by the lack of adequate tools to quantitatively image this process. Here, we introduce an image-processing algorithm that identifies presynaptic clusters in mammalian co-cultures and extracts a range of synapse-specific parameters. Using this software, we assessed the intrinsic variability of this synaptic induction assay and probed the effect of eight neuronal microRNAs on presynaptic assembly. Our analysis revealed a novel role for miR-27b in augmenting the density of presynaptic clusters. Our software is applicable to a wide range of synaptic induction protocols (including spontaneous synaptogenesis observed in neuron cultures) and is a valuable tool to determine the subtle impact of disease-associated genes on presynaptic assembly. PMID:24624059

  19. Regulation of Synaptic Transmission by Presynaptic CaMKII and BK channels

    PubMed Central

    Wang, Zhao-Wen

    2009-01-01

    Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the BK channel are enriched at the presynaptic nerve terminal, where CaMKII associates with synaptic vesicles whereas the BK channel colocalizes with voltage-sensitive Ca2+ channels (VSCCs) in the plasma membrane. Mounting evidence suggests that these two proteins play important roles in controlling neurotransmitter release. Presynaptic BK channels primarily serve as a negative regulator of neurotransmitter release. In contrast, presynaptic CaMKII either enhances or inhibits neurotransmitter release and synaptic plasticity depending on experimental/physiological conditions and properties of specific synapses. The different functions of presynaptic CaMKII appear to be mediated by distinct downstream proteins, including the BK channel. PMID:18759010

  20. Protein tyrosine phosphatases PTPδ, PTPσ, and LAR: presynaptic hubs for synapse organization.

    PubMed

    Takahashi, Hideto; Craig, Ann Marie

    2013-09-01

    Synapse development requires differentiation of presynaptic neurotransmitter release sites and postsynaptic receptive apparatus coordinated by synapse organizing proteins. In addition to the well-characterized neurexins, recent studies identified presynaptic type IIa receptor-type protein tyrosine phosphatases (RPTPs) as mediators of presynaptic differentiation and triggers of postsynaptic differentiation, thus extending the roles of RPTPs from axon outgrowth and guidance. Similarly to neurexins, RPTPs exist in multiple isoforms generated by alternative splicing that interact in a splice-selective code with diverse postsynaptic partners. The parallel RPTP and neurexin hub design facilitates synapse self-assembly through cooperation, pairs presynaptic similarity with postsynaptic diversity, and balances excitation with inhibition. Upon mutation of individual genes in neuropsychiatric disorders, imbalance of this synaptic organizing network may contribute to impaired cognitive function.

  1. Protein tyrosine phosphatases PTPδ, PTPσ, and LAR: presynaptic hubs for synapse organization

    PubMed Central

    Takahashi, Hideto; Craig, Ann Marie

    2013-01-01

    Synapse development requires differentiation of presynaptic neurotransmitter release sites and postsynaptic receptive apparatus coordinated by synapse organizing proteins. In addition to the well-characterized neurexins, recent studies identified presynaptic type IIa receptor-type protein tyrosine phosphatases (RPTPs) as mediators of presynaptic differentiation and triggers of postsynaptic differentiation, thus extending the roles of RPTPs from axon outgrowth and guidance. Similarly to neurexins, RPTPs exist in multiple isoforms generated by alternative splicing that interact in a splice-selective code with diverse postsynaptic partners. The parallel RPTP and neurexin hub design facilitates synapse self-assembly through cooperation, pairs presynaptic similarity with postsynaptic diversity, and balances excitation with inhibition. Upon mutation of individual genes in neuropsychiatric disorders, imbalance of this synaptic organizing network may contribute to impaired cognitive function. PMID:23835198

  2. The proteasome controls presynaptic differentiation through modulation of an on-site pool of polyubiquitinated conjugates

    PubMed Central

    Pinto, Maria J.; Alves, Pedro L.; Martins, Luís; Pedro, Joana R.; Ryu, Hyun R.; Jeon, Noo Li; Taylor, Anne M.

    2016-01-01

    Differentiation of the presynaptic terminal is a complex and rapid event that normally occurs in spatially specific axonal regions distant from the soma; thus, it is believed to be dependent on intra-axonal mechanisms. However, the full nature of the local events governing presynaptic assembly remains unknown. Herein, we investigated the involvement of the ubiquitin–proteasome system (UPS), the major degradative pathway, in the local modulation of presynaptic differentiation. We found that proteasome inhibition has a synaptogenic effect on isolated axons. In addition, formation of a stable cluster of synaptic vesicles onto a postsynaptic partner occurs in parallel to an on-site decrease in proteasome degradation. Accumulation of ubiquitinated proteins at nascent sites is a local trigger for presynaptic clustering. Finally, proteasome-related ubiquitin chains (K11 and K48) function as signals for the assembly of presynaptic terminals. Collectively, we propose a new axon-intrinsic mechanism for presynaptic assembly through local UPS inhibition. Subsequent on-site accumulation of proteins in their polyubiquitinated state triggers formation of presynapses. PMID:27022091

  3. Stereoselectivity of presynaptic autoreceptors modulating dopamine release.

    PubMed

    Arbilla, S; Langer, S Z

    1981-12-17

    The effects of the (R)- and (S)-enantiomers of sulpiride and butaclamol were studied on the spontaneous and field stimulation-evoked release of total radioactivity from slices of rabbit caudate nucleus prelabelled with [3H]dopamine. (S)-Sulpiride in concentrations ranging from 0.01--1 microM enhanced the electrically evoked release of [3H]dopamine while (R)-sulpiride was 10 times less potent than (S)-sulpiride. Exposure to (S)-butaclamol (0.01--1 microM) but not to (R)-butaclamol (0.1--10 microM) enhanced the field-stimulated release of [3H]dopamine. The facilitatory effects of (S)- and (R)-sulpiride and (S)-butaclamol on the stimulated release of the labelled neurotransmitter were observed under conditions in which these drugs did not modify the spontaneous outflow of radioactivity. Only the active enantiomers of sulpiride and butaclamol antagonized the inhibition by apomorphine (1 microM) of the stimulated release of [3H]dopamine. Our results indicate that the presynaptic inhibitory dopamine autoreceptors modulating the stimulation-evoked release of [3H]dopamine in the caudate nucleus are, like the classical postsynaptic dopamine receptors, chemically stereoselective.

  4. Human immunodeficiency virus-1 protein Tat induces excitotoxic loss of presynaptic terminals in hippocampal cultures

    PubMed Central

    Shin, Angela H.; Thayer, Stanley A.

    2013-01-01

    Human Immunodeficiency Virus (HIV) infection of the CNS produces dendritic damage that correlates with cognitive decline in patients with HIV-associated neurocognitive disorders (HAND). HIV-induced neurotoxicity results in part from viral proteins shed from infected cells, including the HIV transactivator of transcription (Tat). We previously showed that Tat binds to the low density lipoprotein receptor-related protein (LRP), resulting in overactivation of NMDA receptors, activation of the ubiquitin-proteasome pathway, and subsequent loss of postsynaptic densities. Here, we show that Tat also induces a loss of presynaptic terminals. The number of presynaptic terminals was quantified using confocal imaging of synaptophysin fused to green fluorescent protein (Syn-GFP). Tat-induced loss of presynaptic terminals was secondary to excitatory postsynaptic mechanisms because treatment with an LRP antagonist or an NMDA receptor antagonist inhibited this loss. Treatment with nutlin-3, an E3 ligase inhibitor, prevented Tat-induced loss of presynaptic terminals. These data suggest that Tat-induced loss of presynaptic terminals is a consequence of excitotoxic postsynaptic activity. We previously found that ifenprodil, an NR2B subunit-selective NMDA receptor antagonist, induced recovery of postsynaptic densities. Here we show that Tat-induced loss of presynaptic terminals was reversed by ifenprodil treatment. Thus, Tat-induced loss of presynaptic terminals is reversible, and this recovery can be initiated by inhibiting a subset of postsynaptic NMDA receptors. Understanding the dynamics of synaptic changes in response to HIV infection of the CNS may lead to the design of improved pharmacotherapies for HAND patients. PMID:23267846

  5. Mechanisms underlying presynaptic Ca2+ transient and vesicular glutamate release at a CNS nerve terminal during in vitro ischaemia

    PubMed Central

    Lee, Seul Yi; Kim, Jun Hee

    2015-01-01

    ischaemia-induced increases in presynaptic Ca2+ and vesicular glutamate release. In addition, the removal of extracellular Na+ completely inhibited the ischaemia-induced Ca2+ rise. It therefore appears that a link between Na+ accumulation and Ca2+ uptake via NCX underlies the ischaemia-induced Ca2+ rise and the consequent increase in vesicular glutamate release from presynaptic terminals in the early phase of brain ischaemia. PMID:25833340

  6. Presynaptic Mechanisms of Lead Neurotoxicity: Effects on Vesicular Release, Vesicle Clustering and Mitochondria Number

    PubMed Central

    McGlothan, Jennifer L.; Stansfield, Kirstie H.; Stanton, Patric K.; Guilarte, Tomás R.

    2015-01-01

    Childhood lead (Pb2+) intoxication is a global public health problem and accounts for 0.6% of the global burden of disease associated with intellectual disabilities. Despite the recognition that childhood Pb2+ intoxication contributes significantly to intellectual disabilities, there is a fundamental lack of knowledge on presynaptic mechanisms by which Pb2+ disrupts synaptic function. In this study, using a well-characterized rodent model of developmental Pb2+ neurotoxicity, we show that Pb2+ exposure markedly inhibits presynaptic vesicular release in hippocampal Schaffer collateral-CA1 synapses in young adult rats. This effect was associated with ultrastructural changes which revealed a reduction in vesicle number in the readily releasable/docked vesicle pool, disperse vesicle clusters in the resting pool, and a reduced number of presynaptic terminals with multiple mitochondria with no change in presynaptic calcium influx. These studies provide fundamental knowledge on mechanisms by which Pb2+ produces profound inhibition of presynaptic vesicular release that contribute to deficits in synaptic plasticity and intellectual development. PMID:26011056

  7. Non-Markovian State-Dependent Networks in Critical Loading

    DTIC Science & Technology

    2013-01-23

    orthant. We give an application to generalised Jackson networks with state-dependent rates. 1. REPORT DATE (DD-MM-YYYY) 4. TITLE AND SUBTITLE 13...process is a continuous-path reflected process on the nonnegative orthant. We give an application to generalised Jackson networks with state-dependent...We give an application to generalised Jackson networks with state-dependent rates. Keywords: State-dependent networks, non-Markovian networks

  8. Presynaptic kainate receptors that enhance the release of GABA on CA1 hippocampal interneurons.

    PubMed

    Cossart, R; Tyzio, R; Dinocourt, C; Esclapez, M; Hirsch, J C; Ben-Ari, Y; Bernard, C

    2001-02-01

    We report that kainate receptors are present on presynaptic GABAergic terminals contacting interneurons and that their activation increases GABA release. Application of kainate increased the frequency of miniature inhibitory postsynaptic currents recorded in CA1 interneurons. Local applications of glutamate but not of AMPA or NMDA also increased GABA quantal release. Application of kainate as well as synaptically released glutamate reduced the number of failures of GABAergic neurotransmission between interneurons. Thus, activation of presynaptic kainate receptors increases the probability of GABA release at interneuron-interneuron synapses. Glutamate may selectively control the communication between interneurons by increasing their mutual inhibition.

  9. Presynaptic spike broadening reduces junctional potential amplitude.

    PubMed

    Spencer, A N; Przysiezniak, J; Acosta-Urquidi, J; Basarsky, T A

    1989-08-24

    Presynaptic modulation of action potential duration may regulate synaptic transmission in both vertebrates and invertebrates. Such synaptic plasticity is brought about by modifications to membrane currents at presynaptic release sites, which, in turn, lead to changes in the concentration of cytosolic calcium available for mediating transmitter release. The 'primitive' neuromuscular junction of the jellyfish Polyorchis penicillatus is a useful model of presynaptic modulation. In this study, we show that the durations of action potentials in the motor neurons of this jellyfish are negatively correlated with the amplitude of excitatory junctional potentials. We present data from in vitro voltage-clamp experiments showing that short duration voltage spikes, which elicit large excitatory junctional potentials in vivo, produce larger and briefer calcium currents than do long duration action potentials, which elicit small excitatory junctional potentials.

  10. Presynaptic active zones in invertebrates and vertebrates

    PubMed Central

    Ackermann, Frauke; Waites, Clarissa L; Garner, Craig C

    2015-01-01

    The regulated release of neurotransmitter occurs via the fusion of synaptic vesicles (SVs) at specialized regions of the presynaptic membrane called active zones (AZs). These regions are defined by a cytoskeletal matrix assembled at AZs (CAZ), which functions to direct SVs toward docking and fusion sites and supports their maturation into the readily releasable pool. In addition, CAZ proteins localize voltage-gated Ca2+ channels at SV release sites, bringing the fusion machinery in close proximity to the calcium source. Proteins of the CAZ therefore ensure that vesicle fusion is temporally and spatially organized, allowing for the precise and reliable release of neurotransmitter. Importantly, AZs are highly dynamic structures, supporting presynaptic remodeling, changes in neurotransmitter release efficacy, and thus presynaptic forms of plasticity. In this review, we discuss recent advances in the study of active zones, highlighting how the CAZ molecularly defines sites of neurotransmitter release, endocytic zones, and the integrity of synapses. PMID:26160654

  11. How Addictive Drugs Disrupt Presynaptic Dopamine Neurotransmission

    PubMed Central

    Sulzer, David

    2011-01-01

    The fundamental principle that unites addictive drugs appears to be that each enhances synaptic dopamine by means that dissociate it from normal behavioral control, so that they act to reinforce their own acquisition. This occurs via the modulation of synaptic mechanisms involved in learning, including enhanced excitation or disinhibition of dopamine neuron activity, blockade of dopamine reuptake, and altering the state of the presynaptic terminal to enhance evoked over basal transmission. Amphetamines offer an exception to such modulation in that they combine multiple effects to produce non-exocytic stimulation-independent release of neurotransmitter via reverse transport independent from normal presynaptic function. Questions on the molecular actions of addictive drugs, prominently including the actions of alcohol and solvents, remain unresolved, but their ability to co-opt normal presynaptic functions helps to explain why treatment for addiction has been challenging. PMID:21338876

  12. Presynaptic calcium currents in squid giant synapse.

    PubMed Central

    Llinás, R; Steinberg, I Z; Walton, K

    1981-01-01

    A voltage clamp study has been performed in the presynaptic terminal of the squid stellate ganglion. After blockage of the voltage-dependent sodium and potassium conductances, an inward calcium current is demonstrated. Given a step-depolarization pulse, this voltage- and time-dependent conductance has an S-shaped onset. At the "break" of the voltage step, a rapid tail current is observed. From these results a kinetic model is generated which accounts for the experimental results and predicts for the time course and amplitude a possible calcium entry during presynaptic action potentials. Images FIGURE 1 PMID:7225510

  13. State-dependent control of breathing by the retrotrapezoid nucleus

    PubMed Central

    Burke, Peter GR; Kanbar, Roy; Basting, Tyler M; Hodges, Walter M; Viar, Kenneth E; Stornetta, Ruth L; Guyenet, Patrice G

    2015-01-01

    Key points This study explores the state dependence of the hypercapnic ventilatory reflex (HCVR). We simulated an instantaneous increase or decrease of central chemoreceptor activity by activating or inhibiting the retrotrapezoid nucleus (RTN) by optogenetics in conscious rats. During quiet wake or non-REM sleep, hypercapnia increased both breathing frequency (fR) and tidal volume (VT) whereas, in REM sleep, hypercapnia increased VT exclusively. Optogenetic inhibition of RTN reduced VT in all sleep–wake states, but reduced fR only during quiet wake and non-REM sleep. RTN stimulation always increased VT but raised fR only in quiet wake and non-REM sleep. Phasic RTN stimulation produced active expiration and reduced early expiratory airflow (i.e. increased upper airway resistance) only during wake. We conclude that the HCVR is highly state-dependent. The HCVR is reduced during REM sleep because fR is no longer under chemoreceptor control and thus could explain why central sleep apnoea is less frequent in REM sleep. Abstract Breathing has different characteristics during quiet wake, non-REM or REM sleep, including variable dependence on . We investigated whether the retrotrapezoid nucleus (RTN), a proton-sensitive structure that mediates a large portion of the hypercapnic ventilatory reflex, regulates breathing differently during sleep vs. wake. Electroencephalogram, neck electromyogram, blood pressure, respiratory frequency (fR) and tidal volume (VT) were recorded in 28 conscious adult male Sprague–Dawley rats. Optogenetic stimulation of RTN with channelrhodopsin-2, or inhibition with archaerhodopsin, simulated an instantaneous increase or decrease of central chemoreceptor activity. Both opsins were delivered with PRSX8-promoter-containing lentiviral vectors. RTN and catecholaminergic neurons were transduced. During quiet wake or non-REM sleep, hypercapnia (3 or 6% ) increased both fR and VT whereas, in REM sleep, hypercapnia increased VT exclusively. RTN

  14. Presynaptic and extrasynaptic regulation of posterior nucleus of thalamus.

    PubMed

    Park, Anthony; Li, Ying; Masri, Radi; Keller, Asaf

    2017-03-22

    The posterior nucleus of thalamus (PO) is a higher-order nucleus involved in sensorimotor processing, including nociception. An important characteristic of PO is its wide range of activity profiles that vary across states of arousal, thought to underlie differences in somatosensory perception subject to attention and degree of consciousness. Further, PO loses the ability to down-regulate its activity level in some forms of chronic pain, suggesting that regulatory mechanisms underlying the normal modulation of PO activity may be pathologically altered. Yet, the mechanisms responsible for regulating such a wide dynamic range of activity are unknown. Here, we test a series of hypotheses regarding the function of several presynaptic receptors on both GABAergic and glutamatergic afferents targeting PO in mouse, using acute slice electrophysiology. We found that presynaptic GABAB receptors are present on both GABAergic and glutamatergic terminals in PO, but only those on GABAergic terminals are tonically active. We also found that release from GABAergic terminals, but not glutamatergic terminals, is suppressed by cholinergic activation, and that a subpopulation of GABAergic terminals is regulated by cannabinoids. Finally, we discovered the presence of tonic currents mediated by extrasynaptic GABAA receptors in PO that are heterogeneously distributed across the nucleus. Thus, we demonstrate that multiple regulatory mechanisms concurrently exist in PO, and we propose that regulation of inhibition, rather than excitation, is the more consequential mechanism by which PO activity can be regulated.

  15. Presynaptic modulation of Ia afferents in young and old adults when performing force and position control.

    PubMed

    Baudry, Stéphane; Maerz, Adam H; Enoka, Roger M

    2010-02-01

    The present work investigated presynaptic modulation of Ia afferents in the extensor carpi radialis (ECR) when young and old adults exerted a wrist extension force either to support an inertial load (position control) or to achieve an equivalent constant torque against a rigid restraint (force control) at 5, 10, and 15% of the maximal force. H reflexes were evoked in the ECR by stimulating the radial nerve above the elbow. A conditioning stimulus was applied to the median nerve above the elbow to assess presynaptic inhibition of homonymous Ia afferents (D1 inhibition) or at the wrist (palmar branch) to assess the ongoing presynaptic inhibition of heteronymous Ia afferents that converge onto the ECR motor neuron pool (heteronymous Ia facilitation). The young adults had less D1 inhibition and greater heteronymous Ia facilitation during the position task (79 and 132.1%, respectively) compared with the force task (69.1 and 115.1%, respectively, P < 0.05). In contrast, the old adults exhibited no difference between the two tasks for either D1 inhibition ( approximately 72%) or heteronymous Ia facilitation ( approximately 114%). Contraction intensity did not influence the amount of D1 inhibition or heteronymous Ia facilitation for either group of subjects. The amount of antagonist coactivation was similar between tasks for young adults, whereas it was greater in the position task for old adults (P = 0.02). These data indicate that in contrast to young adults, old adults did not modulate presynaptic inhibition of Ia afferents when controlling the position of a compliant load but rather increased coactivation of the antagonist muscle.

  16. Presynaptic selection of afferent inflow in the spinal cord.

    PubMed

    Rudomin, P

    1999-01-01

    The synaptic effectiveness of sensory fibers ending in the spinal cord of vertebrates can be centrally controlled by means of specific sets of GABAergic interneurons that make axo-axonic synapses with the terminal arborizations of the afferent fibers. In the steady state, the intracellular concentration of chloride ions in these terminals is higher than that predicted from a passive distribution, because of an active transport mechanism. Following the release of GABA by spinal interneurons and activation of GABA(A) receptors in the afferent terminals, there is an outwardly directed efflux of chloride ions that produces primary afferent depolarization (PAD) and reduces transmitter release (presynaptic inhibition). Studies made by intrafiber recording of PAD, or by measuring changes in the intraspinal threshold of single afferent terminals (which is reduced during PAD), have further indicated that muscle and cutaneous afferents have distinctive, but modifiable PAD patterns in response to segmental and descending stimuli. This has suggested that PAD and presynaptic inhibition in the various types of afferents is mediated by separate sets of last-order GABAergic interneurons. Direct activation, by means of intraspinal microstimulation, of single or small groups of last-order PAD-mediating interneurons shows that the monosynaptic PAD elicited in Ia and Ib afferents can remain confined to some sets of the intraspinal collaterals and not spread to nearby collaterals. The local character of PAD allows cutaneous and descending inputs to selectively inhibit the PAD of segmental and ascending intraspinal collaterals of individual muscle spindle afferents. It thus seems that the intraspinal branches of the sensory fibers are not hard wired routes that diverge excitation to spinal neurons, but are instead dynamic pathways that can be centrally controlled to address information to selected neuronal targets. This feature appears to play an important role in the selection of

  17. Presynaptic nanodomains: a tale of two synapses.

    PubMed

    Wang, Lu-Yang; Augustine, George J

    2014-01-01

    Here we summarize the evidence from two "giant" presynaptic terminals-the squid giant synapse and the mammalian calyx of Held-supporting the involvement of nanodomain calcium signals in triggering of neurotransmitter release. At the squid synapse, there are three main lines of experimental evidence for nanodomain signaling. First, changing the size of the unitary calcium channel current by altering external calcium concentration causes a non-linear change in transmitter release, while changing the number of open channels by broadening the presynaptic action potential causes a linear change in release. Second, low-affinity calcium indicators, calcium chelators, and uncaging of calcium all suggest that presynaptic calcium concentrations are as high as hundreds of micromolar, which is more compatible with a nanodomain type of calcium signal. Finally, neurotransmitter release is much less affected by the slow calcium chelator, ethylene glycol tetraacetic acid (EGTA), in comparison to the rapid chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Similarly, as the calyx of Held synapse matures, EGTA becomes less effective in attenuating transmitter release while the number of calcium channels required to trigger a single fusion event declines. This suggests a developmental transformation of microdomain to nanodomain coupling between calcium channels and transmitter release. Calcium imaging and uncaging experiments, in combination with simulations of calcium diffusion, indicate the peak calcium concentration seen by presynaptic calcium sensors reaches at least tens of micromolar at the calyx of Held. Taken together, data from these provide a compelling argument that nanodomain calcium signaling gates very rapid transmitter release.

  18. Presynaptic nanodomains: a tale of two synapses

    PubMed Central

    Wang, Lu-Yang; Augustine, George J.

    2014-01-01

    Here we summarize the evidence from two “giant” presynaptic terminals—the squid giant synapse and the mammalian calyx of Held—supporting the involvement of nanodomain calcium signals in triggering of neurotransmitter release. At the squid synapse, there are three main lines of experimental evidence for nanodomain signaling. First, changing the size of the unitary calcium channel current by altering external calcium concentration causes a non-linear change in transmitter release, while changing the number of open channels by broadening the presynaptic action potential causes a linear change in release. Second, low-affinity calcium indicators, calcium chelators, and uncaging of calcium all suggest that presynaptic calcium concentrations are as high as hundreds of micromolar, which is more compatible with a nanodomain type of calcium signal. Finally, neurotransmitter release is much less affected by the slow calcium chelator, ethylene glycol tetraacetic acid (EGTA), in comparison to the rapid chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid (BAPTA). Similarly, as the calyx of Held synapse matures, EGTA becomes less effective in attenuating transmitter release while the number of calcium channels required to trigger a single fusion event declines. This suggests a developmental transformation of microdomain to nanodomain coupling between calcium channels and transmitter release. Calcium imaging and uncaging experiments, in combination with simulations of calcium diffusion, indicate the peak calcium concentration seen by presynaptic calcium sensors reaches at least tens of micromolar at the calyx of Held. Taken together, data from these provide a compelling argument that nanodomain calcium signaling gates very rapid transmitter release. PMID:25674049

  19. Optical measurement of presynaptic calcium currents.

    PubMed Central

    Sabatini, B L; Regehr, W G

    1998-01-01

    Measurements of presynaptic calcium currents are vital to understanding the control of transmitter release. However, most presynaptic boutons in the vertebrate central nervous system are too small to allow electrical recordings of presynaptic calcium currents (I(Ca)pre). We therefore tested the possibility of measuring I(Ca)pre optically in boutons loaded with calcium-sensitive fluorophores. From a theoretical treatment of a system containing an endogenous buffer and an indicator, we determined the conditions necessary for the derivative of the stimulus-evoked change in indicator fluorescence to report I(Ca)pre accurately. Matching the calcium dissociation rates of the endogenous buffer and indicator allows the most precise optical measurements of I(Ca)pre. We tested our ability to measure I(Ca)pre in granule cells in rat cerebellar slices. The derivatives of stimulus-evoked fluorescence transients from slices loaded with the low-affinity calcium indicators magnesium green and mag-fura-5 had the same time courses and were unaffected by changes in calcium influx or indicator concentration. Thus both of these indicators were well suited to measuring I(Ca)pre. In contrast, the high-affinity indicator fura-2 distorted I(Ca)pre. The optically determined I(Ca)pre was well approximated by a Gaussian with a half-width of 650 micros at 24 degrees C and 340 micros at 34 degrees C. PMID:9512051

  20. Behavioral state-dependent thermal feedback influencing the hypothalamic thermostat.

    PubMed

    Parmeggiani, P L; Azzaroni, A; Calasso, M

    2000-11-01

    The experimental evidence on the behavioral state-dependent compartmentalization of temperature in the central nervous system of three homeothermic species has been reviewed to address the question of how selective brain cooling influences hypothalamic temperature regulation.

  1. Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism

    PubMed Central

    Mitroi, Daniel N.; Deutschmann, André U.; Raucamp, Maren; Karunakaran, Indulekha; Glebov, Konstantine; Hans, Michael; Walter, Jochen; Saba, Julie; Gräler, Markus; Ehninger, Dan; Sopova, Elena; Shupliakov, Oleg; Swandulla, Dieter; van Echten-Deckert, Gerhild

    2016-01-01

    The bioactive lipid sphingosine 1-phosphate (S1P) is a degradation product of sphingolipids that are particularly abundant in neurons. We have shown previously that neuronal S1P accumulation is toxic leading to ER-stress and an increase in intracellular calcium. To clarify the neuronal function of S1P, we generated brain-specific knockout mouse models in which S1P-lyase (SPL), the enzyme responsible for irreversible S1P cleavage was inactivated. Constitutive ablation of SPL in the brain (SPLfl/fl/Nes) but not postnatal neuronal forebrain-restricted SPL deletion (SPLfl/fl/CaMK) caused marked accumulation of S1P. Hence, altered presynaptic architecture including a significant decrease in number and density of synaptic vesicles, decreased expression of several presynaptic proteins, and impaired synaptic short term plasticity were observed in hippocampal neurons from SPLfl/fl/Nes mice. Accordingly, these mice displayed cognitive deficits. At the molecular level, an activation of the ubiquitin-proteasome system (UPS) was detected which resulted in a decreased expression of the deubiquitinating enzyme USP14 and several presynaptic proteins. Upon inhibition of proteasomal activity, USP14 levels, expression of presynaptic proteins and synaptic function were restored. These findings identify S1P metabolism as a novel player in modulating synaptic architecture and plasticity. PMID:27883090

  2. Presynaptic LTP and LTD of excitatory and inhibitory synapses.

    PubMed

    Castillo, Pablo E

    2012-02-01

    Ubiquitous forms of long-term potentiation (LTP) and depression (LTD) are caused by enduring increases or decreases in neurotransmitter release. Such forms or presynaptic plasticity are equally observed at excitatory and inhibitory synapses and the list of locations expressing presynaptic LTP and LTD continues to grow. In addition to the mechanistically distinct forms of postsynaptic plasticity, presynaptic plasticity offers a powerful means to modify neural circuits. A wide range of induction mechanisms has been identified, some of which occur entirely in the presynaptic terminal, whereas others require retrograde signaling from the postsynaptic to presynaptic terminals. In spite of this diversity of induction mechanisms, some common induction rules can be identified across synapses. Although the precise molecular mechanism underlying long-term changes in transmitter release in most cases remains unclear, increasing evidence indicates that presynaptic LTP and LTD can occur in vivo and likely mediate some forms of learning.

  3. The Proteome of the Murine Presynaptic Active Zone

    PubMed Central

    Laßek, Melanie; Weingarten, Jens; Volknandt, Walter

    2014-01-01

    The proteome of the presynaptic active zone controls neurotransmitter release and the short- and long-term structural and functional dynamics of the nerve terminal. The proteinaceous inventory of the presynaptic active zone has recently been reported. This review will evaluate the subcellular fractionation protocols and the proteomic approaches employed. A breakthrough for the identification of the proteome of the presynaptic active zone was the successful employment of antibodies directed against a cytosolic epitope of membrane integral synaptic vesicle proteins for the immunopurification of synaptic vesicles docked to the presynaptic plasma membrane. Combining immunopurification and subsequent analytical mass spectrometry, hundreds of proteins, including synaptic vesicle proteins, components of the presynaptic fusion and retrieval machinery, proteins involved in intracellular and extracellular signaling and a large variety of adhesion molecules, were identified. Numerous proteins regulating the rearrangement of the cytoskeleton are indicative of the functional and structural dynamics of the presynapse. This review will critically discuss both the experimental approaches and prominent protein candidates identified. Many proteins have not previously been assigned to the presynaptic release sites and may be directly involved in the short- and long-term structural modulation of the presynaptic compartment. The identification of proteinaceous constituents of the presynaptic active zone provides the basis for further analyzing the interaction of presynaptic proteins with their targets and opens novel insights into the functional role of these proteins in neuronal communication. PMID:28250380

  4. Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

    PubMed Central

    Johnson, Kari A.; Lovinger, David M.

    2016-01-01

    Drug abuse and addiction cause widespread social and public health problems, and the neurobiology underlying drug actions and drug use and abuse is an area of intensive research. Drugs of abuse alter synaptic transmission, and these actions contribute to acute intoxication as well as the chronic effects of abused substances. Transmission at most mammalian synapses involves neurotransmitter activation of two receptor subtypes, ligand-gated ion channels that mediate fast synaptic responses and G protein-coupled receptors (GPCRs) that have slower neuromodulatory actions. The GPCRs represent a large proportion of neurotransmitter receptors involved in almost all facets of nervous system function. In addition, these receptors are targets for many pharmacotherapeutic agents. Drugs of abuse directly or indirectly affect neuromodulation mediated by GPCRs, with important consequences for intoxication, drug taking and responses to prolonged drug exposure, withdrawal and addiction. Among the GPCRs are several subtypes involved in presynaptic inhibition, most of which are coupled to the Gi/o class of G protein. There is increasing evidence that these presynaptic Gi/o-coupled GPCRs have important roles in the actions of drugs of abuse, as well as behaviors related to these drugs. This topic will be reviewed, with particular emphasis on receptors for three neurotransmitters, Dopamine (DA; D1- and D2-like receptors), Endocannabinoids (eCBs; CB1 receptors) and glutamate (group II metabotropic glutamate (mGlu) receptors). The focus is on recent evidence from laboratory animal models (and some evidence in humans) implicating these receptors in the acute and chronic effects of numerous abused drugs, as well as in the control of drug seeking and taking. The ability of drugs targeting these receptors to modify drug seeking behavior has raised the possibility of using compounds targeting these receptors for addiction pharmacotherapy. This topic is also discussed, with emphasis on

  5. Ketamine regulates the presynaptic release machinery in the hippocampus.

    PubMed

    Müller, Heidi Kaastrup; Wegener, Gregers; Liebenberg, Nico; Zarate, Carlos A; Popoli, Maurizio; Elfving, Betina

    2013-07-01

    In the search for new drug targets, that may help point the way to develop fast-acting treatments for mood disorders, we have explored molecular pathways regulated by ketamine, an NMDA receptor antagonist, which has consistently shown antidepressant response within a few hours of administration. Using Sprague-Dawley rats we investigated the effects of ketamine on the presynaptic release machinery responsible for neurotransmitter release at 1, 2 and 4 h as well as 7 days after administration of a single subanesthetic dose of ketamine (15 mg/kg). A large reduction in the accumulation of SNARE complexes was observed in hippocampal synaptic membranes after 1, 2 and 4 h of ketamine administration. In parallel, we found a selective reduction in the expression of the synaptic vesicle protein synaptotagmin I and an increase in the levels of synapsin I in hippocampal synaptosomes suggesting a mechanism by which ketamine reduces SNARE complex formation, in part, by regulating the number of synaptic vesicles in the nerve terminals. Moreover, ketamine reduced Thr(286)-phosphorylated αCaMKII and its interaction with syntaxin 1A, which identifies CaMKII as a potential target for second messenger-mediated actions of ketamine. In addition, despite previous reports of ketamine-induced inhibition of GSK-3, we were unable to detect regulation of its activity after ketamine administration. Our findings demonstrate that ketamine rapidly induces changes in the hippocampal presynaptic machinery similar to those that are obtained only with chronic treatments with traditional antidepressants. This suggests that reduction of neurotransmitter release in the hippocampus has possible relevance for the rapid antidepressant effect of ketamine.

  6. Ketamine regulates the presynaptic release machinery in the hippocampus

    PubMed Central

    Müller, Heidi Kaastrup; Wegener, Gregers; Liebenberg, Nico; Zarate, Carlos A.; Popoli, Maurizio; Elfving, Betina

    2013-01-01

    In the search for new drug targets, that may help point the way to develop fast-acting treatments for mood disorders, we have explored molecular pathways regulated by ketamine, an NMDA receptor antagonist, which has consistently shown antidepressant response within a few hours of administration. Using Sprague-Dawley rats we investigated the effects of ketamine on the presynaptic release machinery responsible for neurotransmitter release at 1, 2 and 4 h as well as 7 days after administration of a single subanesthetic dose of ketamine (15 mg/kg). A large reduction in the accumulation of SNARE complexes was observed in hippocampal synaptic membranes after 1, 2 and 4 h of ketamine administration. In parallel, we found a selective reduction in the expression of the synaptic vesicle protein synaptotagmin I and an increase in the levels of synapsin I in hippocampal synaptosomes suggesting a mechanism by which ketamine reduces SNARE complex formation, in part, by regulating the number of synaptic vesicles in the nerve terminals. Moreover, ketamine reduced Thr286-phosphorylated αCaMKII and its interaction with syntaxin 1A, which identifies CaMKII as a potential target for second messenger-mediated actions of ketamine. In addition, despite previous reports of ketamine-induced inhibition of GSK-3, we were unable to detect regulation of its activity after ketamine administration. Our findings demonstrate that ketamine rapidly induces changes in the hippocampal presynaptic machinery similar to those that are obtained only with chronic treatments with traditional antidepressants. This suggests that reduction of neurotransmitter release in the hippocampus has possible relevance for the rapid antidepressant effect of ketamine. PMID:23548331

  7. Action potential broadening in a presynaptic channelopathy

    PubMed Central

    Begum, Rahima; Bakiri, Yamina; Volynski, Kirill E.; Kullmann, Dimitri M.

    2016-01-01

    Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca2+ influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction. PMID:27381274

  8. Action potential broadening in a presynaptic channelopathy

    NASA Astrophysics Data System (ADS)

    Begum, Rahima; Bakiri, Yamina; Volynski, Kirill E.; Kullmann, Dimitri M.

    2016-07-01

    Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca2+ influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

  9. Action potential broadening in a presynaptic channelopathy.

    PubMed

    Begum, Rahima; Bakiri, Yamina; Volynski, Kirill E; Kullmann, Dimitri M

    2016-07-06

    Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca(2+) influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

  10. [Presynaptic mechanisms of learning and memory].

    PubMed

    Yawo, Hiromu; Ishizuka, Toru

    2008-07-01

    Synaptic transmission is regulated by vesicular exocytosis and subsequent recycling at the presynaptic terminals. These vesicular dynamics were quantified by measuring the synaptop Hluorin fluorescence from individual large mossy fiber boutons in the hippocampus of a TV-42 transgenic mouse in which synaptopHluorin is specifically expressed in the mossy fiber boutons. We found that there are 2 distinct vesicle pools: a resting pool, which is resistant to exocytosis, and a releasable pool. The initially docked vesicles are easily depleted and the readily releasable pool (RRP) is replenished by the reserve subpopulation of the releasable pool ("reserve" releasable pool, RsvRP). When some of the silent synapses, which are pre-existing but are incapable of transmission, are recruited for transmission, a large number of alternative neuronal circuits are created in an off/on-switching manner. Here, we show that protein kinase C (PKC) activation facilitates presynaptic unsilencing at certain release sites, provided by the large mossy fiber boutons in the mouse hippocampus, by redirecting the synaptic vesicles from the resting pool to the RsvRP. At other sites PKC also facilitates the replenishment of the RRP from the RsvRP. Synaptic transmission was also potentiated through a mechanism involving non-PKC C1 domain-containing receptors, which would increase the size of the RRP. Thus, PKC and non-PKC mechanisms differentially reorganize vesicular dynamics and synergistically potentiate transmission.

  11. Heterogeneous reallocation of presynaptic efficacy in recurrent excitatory circuits adapting to inactivity.

    PubMed

    Mitra, Ananya; Mitra, Siddhartha S; Tsien, Richard W

    2011-12-18

    Recurrent excitatory circuits face extreme challenges in balancing efficacy and stability. We recorded from CA3 pyramidal neuron pairs in rat hippocampal slice cultures to characterize synaptic and circuit-level changes in recurrent synapses resulting from long-term inactivity. Chronic tetrodotoxin treatment greatly reduced the percentage of connected CA3-CA3 neurons, but enhanced the strength of the remaining connections; presynaptic release probability sharply increased, whereas quantal size was unaltered. Connectivity was decreased in activity-deprived circuits by functional silencing of synapses, whereas three-dimensional anatomical analysis revealed no change in spine or bouton density or aggregate dendrite length. The silencing arose from enhanced Cdk5 activity and could be reverted by acute Cdk5 inhibition with roscovitine. Our results suggest that recurrent circuits adapt to chronic inactivity by reallocating presynaptic weights heterogeneously, strengthening certain connections while silencing others. This restricts synaptic output and input, preserving signaling efficacy among a subset of neuronal ensembles while protecting network stability.

  12. Complex state-dependent games between owls and gerbils.

    PubMed

    Berger-Tal, Oded; Mukherjee, Shomen; Kotler, Burt P; Brown, Joel S

    2010-03-01

    Predator-prey interactions are often behaviourally sophisticated games in which the predator and prey are players. Past studies teach us that hungrier prey take higher risks when foraging and that hungrier predators increase their foraging activity and are willing to take higher risks of injury. Yet no study has looked at the simultaneous responses of predator and prey to their own and each other's hunger levels in a controlled environment. We looked for evidence of a state-dependent game between predators and their prey by simultaneously manipulating the hunger state of barn owls, and Allenby's gerbils as prey. The owls significantly increased their activity when hungry. However, they did not appear to respond to changes in the hunger state of the gerbils. The gerbils reacted strongly to the owls' state, as well as to their own state when the risk was perceived as high. Our study shows that predator-prey interactions give rise to a complex state-dependent game.

  13. State-dependent neutral delay equations from population dynamics.

    PubMed

    Barbarossa, M V; Hadeler, K P; Kuttler, C

    2014-10-01

    A novel class of state-dependent delay equations is derived from the balance laws of age-structured population dynamics, assuming that birth rates and death rates, as functions of age, are piece-wise constant and that the length of the juvenile phase depends on the total adult population size. The resulting class of equations includes also neutral delay equations. All these equations are very different from the standard delay equations with state-dependent delay since the balance laws require non-linear correction factors. These equations can be written as systems for two variables consisting of an ordinary differential equation (ODE) and a generalized shift, a form suitable for numerical calculations. It is shown that the neutral equation (and the corresponding ODE--shift system) is a limiting case of a system of two standard delay equations.

  14. Risk, resources and state-dependent adaptive behavioural syndromes.

    PubMed

    Luttbeg, Barney; Sih, Andrew

    2010-12-27

    Many animals exhibit behavioural syndromes-consistent individual differences in behaviour across two or more contexts or situations. Here, we present adaptive, state-dependent mathematical models for analysing issues about behavioural syndromes. We find that asset protection (where individuals with more 'assets' tend be more cautious) and starvation avoidance, two state-dependent mechanisms, can explain short-term behavioural consistency, but not long-term stable behavioural types (BTs). These negative-feedback mechanisms tend to produce convergence in state and behaviour over time. In contrast, a positive-feedback mechanism, state-dependent safety (where individuals with higher energy reserves, size, condition or vigour are better at coping with predators), can explain stable differences in personality over the long term. The relative importance of negative- and positive-feedback mechanisms in governing behavioural consistency depends on environmental conditions (predation risk and resource availability). Behavioural syndromes emerge more readily in conditions of intermediate ecological favourability (e.g. medium risk and medium resources, or high risk and resources, or low risk and resources). Under these conditions, individuals with higher initial state maintain a tendency to be bolder than individuals that start with low initial state; i.e. later BT is determined by state during an early 'developmental window'. In contrast, when conditions are highly favourable (low risk, high resources) or highly unfavourable (high risk, low resources), individuals converge to be all relatively bold or all relatively cautious, respectively. In those circumstances, initial differences in BT are not maintained over the long term, and there is no early developmental window where initial state governs later BT. The exact range of ecological conditions favouring behavioural syndromes depends also on the strength of state-dependent safety.

  15. Reconsolidation may incorporate state-dependency into previously consolidated memories.

    PubMed

    Sierra, Rodrigo O; Cassini, Lindsey F; Santana, Fabiana; Crestani, Ana P; Duran, Johanna M; Haubrich, Josué; de Oliveira Alvares, Lucas; Quillfeldt, Jorge A

    2013-06-19

    Some memories enter into a labile state after retrieval, requiring reconsolidation in order to persist. One functional role of memory reconsolidation is the updating of existing memories. There are reports suggesting that reconsolidation can be modulated by a particular endogenous process taking place concomitantly to its natural course, such as water or sleep deprivation. Here, we investigated whether an endogenous process activated during a natural/physiological experience, or a pharmacological intervention, can also contribute to memory content updating. Using the contextual fear conditioning paradigm in rats, we found that the endogenous content of an aversive memory can be updated during its reconsolidation incorporating consequences of natural events such as water deprivation, transforming a previously stored memory into a state-dependent one. This updating seems to be mediated by the activation of angiotensin AT1 receptors in the dorsal hippocampus and local infusion of human angiotensin II (ANGII) was shown to mimic the water deprivation effects on memory reconsolidation. Systemic morphine injection was also able to turn a previously acquired experience into a state-dependent memory, reproducing the very same effects obtained by water deprivation or local angiotensin II infusion, and suggesting that other state-dependent-inducing protocols would also be able to contribute to memory updating. These findings trigger new insights about the influence of ordinary daily life events upon memory in its continuing reconstruction, adding the realm of reconsolidation to the classical view of endogenous modulation of consolidation.

  16. Muscarinic presynaptic modulation in GABAergic pallidal synapses of the rat.

    PubMed

    Hernández-Martínez, Ricardo; Aceves, José J; Rueda-Orozco, Pavel E; Hernández-Flores, Teresa; Hernández-González, Omar; Tapia, Dagoberto; Galarraga, Elvira; Bargas, José

    2015-02-01

    The external globus pallidus (GPe) is central for basal ganglia processing. It expresses muscarinic cholinergic receptors and receives cholinergic afferents from the pedunculopontine nuclei (PPN) and other regions. The role of these receptors and afferents is unknown. Muscarinic M1-type receptors are expressed by synapses from striatal projection neurons (SPNs). Because axons from SPNs project to the GPe, one hypothesis is that striatopallidal GABAergic terminals may be modulated by M1 receptors. Alternatively, some M1 receptors may be postsynaptic in some pallidal neurons. Evidence of muscarinic modulation in any of these elements would suggest that cholinergic afferents from the PPN, or other sources, could modulate the function of the GPe. In this study, we show this evidence using striatopallidal slice preparations: after field stimulation in the striatum, the cholinergic muscarinic receptor agonist muscarine significantly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) from synapses that exhibited short-term synaptic facilitation. This inhibition was associated with significant increases in paired-pulse facilitation, and quantal content was proportional to IPSC amplitude. These actions were blocked by atropine, pirenzepine, and mamba toxin-7, suggesting that receptors involved were M1. In addition, we found that some pallidal neurons have functional postsynaptic M1 receptors. Moreover, some evoked IPSCs exhibited short-term depression and a different kind of modulation: they were indirectly modulated by muscarine via the activation of presynaptic cannabinoid CB1 receptors. Thus pallidal synapses presenting distinct forms of short-term plasticity were modulated differently.

  17. Presynaptic Control of Corticostriatal Synapses by Endogenous GABA

    PubMed Central

    Logie, Christopher; Bagetta, Vincenza

    2013-01-01

    Corticostriatal terminals have presynaptic GABAB receptors that limit glutamate release, but how these receptors are activated by endogenous GABA released by different types of striatal neurons is still unknown. To address this issue, we used single and paired whole-cell recordings combined with stimulation of corticostriatal fibers in rats and mice. In the presence of opioid, GABAA, and NK1 receptor antagonists, antidromic stimulation of a population of striatal projection neurons caused suppression of subsequently evoked EPSPs in projection neurons. These effects were larger at intervals of 500 ms than 1 or 2 s, and were fully blocked by the selective GABAB receptor antagonist CGP 52432. Bursts of spikes in individual projection neurons were not able to inhibit evoked EPSPs. Similarly, spikes in fast spiking interneurons and low-threshold spike interneurons failed to elicit detectable effects mediated by GABAB receptors. Conversely, spikes in individual neurogliaform interneurons suppressed evoked EPSPs, and these effects were blocked by CGP 52432. These results provide the first demonstration of how GABAB receptors are activated by endogenous GABA released by striatal neuronal types. PMID:24068811

  18. Mitochondria and plasma membrane Ca2+-ATPase control presynaptic Ca2+ clearance in capsaicin-sensitive rat sensory neurons

    PubMed Central

    Shutov, Leonid P; Kim, Man-Su; Houlihan, Patrick R; Medvedeva, Yuliya V; Usachev, Yuriy M

    2013-01-01

    The central processes of primary nociceptors form synaptic connections with the second-order nociceptive neurons located in the dorsal horn of the spinal cord. These synapses gate the flow of nociceptive information from the periphery to the CNS, and plasticity at these synapses contributes to centrally mediated hyperalgesia and allodynia. Although exocytosis and synaptic plasticity are controlled by Ca2+ at the release sites, the mechanisms underlying presynaptic Ca2+ signalling at the nociceptive synapses are not well characterized. We examined the presynaptic mechanisms regulating Ca2+ clearance following electrical stimulation in capsaicin-sensitive nociceptors using a dorsal root ganglion (DRG)/spinal cord neuron co-culture system. Cytosolic Ca2+ concentration ([Ca2+]i) recovery following electrical stimulation was well approximated by a monoexponential function with a τ∼2 s. Inhibition of sarco-endoplasmic reticulum Ca2+-ATPase did not affect presynaptic [Ca2+]i recovery, and blocking plasmalemmal Na+/Ca2+ exchange produced only a small reduction in the rate of [Ca2+]i recovery (∼12%) that was independent of intracellular K+. However, [Ca2+]i recovery in presynaptic boutons strongly depended on the plasma membrane Ca2+-ATPase (PMCA) and mitochondria that accounted for ∼47 and 40%, respectively, of presynaptic Ca2+ clearance. Measurements using a mitochondria-targeted Ca2+ indicator, mtPericam, demonstrated that presynaptic mitochondria accumulated Ca2+ in response to electrical stimulation. Quantitative analysis revealed that the mitochondrial Ca2+ uptake is highly sensitive to presynaptic [Ca2+]i elevations, and occurs at [Ca2+]i levels as low as ∼200–300 nm. Using RT-PCR, we detected expression of several putative mitochondrial Ca2+ transporters in DRG, such as MCU, Letm1 and NCLX. Collectively, this work identifies PMCA and mitochondria as the major regulators of presynaptic Ca2+ signalling at the first sensory synapse, and underlines the high

  19. Predicting Presynaptic and Postsynaptic Neurotoxins by Developing Feature Selection Technique

    PubMed Central

    Yang, Yunchun; Zhang, Chunmei; Chen, Rong; Huang, Po

    2017-01-01

    Presynaptic and postsynaptic neurotoxins are proteins which act at the presynaptic and postsynaptic membrane. Correctly predicting presynaptic and postsynaptic neurotoxins will provide important clues for drug-target discovery and drug design. In this study, we developed a theoretical method to discriminate presynaptic neurotoxins from postsynaptic neurotoxins. A strict and objective benchmark dataset was constructed to train and test our proposed model. The dipeptide composition was used to formulate neurotoxin samples. The analysis of variance (ANOVA) was proposed to find out the optimal feature set which can produce the maximum accuracy. In the jackknife cross-validation test, the overall accuracy of 94.9% was achieved. We believe that the proposed model will provide important information to study neurotoxins. PMID:28303250

  20. Effects of fast presynaptic noise in attractor neural networks.

    PubMed

    Cortes, J M; Torres, J J; Marro, J; Garrido, P L; Kappen, H J

    2006-03-01

    We study both analytically and numerically the effect of presynaptic noise on the transmission of information in attractor neural networks. The noise occurs on a very short timescale compared to that for the neuron dynamics and it produces short-time synaptic depression. This is inspired in recent neurobiological findings that show that synaptic strength may either increase or decrease on a short timescale depending on presynaptic activity. We thus describe a mechanism by which fast presynaptic noise enhances the neural network sensitivity to an external stimulus. The reason is that, in general, presynaptic noise induces nonequilibrium behavior and, consequently, the space of fixed points is qualitatively modified in such a way that the system can easily escape from the attractor. As a result, the model shows, in addition to pattern recognition, class identification and categorization, which may be relevant to the understanding of some of the brain complex tasks.

  1. Activation of presynaptic kainate receptors suppresses GABAergic synaptic transmission in the rat globus pallidus

    PubMed Central

    Jin, Xiao-Tao; Smith, Yoland

    2007-01-01

    The globus pallidus (GP) plays a central integrative role in the basal ganglia circuitry. It receives strong GABAergic inputs from the striatum and significant glutamatergic afferents from the subthalamic nucleus (STN). The change in firing rate and pattern of GP neurons is a cardinal feature of Parkinson’s disease pathophysiology. Kainate receptor GluR6/7 subunits immunoreactivity is expressed presynaptically in GABAergic striatopallidal terminals (Kane-Jackson and Smith 2003; Jin et al., 2006), which provides a substrate for regulation of GABAergic transmission in GP. To test this hypothesis, we recorded GABAA-mediated inhibitory postsynaptic currents (IPSCs) in the GP following electrical stimulation of the striatum. Following blockade of AMPA and NMDA receptors with selective antagonists, bath application of kainate (KA) (0.3–3 μM) reduced significantly the amplitude of evoked IPSCs. This inhibition was associated with a significant increase in paired-pulse facilitation ratio and a reduction of the frequency, but not amplitude, of miniature IPSCs (mIPSCs), suggesting a presynaptic site of KA action. The KA effects on striatopallidal GABAergic transmission were blocked by the G-protein inhibitor, N-ethylmaleimide (NEM), or protein kinase C (PKC) inhibitor calphostin C. Our results demonstrate that KAR activation inhibits GABAergic transmission through a presynaptic G protein-coupled, PKC-dependent metabotropic mechanism in the rat GP. These findings open up the possibility for the development of kainate-mediated pharmacotherapies aim at decreasing the excessive and abnormally regulated inhibition of GP neurons in Parkinson’s disease. PMID:17881134

  2. On the background state dependency of (palaeo) climate sensitivity

    NASA Astrophysics Data System (ADS)

    von der Heydt, Anna; Dijkstra, Henk; Köhler, Peter; van de Wal, Roderik

    2014-05-01

    The equilibrium (Charney) climate sensitivity, here indicated by Sa, is the equilibrium change in Earth's global mean surface temperature due to a radiative forcing associated with a doubling of pCO2, the atmospheric CO2 concentration. Although known for decades, little progress has been made in constraining upper and lower limits for climate sensitivity. Originally, Sa was derived from climate models where the atmospheric CO2 concentration is doubled in typically about 100 years. Also palaeo data have been frequently used to determine Sa, and - if slow feedback processes are adequately taken into account - indicate a similar range as those based on climate models used in the IPCC. However, palaeo data usually span a much larger time than the 100 year model experiments. Here, we focus on the last 800 kyr, where climate variability has occurred on time scales ranging from the 100.000-year ice-age cycles to millennial-scale climate variations. The traditional linear and equilibrium concept of climate sensitivity as is applied in typical (short time scale) climate model simulations might not apply to the climate system's non-stationary and non-linear response to changing forcing. One example is the background state dependency of the fast feedback processes. In this presentation, we assess the dependency of the fast feedback processes on the background climate state using data of the last 800 kyr and a conceptual climate model. Though still (locally) linear, we propose a different approach to estimate climate sensitivity which better accounts for a possible state dependency of the fast feedbacks. This approach uses local slopes of temperature versus radiative perturbation and is most suitable for palaeo-data spanning a range of background climate states. We find the specific climate sensitivities generally lower during cold (glacial) than during warm periods. Within the conceptual climate model we further estimate how the background state-dependency of the fast

  3. The molecular architecture of ribbon presynaptic terminals

    PubMed Central

    Zanazzi, George; Matthews, Gary

    2009-01-01

    The primary receptor neurons of the auditory, vestibular, and visual systems encode a broad range of sensory information by modulating the tonic release of the neurotransmitter glutamate in response to graded changes in membrane potential. The output synapses of these neurons are marked by structures called synaptic ribbons, which tether a pool of releasable synaptic vesicles at the active zone, where glutamate release occurs in response to calcium influx through L-type channels. Ribbons are composed primarily of the protein, RIBEYE, which is unique to ribbon synapses, but cytomatrix proteins that regulate the vesicle cycle in conventional terminals, such as Piccolo and Bassoon, also are found at ribbons. Conventional and ribbon terminals differ, however, in the size, molecular composition, and mobilization of their synaptic vesicle pools. Calcium-binding proteins and plasma-membrane calcium pumps, together with endomembrane pumps and channels, play important roles in calcium handling at ribbon synapses. Taken together, emerging evidence suggests that several molecular and cellular specializations work in concert to support the sustained exocytosis of glutamate that is a hallmark of ribbon synapses. Consistent with its functional importance, abnormalities in a variety of functional aspects of the ribbon presynaptic terminal underlie several forms of auditory neuropathy and retinopathy. PMID:19253034

  4. The structure and function of presynaptic endosomes

    SciTech Connect

    Jähne, Sebastian; Rizzoli, Silvio O.; Helm, Martin S.

    2015-07-15

    The function of endosomes and of endosome-like structures in the presynaptic compartment is still controversial. This is in part due to the absence of a consensus on definitions and markers for these compartments. Synaptic endosomes are sometimes seen as stable organelles, permanently present in the synapse. Alternatively, they are seen as short-lived intermediates in synaptic vesicle recycling, arising from the endocytosis of large vesicles from the plasma membrane, or from homotypic fusion of small vesicles. In addition, the potential function of the endosome is largely unknown in the synapse. Some groups have proposed that the endosome is involved in the sorting of synaptic vesicle proteins, albeit others have produced data that deny this possibility. In this review, we present the existing evidence for synaptic endosomes, we discuss their potential functions, and we highlight frequent technical pitfalls in the analysis of this elusive compartment. We also sketch a roadmap to definitely determine the role of synaptic endosomes for the synaptic vesicle cycle. Finally, we propose a common definition of synaptic endosome-like structures.

  5. Brain-derived neurotrophic factor controls activity-dependent maturation of CA1 synapses by downregulating tonic activation of presynaptic kainate receptors.

    PubMed

    Sallert, Marko; Rantamäki, Tomi; Vesikansa, Aino; Anthoni, Heidi; Harju, Kirsi; Yli-Kauhaluoma, Jari; Taira, Tomi; Castren, Eero; Lauri, Sari E

    2009-09-09

    Immature hippocampal synapses express presynaptic kainate receptors (KARs), which tonically inhibit glutamate release. Presynaptic maturation involves activity-dependent downregulation of the tonic KAR activity and consequent increase in release probability; however, the molecular mechanisms underlying this developmental process are unknown. Here, we have investigated whether brain derived neurotrophic factor (BDNF), a secreted protein implicated in developmental plasticity in several areas of the brain, controls presynaptic maturation by regulating KARs. Application of BDNF in neonate hippocampal slices resulted in increase in synaptic transmission that fully occluded the immature-type KAR activity in area CA1. Conversely, genetic ablation of BDNF was associated with delayed synaptic maturation and persistent presynaptic KAR activity, suggesting a role for endogenous BDNF in the developmental regulation of KAR function. In addition, our data suggests a critical role for BDNF TrkB signaling in fast activity-dependent regulation of KARs. Selective acute inhibition of TrkB receptors using a chemical-genetic approach prevented rapid change in synapse dynamics and loss of tonic KAR activity that is typically seen in response to induction of LTP at immature synapses. Together, these data show that BDNF-TrkB-dependent maturation of glutamatergic synapses is tightly associated with a loss of endogenous KAR activity. The coordinated action of these two receptor mechanisms has immediate physiological relevance in controlling presynaptic efficacy and transmission dynamics at CA3-CA1 synapses at a stage of development when functional contact already exists but transmission is weak.

  6. State-dependent μ-opioid modulation of social motivation

    PubMed Central

    Loseth, Guro E.; Ellingsen, Dan-Mikael; Leknes, Siri

    2014-01-01

    Social mammals engage in affiliative interactions both when seeking relief from negative affect and when searching for pleasure and joy. These two motivational states are both modulated by μ-opioid transmission. The μ-opioid receptor (MOR) system in the brain mediates pain relief and reward behaviors, and is implicated in social reward processing and affiliative bonding across mammalian species. However, pharmacological manipulation of the μ-opioid system has yielded opposite effects on rodents and primates: in rodents, social motivation is generally increased by MOR agonists and reduced by antagonists, whereas the opposite pattern has been shown in primates. Here, we address this paradox by taking into account differences in motivational state. We first review evidence for μ-opioid mediation of reward processing, emotion regulation, and affiliation in humans, non-human primates, rodents and other species. Based on the consistent cross-species similarities in opioid functioning, we propose a unified, state-dependent model for μ-opioid modulation of affiliation across the mammalian species. Finally, we show that this state-dependent model is supported by evidence from both rodent and primate studies, when species and age differences in social separation response are taken into account. PMID:25565999

  7. State-dependent μ-opioid modulation of social motivation.

    PubMed

    Loseth, Guro E; Ellingsen, Dan-Mikael; Leknes, Siri

    2014-01-01

    Social mammals engage in affiliative interactions both when seeking relief from negative affect and when searching for pleasure and joy. These two motivational states are both modulated by μ-opioid transmission. The μ-opioid receptor (MOR) system in the brain mediates pain relief and reward behaviors, and is implicated in social reward processing and affiliative bonding across mammalian species. However, pharmacological manipulation of the μ-opioid system has yielded opposite effects on rodents and primates: in rodents, social motivation is generally increased by MOR agonists and reduced by antagonists, whereas the opposite pattern has been shown in primates. Here, we address this paradox by taking into account differences in motivational state. We first review evidence for μ-opioid mediation of reward processing, emotion regulation, and affiliation in humans, non-human primates, rodents and other species. Based on the consistent cross-species similarities in opioid functioning, we propose a unified, state-dependent model for μ-opioid modulation of affiliation across the mammalian species. Finally, we show that this state-dependent model is supported by evidence from both rodent and primate studies, when species and age differences in social separation response are taken into account.

  8. Cross state-dependent retrieval between histamine and lithium.

    PubMed

    Zarrindast, Mohammad-Reza; Fazli-Tabaei, Soheila; Khalilzadeh, Azita; Farahmanfar, Maryam; Yahyavi, Seyed-Hossein

    2005-09-15

    Histamine and lithium state-dependent (StD) retrieval of passive avoidance task and their interactions was examined in mice. The pre-training or pre-test intracerebroventricular (i.c.v.) injection of histamine (20 microg/mouse) impaired retrieval when it was tested 24 h later. In the animals, in which retrieval was impaired due to histamine pre-training administration, pre-test administration of histamine, with the same dose, restored retrieval. The H1 blocker, pyrilamine (20 microg/mouse, i.c.v.), but not the H(2) blocker; ranitidine prevented the restoration of retrieval by pre-test histamine. The pre-training (5 and 10 mg/kg) or pre-test (5 mg/kg) injection of lithium also impaired retrieval, when it was tested 24 h later. In the animals that received lithium (5 mg/kg) or histamine (20 microg/mouse) as pre-training treatment, administration of histamine, clobenpropit or lithium, respectively, resulted in restoration of memory retrieval. Neither pyrilamine nor ranitidine prevented the restoration of retrieval by pre-test lithium. In conclusion, histamine or lithium can induce state-dependent retrieval and a cross-StD exists between these drugs, which may be mediated through the inositol pathway.

  9. Blockade of dorsal hippocampal orexin-1 receptors impaired morphine-induced state-dependent learning.

    PubMed

    Farahmandfar, Maryam; Kadivar, Mehdi; Rastipisheh, Sareh

    2016-12-01

    Behavioral abnormalities associated with opiate addiction include memory and learning deficits, which are the result of some alterations in the neuromodulatory systems. Recently, orexin has shown to influence drug addiction neural circuitry, specifically in mediating reward-related perception and memory. To explore the possible interaction of orexinergic and opioidergic system on modulation of learning and memory, we have investigated the effects of intra-dorsal hippocampal (intra-CA1) administration of orexin-1 receptor agonist and the competitive orexin-1 antagonist, SB-334867, on morphine-induced memory impairment by using step-down passive avoidance task in mice. Pre-training injection of morphine (5mg/kg, i.p.) impaired memory, which was restored when 24h later the same dose of the drug was administered. Pre-test administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) had not a significant effect on the retention latency compared to the saline-treated animals, but it restored the memory impairment induced by pre-training morphine (5mg/kg, i.p.). Pre-test administration of SB-334867 (10, 20 and 40nmol, intra-CA1) by itself decreased the retention latencies of passive avoidance task. Co-administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) and morphine (1mg/kg, i.p.) on the test day induced morphine state-dependent memory. Conversely, pre-test injection of SB-334867 (10, 20 and 40nmol, intra-CA1) inhibited the orexin-1-induced potentiation of morphine state-dependent learning on the test day. It is concluded that dorsal hippocampal orexin-1 receptors may be involved, at least in part, in morphine state-dependent learning in mice.

  10. The determination of presynaptic KA values of methacholine and pilocarpine and of a presynaptic receptor reserve in the rat perfused heart.

    PubMed Central

    Fuchs, P.; Fuder, H.

    1985-01-01

    Rat isolated perfused hearts with the right sympathetic nerves attached were loaded with [3H]-noradrenaline. The nerves were stimulated with up to 11 trains of 10 pulses at 0.1 Hz. The evoked increases of [3H]-noradrenaline overflow into the perfusate were measured in the presence of cocaine, corticosterone and propranolol. Activation of presynaptic muscarinic receptors by methacholine or pilocarpine inhibited the evoked transmitter release in a reversible and concentration-dependent manner. Preperfusion with phenoxybenzamine (5 microM) for 15 min (followed by a washout of 35 min) changed neither resting nor evoked overflow of [3H]-noradrenaline. The concentration-response curve of methacholine was shifted to the right after exposure of the hearts to phenoxybenzamine (1 microM) without depression of the maximum effect. Pretreatment with phenoxybenzamine (5 microM) reduced the maximum inhibition of release by about 50%. Analysis of the data gave a dissociation constant for the agonist-receptor complex (KA) of 4.0 microM and a receptor reserve of roughly 70%. Half-maximal inhibition of [3H]-noradrenaline release occurred when about 2% of the total receptor population was occupied. Comparison of the concentration-response data for methacholine and pilocarpine revealed a relative efficacy (methacholine/pilocarpine) of 16, a KA of 10 microM for pilocarpine and no receptor reserve for this agonist. The results show that KA values for methacholine and pilocarpine obtained at presynaptic receptors are similar to those obtained at postsynaptic muscarinic receptors. This is in agreement with the idea that muscarinic receptors located on postganglionic adrenergic nerves are not different from those located on effector sites of non-neuronal tissue. PMID:2983804

  11. Nutritional state-dependent ghrelin activation of vasopressin neurons via retrograde trans-neuronal-glial stimulation of excitatory GABA circuits.

    PubMed

    Haam, Juhee; Halmos, Katalin C; Di, Shi; Tasker, Jeffrey G

    2014-04-30

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal-glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal-glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal-glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis.

  12. Nutritional State-Dependent Ghrelin Activation of Vasopressin Neurons via Retrograde Trans-Neuronal–Glial Stimulation of Excitatory GABA Circuits

    PubMed Central

    Haam, Juhee; Halmos, Katalin C.; Di, Shi

    2014-01-01

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal–glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal–glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal–glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis. PMID:24790191

  13. State-dependent sculpting of olfactory sensory neurons is attributed to sensory enrichment, odor deprivation, and aging.

    PubMed

    Cavallin, Melissa Ann; Powell, Katelyn; Biju, K C; Fadool, Debra Ann

    2010-10-11

    Gene-targeted deletion of the predominant Shaker potassium channel, Kv1.3, in the mitral cells of the olfactory bulb, decreases the number of presynaptic, odorant receptor (OR)-identified olfactory sensory neurons (OSNs) in the main olfactory epithelium (MOE) and alters the nature of their postsynaptic connections to mitral cell targets. The current study examined whether OSN density was state-dependent by examining the impact of (1) odor enrichment, (2) sensory deprivation, and (3) aging upon the number of P2- or M72-expressing neurons. Histological approaches were used to quantify the number of OSNs across entire epithelia for wildtype (WT) vs. Kv1.3-null (KO) mice bred onto an ORtauLacZ reporter background. Following either odor enrichment or early unilateral naris-occlusion, the number of M72-expressing OSNs was significantly decreased in WT mice, but was unchanged in KO animals. Following naris-occlusion, the number of P2-expressing OSNs was decreased regardless of genotype. Animals that were reared to 2 years of age demonstrated loss of both P2- and M72-expressing OSNs in WT mice and a concomitant loss of only M72-expressing neurons in KO mice. These findings suggest that voltage-gated activity of the mitral cells is important for OSN plasticity, and can prevent neuronal loss via sensory- and OR-dependent mechanisms.

  14. Dynamic Control of Neurotransmitter Release by Presynaptic Potential

    PubMed Central

    Zbili, Mickael; Rama, Sylvain; Debanne, Dominique

    2016-01-01

    Action potentials (APs) in the mammalian brain are thought to represent the smallest unit of information transmitted by neurons to their postsynaptic targets. According to this view, neuronal signaling is all-or-none or digital. Increasing evidence suggests, however, that subthreshold changes in presynaptic membrane potential before triggering the spike also determines spike-evoked release of neurotransmitter. We discuss here how analog changes in presynaptic voltage may regulate spike-evoked release of neurotransmitter through the modulation of biophysical state of voltage-gated potassium, calcium and sodium channels in the presynaptic compartment. The contribution of this regulation has been greatly underestimated and we discuss the impact for information processing in neuronal circuits. PMID:27994539

  15. Motile axonal mitochondria contribute to the variability of presynaptic strength.

    PubMed

    Sun, Tao; Qiao, Haifa; Pan, Ping-Yue; Chen, Yanmin; Sheng, Zu-Hang

    2013-08-15

    One of the most notable characteristics of synaptic transmission is the wide variation in synaptic strength in response to identical stimulation. In hippocampal neurons, approximately one-third of axonal mitochondria are highly motile, and some dynamically pass through presynaptic boutons. This raises a fundamental question: can motile mitochondria contribute to the pulse-to-pulse variability of presynaptic strength? Recently, we identified syntaphilin as an axonal mitochondrial-docking protein. Using hippocampal neurons and slices of syntaphilin knockout mice, we demonstrate that the motility of axonal mitochondria correlates with presynaptic variability. Enhancing mitochondrial motility increases the pulse-to-pulse variability, whereas immobilizing mitochondria reduces the variability. By dual-color live imaging at single-bouton levels, we further show that motile mitochondria passing through boutons dynamically influence synaptic vesicle release, mainly by altering ATP homeostasis in axons. Thus, our study provides insight into the fundamental properties of the CNS to ensure the plasticity and reliability of synaptic transmission.

  16. Strength and precision of neurotransmission at mammalian presynaptic terminals

    PubMed Central

    TAKAHASHI, Tomoyuki

    2015-01-01

    Classically, the basic concept of chemical synaptic transmission was established at the frog neuromuscular junction, and direct intracellular recordings from presynaptic terminals at the squid giant presynaptic terminal have further clarified principles of neurotransmitter release. More recently, whole-cell patch-camp recordings from the calyx of Held in rodent brainstem slices have extended the classical concept to mammalian synapses providing new insights into the mechanisms underlying strength and precision of neurotransmission and developmental changes therein. This review summarizes findings from our laboratory and others on these subjects, mainly at the calyx of Held, with a particular focus on precise, high-fidelity, fast neurotransmission. The mechanisms by which presynaptic terminals acquire strong, precise neurotransmission during postnatal development are also discussed. PMID:26194855

  17. Roles of presynaptic NMDA receptors in neurotransmission and plasticity

    PubMed Central

    Banerjee, Abhishek; Larsen, Rylan S.; Philpot, Benjamin D.; Paulsen, Ole

    2015-01-01

    Presynaptic NMDA receptors (preNMDARs) play pivotal roles in excitatory neurotransmission and synaptic plasticity. They facilitate presynaptic neurotransmitter release and modulate mechanisms controlling synaptic maturation and plasticity during formative periods of brain development. There is an increasing understanding of the roles of preNMDARs in experience-dependent synaptic and circuit-specific computation. In this review, we summarize the latest understanding of compartment-specific expression and function of preNMDARs, and how they contribute to synapse-specific and circuit-level information processing. PMID:26726120

  18. Presynaptic glutamate receptors: physiological functions and mechanisms of action.

    PubMed

    Pinheiro, Paulo S; Mulle, Christophe

    2008-06-01

    Glutamate acts on postsynaptic glutamate receptors to mediate excitatory communication between neurons. The discovery that additional presynaptic glutamate receptors can modulate neurotransmitter release has added complexity to the way we view glutamatergic synaptic transmission. Here we review evidence of a physiological role for presynaptic glutamate receptors in neurotransmitter release. We compare the physiological roles of ionotropic and metabotropic glutamate receptors in short- and long-term regulation of synaptic transmission. Furthermore, we discuss the physiological conditions that are necessary for their activation, the source of the glutamate that activates them, their mechanisms of action and their involvement in higher brain function.

  19. Rate and state dependent seismicity during fluid injection in rocks

    NASA Astrophysics Data System (ADS)

    Wenzel, Friedemann

    2014-05-01

    Dieterich (1994) developed a theoretical frame of seismicity evolution from a background seismicity due to stress changes in a medium. The theory assumes a volume density of seismic faults with a specific initial slip velocity distribution upon which the stress changes act. Each fault then follows the rate and state dependent frictional law where instabilities develop, but not as Coulomb failure. The evolution is expressed in the form of a differntial equation, which can be adapted for the case of fluid pressure changes resulting from injection and even linearized to allow for analytic insight into the properties of the solution. For a constant injection rate the seismic activity increases at a given distance from the injection point once the pressure exceeds a threshold value. If the presusure rate is high enough the seismic activity becomes proportional to the pressure rate in accordance with criticality theory of Shapiro (2002). Once the rate drops the seismicity reduced to lower levels. Shut off and variable injection rates must be evaluated numerically but lead to results comparable to the criticality theory. The presentation outlines the physical concept of the rate and state approach in comparison to the criticality approach and shows the main analytic and numerical results.

  20. Noise-induced transitions in state-dependent dichotomous processes.

    PubMed

    Laio, Francesco; Ridolfi, Luca; D'Odorico, Paolo

    2008-09-01

    In a number of stochastic systems the random forcing is represented as a dichotomous Markov noise. A common characteristic of these models is that the noise is usually supposed to be independent of the state of the forced dynamical system. However, there are several situations in which positive or negative feedback exist between the system and the random driver. This paper investigates a class of systems characterized by feedback between dichotomous Markov noise and the system's dynamics. The effect of the feedback is accounted for through a state dependency in the transition rates of the dichotomous noise. We study noise-induced transitions in these systems, with special attention to the delicate problem of correctly defining the deterministic counterpart of the stochastic system. We find that (i) if in the absence of any feedback the dynamical system has a single deterministic stable point, the deterministic dynamics remain monostable when a negative feedback is introduced, while they may become bistable in the presence of a positive feedback. (ii) Noise may induce bistability in the presence of a null or negative feedback. (iii) Bistable deterministic dynamics, induced by the positive feedback, may be destroyed by the noise, which tends to stabilize the system around a new intermediate stable state between those of the deterministic dynamics.

  1. State-dependent inactivation of the Kv3 potassium channel.

    PubMed Central

    Marom, S; Levitan, I B

    1994-01-01

    Inactivation of Kv3 (Kv1.3) delayed rectifier potassium channels was studied in the Xenopus oocyte expression system. These channels inactivate slowly during a long depolarizing pulse. In addition, inactivation accumulates in response to a series of short depolarizing pulses (cumulative inactivation), although no significant inactivation occurs within each short pulse. The extent of cumulative inactivation does not depend on the voltage during the depolarizing pulse, but it does vary in a biphasic manner as a function of the interpulse duration. Furthermore, the rate of cumulative inactivation is influenced by changing the rate of deactivation. These data are consistent with a model in which Kv3 channel inactivation is a state-dependent and voltage-independent process. Macroscopic and single channel experiments indicate that inactivation can occur from a closed (silent) state before channel opening. That is, channels need not open to inactivate. The transition that leads to the inactivated state from the silent state is, in fact, severalfold faster then the observed inactivation of current during long depolarizing pulses. Long pulse-induced inactivation appears to be slow, because its rate is limited by the probability that channels are in the open state, rather than in the silent state from which they can inactivate. External potassium and external calcium ions alter the rates of cumulative and long pulse-induced inactivation, suggesting that antagonistic potassium and calcium binding steps are involved in the normal gating of the channel. PMID:7948675

  2. The ecological rationality of state-dependent valuation.

    PubMed

    McNamara, J M; Trimmer, P C; Houston, A I

    2012-01-01

    Laboratory studies on a range of animals have identified a bias that seems to violate basic principles of rational behavior: a preference is shown for feeding options that previously provided food when reserves were low, even though another option had been found to give the same reward with less delay. The bias presents a challenge to normative models of decision making (which only take account of expected rewards and the state of the animal at the decision time). To understand the behavior, we take a broad ecological perspective and consider how valuation mechanisms evolve when the best action depends upon the environment being faced. We show that in a changing and uncertain environment, state-dependent valuation can be favored by natural selection: Individuals should allow their hunger to affect learning for future decisions. The valuation mechanism that typically evolves produces the kind of behavior seen in standard laboratory tests. By providing an insight into why learning should be affected by the state of an individual, we provide a basis for understanding psychological principles in terms of an animal's ecology.

  3. Control of Autophagosome Axonal Retrograde Flux by Presynaptic Activity Unveiled Using Botulinum Neurotoxin Type A

    PubMed Central

    Wang, Tong; Martin, Sally; Papadopulos, Andreas; Harper, Callista B.; Mavlyutov, Timur A.; Niranjan, Dhevahi; Glass, Nick R.; Cooper-White, Justin J.; Sibarita, Jean-Baptiste; Choquet, Daniel; Davletov, Bazbek; Meunier, Frédéric A.

    2015-01-01

    Botulinum neurotoxin type A (BoNT/A) is a highly potent neurotoxin that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. However, recent evidence suggests that the neurotoxic activity of BoNT/A is not restricted to the periphery, but also reaches the CNS after retrograde axonal transport. Because BoNT/A is internalized in recycling synaptic vesicles, it is unclear which compartment facilitates this transport. Using live-cell confocal and single-molecule imaging of rat hippocampal neurons cultured in microfluidic devices, we show that the activity-dependent uptake of the binding domain of the BoNT/A heavy chain (BoNT/A-Hc) is followed by a delayed increase in retrograde axonal transport of BoNT/A-Hc carriers. Consistent with a role of presynaptic activity in initiating transport of the active toxin, activity-dependent uptake of BoNT/A in the terminal led to a significant increase in SNAP25 cleavage detected in the soma chamber compared with nonstimulated neurons. Surprisingly, most endocytosed BoNT/A-Hc was incorporated into LC3-positive autophagosomes generated in the nerve terminals, which then underwent retrograde transport to the cell soma, where they fused with lysosomes both in vitro and in vivo. Blocking autophagosome formation or acidification with wortmannin or bafilomycin A1, respectively, inhibited the activity-dependent retrograde trafficking of BoNT/A-Hc. Our data demonstrate that both the presynaptic formation of autophagosomes and the initiation of their retrograde trafficking are tightly regulated by presynaptic activity. PMID:25878289

  4. Presynaptic α7 Nicotinic Acetylcholine Receptors Enhance Hippocampal Mossy Fiber Glutamatergic Transmission via PKA Activation

    PubMed Central

    Cheng, Qing

    2014-01-01

    Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory. However, the mechanism of nicotine's action on cognitive function remains elusive. We performed patch-clamp recordings from hippocampal CA3 pyramidal neurons to determine the effect of nicotine on mossy fiber glutamatergic synaptic transmission. We found that nicotine in combination with NS1738, an α7 nAChR-positive allosteric modulator, strongly potentiated the amplitude of evoked EPSCs (eEPSCs), and reduced the EPSC paired-pulse ratio. The action of nicotine and NS1738 was mimicked by PNU-282987 (an α7 nAChR agonist), and was absent in α7 nAChR knock-out mice. These data indicate that activation of α7 nAChRs was both necessary and sufficient to enhance the amplitude of eEPSCs. BAPTA applied postsynaptically failed to block the action of nicotine and NS1738, suggesting again a presynaptic action of the α7 nAChRs. We also observed α7 nAChR-mediated calcium rises at mossy fiber giant terminals, indicating the presence of functional α7 nAChRs at presynaptic terminals. Furthermore, the addition of PNU-282987 enhanced action potential-dependent calcium transient at these terminals. Last, the potentiating effect of PNU-282987 on eEPSCs was abolished by inhibition of protein kinase A (PKA). Our findings indicate that activation of α7 nAChRs at presynaptic sites, via a mechanism involving PKA, plays a critical role in enhancing synaptic efficiency of hippocampal mossy fiber transmission. PMID:24381273

  5. [Presynaptic histamine H3-receptors exist on cardiac sympathetic terminals of guinea pig].

    PubMed

    Luo, X X

    1995-07-01

    This is the first time to report the existence of new presynaptic inhibitory autoreceptors--histamine H3-receptors in guinea pig myocardium. We found that (R)-alpha-methylhistamine (alpha-MeHA), a selective histamine H3-receptor agonist, attenuates the sympathetic inotropic response of isolated guinea pig atria elicited by electrical field stimulation. This inhibition was associated with a marked reduction in endogenous norepinephrine release. The above phenomenon was antagonised by selective histamine H3-receptor antagonists, and inhibited by pretreatment with N ethylmeleimide. The cardiac sympathetic response could be attenuated or facilitated by increase or decrease of endogenous histamine. Our findings indicate that the endogenous histamine might be involved in the modulation of cardiac sympathetic neurotransmission by interacting with histamine H3-receptors and the receptors are probably coupled to a G(o)/Gi protein.

  6. Ethanol potentiation of GABAergic synaptic transmission may be self-limiting: role of presynaptic GABA(B) receptors.

    PubMed

    Ariwodola, Olusegun J; Weiner, Jeffrey L

    2004-11-24

    Ethanol enhances GABAergic synaptic inhibition, and this interaction contributes to many of the behavioral and cognitive effects of this drug. Most studies suggest that ethanol enhances GABAergic neurotransmission via an allosteric potentiation of the postsynaptic GABA(A) receptors that mediate fast synaptic inhibition in the mammalian CNS. Despite widespread acceptance of this hypothesis, direct support for such a mechanism has been difficult to obtain. Ethanol does not enhance GABA(A) receptor function in all brain regions or under all experimental conditions, and factors responsible for this variability remain mostly unknown. Notably, blockade of GABA(B) receptors dramatically enhances ethanol potentiation of hippocampal GABA(A) IPSPs and IPSCs, suggesting that some unknown GABA(B) receptor mechanism limits the overall potentiating effect of ethanol on GABAergic synapses. In this study, we demonstrate that, at perisomatic synapses in the rat hippocampus, ethanol enhances presynaptic GABA(B) autoreceptor function and that this interaction reduces the overall potentiating effect of ethanol at these synapses. We further show that ethanol significantly elevates basal presynaptic GABA(B) receptor tone, possibly via an increase in spontaneous GABA release, and that pretreatment with a subthreshold concentration of the GABA(B) receptor agonist baclofen blocks ethanol but not flunitrazepam or pentobarbital potentiation of GABA(A) IPSCs. These data suggest that an interaction between ethanol and presynaptic GABA(B) autoreceptor activity regulates the ethanol sensitivity of GABAergic synapses. Given that the in vitro ethanol sensitivity of these synapses correlates with in vivo ethanol responsiveness in a number of rodent lines, our data further suggest that presynaptic GABA(B) receptor activity may play a role in regulating behavioral sensitivity to ethanol.

  7. Number sense and state-dependent valuation in cuttlefish.

    PubMed

    Yang, Tsang-I; Chiao, Chuan-Chin

    2016-08-31

    Identifying the amount of prey available is an important part of an animal's foraging behaviour. The risk-sensitive foraging theory predicts that an organism's foraging decisions with regard to food rewards depending upon its satiation level. However, the precise interaction between optimal risk-tolerance and satiation level remains unclear. In this study, we examined, firstly, whether cuttlefish, with one of the most highly evolved nervous system among the invertebrates, have number sense, and secondly, whether their valuation of food reward is satiation state dependent. When food such as live shrimps is present, without training, cuttlefish turn toward the prey and initiate seizure behaviour. Using this visual attack behaviour as a measure, cuttlefish showed a preference for a larger quantity when faced with two-alternative forced choice tasks (1 versus 2, 2 versus 3, 3 versus 4 and 4 versus 5). However, cuttlefish preferred the small quantity when the choice was between one live and two dead shrimps. More importantly, when the choice was between one large live shrimp and two small live shrimps (a prey size and quantity trade-off), the cuttlefish chose the large single shrimp when they felt hunger, but chose the two smaller prey when they were satiated. These results demonstrate that cuttlefish are capable of number discrimination and that their choice of prey number depends on the quality of the prey and on their appetite state. The findings also suggest that cuttlefish integrate both internal and external information when making a foraging decision and that the cost of obtaining food is inversely correlated with their satiation level, a phenomenon similar to the observation that metabolic state alters economic decision making under risk among humans.

  8. Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

    PubMed Central

    Letellier, Mathieu; Park, Yun Kyung; Chater, Thomas E.; Chipman, Peter H.; Gautam, Sunita Ghimire; Oshima-Takago, Tomoko; Goda, Yukiko

    2016-01-01

    Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-d-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca2+ signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca2+ channels. Intracellular infusion of NMDARs or Ca2+-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocyte-dependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites. PMID:27118849

  9. State-dependent trapping of flecainide in the cardiac sodium channel

    PubMed Central

    Ramos, Eugene; O'Leary, Michael E

    2004-01-01

    Flecainide is a Class I antiarrhythmic drug and a potent inhibitor of the cardiac (Nav1.5) sodium channel. Although the flecainide inhibition of Nav1.5 is typically enhanced by depolarization, the contributions of the open and inactivated states to flecainide binding and inhibition remain controversial. We further investigated the state-dependent binding of flecainide by examining its inhibition of rapidly inactivating and non-inactivating mutants of Nav1.5 expressed in Xenopus oocytes. Applying flecainide while briefly depolarizing from a relatively negative holding potential resulted in a low-affinity inhibition of the channel (IC50 = 345 μm). Increasing the frequency of stimulation potentiated the flecainide inhibition (IC50 = 7.4 μm), which progressively increased over the range of voltages where Nav1.5 channels activated. This contrasts with sustained depolarizations that effectively stabilize the channels in inactivated states, which failed to promote significant flecainide inhibition. The voltage sensitivity and strong dependence of the flecainide inhibition on repetitive depolarization suggests that flecainide binding is facilitated by channel opening and that the drug does not directly bind to closed or inactivated channels. The binding of flecainide to open channels was further investigated in a non-inactivating mutant of Nav1.5. Flecainide produced a time-dependent decay in the current of the non-inactivating mutant that displayed kinetics consistent with a simple pore blocking mechanism (KD = 11 μm). At hyperpolarized voltages, flecainide slowed the recovery of both the rapidly inactivating (τ = 81 ± 3 s) and non-inactivating (τ = 42 ± 3 s) channels. Mutation of a conserved isoleucine of the D4S6 segment (I1756C) creates an alternative pathway that permits the rapid diffusion of anaesthetics out of the Nav1.5 channel. The I1756C mutation accelerated the recovery of both the rapidly inactivating (τ = 12.6 ± 0.4 s) and non-inactivating (τ = 7

  10. Cytosolic calcium coordinates mitochondrial energy metabolism with presynaptic activity.

    PubMed

    Chouhan, Amit K; Ivannikov, Maxim V; Lu, Zhongmin; Sugimori, Mutsuyuki; Llinas, Rodolfo R; Macleod, Gregory T

    2012-01-25

    Most neurons fire in bursts, imposing episodic energy demands, but how these demands are coordinated with oxidative phosphorylation is still unknown. Here, using fluorescence imaging techniques on presynaptic termini of Drosophila motor neurons (MNs), we show that mitochondrial matrix pH (pHm), inner membrane potential (Δψm), and NAD(P)H levels ([NAD(P)H]m) increase within seconds of nerve stimulation. The elevations of pHm, Δψm, and [NAD(P)H]m indicate an increased capacity for ATP production. Elevations in pHm were blocked by manipulations that blocked mitochondrial Ca2+ uptake, including replacement of extracellular Ca2+ with Sr2+ and application of either tetraphenylphosphonium chloride or KB-R7943, indicating that it is Ca2+ that stimulates presynaptic mitochondrial energy metabolism. To place this phenomenon within the context of endogenous neuronal activity, the firing rates of a number of individually identified MNs were determined during fictive locomotion. Surprisingly, although endogenous firing rates are significantly different, there was little difference in presynaptic cytosolic Ca2+ levels ([Ca2+]c) between MNs when each fires at its endogenous rate. The average [Ca2+]c level (329±11 nM) was slightly above the average Ca2+ affinity of the mitochondria (281±13 nM). In summary, we show that when MNs fire at endogenous rates, [Ca2+]c is driven into a range where mitochondria rapidly acquire Ca2+. As we also show that Ca2+ stimulates presynaptic mitochondrial energy metabolism, we conclude that [Ca2+]c levels play an integral role in coordinating mitochondrial energy metabolism with presynaptic activity in Drosophila MNs.

  11. Cytosolic Calcium Coordinates Mitochondrial Energy Metabolism with Presynaptic Activity

    PubMed Central

    Chouhan, Amit K.; Ivannikov, Maxim V.; Lu, Zhongmin; Sugimori, Mutsuyuki; Llinas, Rodolfo R.; Macleod, Gregory T.

    2012-01-01

    Most neurons fire in bursts, imposing episodic energy demands, but how these demands are coordinated with oxidative phosphorylation is still unknown. Here, using fluorescence imaging techniques on presynaptic termini of Drosophila motor neurons (MNs), we show that mitochondrial matrix pH (pHm), inner membrane potential (Δψm), and NAD(P)H levels ([NAD(P)H]m) increase within seconds of nerve stimulation. The elevations of pHm, Δψm, and [NAD(P)H]m indicate an increased capacity for ATP production. Elevations in pHm were blocked by manipulations which blocked mitochondrial Ca2+ uptake, including replacement of extracellular Ca2+ with Sr2+, and application of either tetraphenylphosphonium chloride or KB-R7943, indicating that it is Ca2+ that stimulates presynaptic mitochondrial energy metabolism. To place this phenomenon within the context of endogenous neuronal activity, the firing rates of a number of individually identified MNs were determined during fictive locomotion. Surprisingly, although endogenous firing rates are significantly different, there was little difference in presynaptic cytosolic Ca2+ levels ([Ca2+]c) between MNs when each fires at its endogenous rate. The average [Ca2+]c level (329±11nM) was slightly above the average Ca2+ affinity of the mitochondria (281±13nM). In summary, we show that when MNs fire at endogenous rates [Ca2+]c is driven into a range where mitochondria rapidly acquire Ca2+. As we also show that Ca2+ stimulates presynaptic mitochondrial energy metabolism, we conclude that [Ca2+]c levels play an integral role in coordinating mitochondrial energy metabolism with presynaptic activity in Drosophila MNs. PMID:22279208

  12. State dependence of climate sensitivity and its implications

    NASA Astrophysics Data System (ADS)

    Allen, M.; Knutti, R.; Stone, D.; Frame, D.

    2007-12-01

    It has long been noted (Senior and Mitchell, 2000; Boer and Yu, 2004) that the climate sensitivity of global climate models evolves over time, changing by up to +/-20% in long runs following stabilization of greenhouse forcing. We explore the magnitude and origins of this effect in the ensemble of global coupled models contributed to the IPCC AR4 ensemble. Two possible parameterizations of this effect are discussed, the first in which the net feedback parameter, λ, depends on the degree to which global temperature is out of equilibrium and the second in which λ simply depends simply on global temperature itself. We show that the second parameterization provides a generally better fit to the GCMs' output and explore its implications for recent attempts to constrain long-term climate sensitivity using recent observed climate change. The possibility of an uncertain temperature- dependence of λ has even more profound implications for efforts to constrain climate sensitivity using the last glacial maximum, but this is not the focus of this talk. The possibility of state-dependent feedbacks is a further nail in the coffin of attempts to provide a useful, objectively constrained, upper bound on the long-term equilibrium response to stabilization of atmospheric greenhouse gases at any currently conceivable level. We note, however, that this does not preclude our use of observations to constrain equally policy-relevant quantities, such as the familiar transient climate response, or TCR, the equivalent carbon dioxide concentration consistent with a two degree warming, or C2K, or the transient warming commitment, or TWC. The TWC is the maximum warming we expect to result from a linear ramp increase in radiative forcing followed by a linear decrease: at current values of the atmospheric airborne fraction for carbon dioxide, this is approximately equivalent to the forcing that would result from a complete cessation of emissions at any given time. Although this is not a

  13. Enhanced nitric oxide production during lead (Pb²⁺) exposure recovers protein expression but not presynaptic localization of synaptic proteins in developing hippocampal neurons.

    PubMed

    Neal, April P; Stansfield, Kirstie H; Guilarte, Tomás R

    2012-02-23

    We have previously reported that lead (Pb(2+)) exposure results in both presynaptic and postsynaptic changes in developing neurons as a result of inhibition of the N-methyl-d-aspartate receptor (NMDAR). NMDAR inhibition by Pb(2+) during synaptogenesis disrupts downstream trans-synaptic signaling of brain-derived neurotrophic factor (BDNF) and exogenous addition of BDNF can recover the effects of Pb(2+) on both presynaptic protein expression and presynaptic vesicular release. NMDAR activity can modulate other trans-synaptic signaling pathways, such as nitric oxide (NO) signaling. Thus, it is possible that other trans-synaptic pathways in addition to BDNF signaling may be disrupted by Pb(2+) exposure. The current study investigated whether exogenous addition of NO could recover the presynaptic vesicular proteins lost as a result of Pb(2+) exposure during synaptogenesis, namely Synaptophysin (Syn) and Synaptobrevin (Syb). We observed that exogenous addition of NO during Pb(2+) exposure results in complete recovery of whole-cell Syn levels and partial recovery of Syn and Syb synaptic targeting in Pb(2+)-exposed neurons.

  14. State-Dependent Function of Neocortical Chandelier Cells

    PubMed Central

    Woodruff, Alan R.; McGarry, Laura M.; Vogels, Tim P.; Inan, Melis; Anderson, Stewart A.; Yuste, Rafael

    2013-01-01

    Chandelier (axoaxonic) cells (ChCs) are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells. However, their circuit role and the function of their clearly defined anatomical specificity remain unclear. Recent work has demonstrated that chandelier cells can produce depolarizing GABAergic PSPs, occasionally driving postsynaptic targets to spike. On the other hand, other work suggests that ChCs are hyperpolarizing and may have an inhibitory role. These disparate functional effects may reflect heterogeneity among ChCs. Here, using brain slices from transgenic mouse strains, we first demonstrate that, across different neocortical areas and genetic backgrounds, upper Layer 2/3 ChCs belong to a single electrophysiologically and morphologically defined population, extensively sampling Layer 1 inputs with asymmetric dendrites. Consistent with being a single cell type, we find electrical coupling between ChCs. We then investigate the effect of chandelier cell activation on pyramidal neuron spiking in several conditions, ranging from the resting membrane potential to stimuli designed to approximate in vivo membrane potential dynamics. We find that under quiescent conditions, chandelier cells are capable of both promoting and inhibiting spike generation, depending on the postsynaptic membrane potential. However, during in vivo-like membrane potential fluctuations, the dominant postsynaptic effect was a strong inhibition. Thus, neocortical chandelier cells, even from within a homogeneous population, appear to play a dual role in the circuit, helping to activate quiescent pyramidal neurons, while at the same time inhibiting active ones. PMID:22159102

  15. Neural Control of the Upper Airway: Respiratory and State-Dependent Mechanisms

    PubMed Central

    Kubin, Leszek

    2017-01-01

    Upper airway muscles subserve many essential for survival orofacial behaviors, including their important role as accessory respiratory muscles. In the face of certain predisposition of craniofacial anatomy, both tonic and phasic inspiratory activation of upper airway muscles is necessary to protect the upper airway against collapse. This protective action is adequate during wakefulness, but fails during sleep which results in recurrent episodes of hypopneas and apneas, a condition known as the obstructive sleep apnea syndrome (OSA). Although OSA is almost exclusively a human disorder, animal models help unveil the basic principles governing the impact of sleep on breathing and upper airway muscle activity. This article discusses the neuroanatomy, neurochemistry, and neurophysiology of the different neuronal systems whose activity changes with sleep-wake states, such as the noradrenergic, serotonergic, cholinergic, orexinergic, histaminergic, GABAergic and glycinergic, and their impact on central respiratory neurons and upper airway motoneurons. Observations of the interactions between sleep-wake states and upper airway muscles in healthy humans and OSA patients are related to findings from animal models with normal upper airway, and various animal models of OSA, including the chronic-intermittent hypoxia model. Using a framework of upper airway motoneurons being under concurrent influence of central respiratory, reflex and state-dependent inputs, different neurotransmitters, and neuropeptides are considered as either causing a sleep-dependent withdrawal of excitation from motoneurons or mediating an active, sleep-related inhibition of motoneurons. Information about the neurochemistry of state-dependent control of upper airway muscles accumulated to date reveals fundamental principles and may help understand and treat OSA. PMID:27783860

  16. High-resolution structure of the presynaptic RAD51 filament on single-stranded DNA by electron cryo-microscopy

    PubMed Central

    Short, Judith M.; Liu, Yang; Chen, Shaoxia; Soni, Neelesh; Madhusudhan, Mallur S.; Shivji, Mahmud K.K.; Venkitaraman, Ashok R.

    2016-01-01

    Homologous DNA recombination (HR) by the RAD51 recombinase enables error-free DNA break repair. To execute HR, RAD51 first forms a presynaptic filament on single-stranded (ss) DNA, which catalyses pairing with homologous double-stranded (ds) DNA. Here, we report a structure for the presynaptic human RAD51 filament at 3.5–5.0Å resolution using electron cryo-microscopy. RAD51 encases ssDNA in a helical filament of 103Å pitch, comprising 6.4 protomers per turn, with a rise of 16.1Å and a twist of 56.2°. Inter-protomer distance correlates with rotation of an α-helical region in the core catalytic domain that is juxtaposed to ssDNA, suggesting how the RAD51–DNA interaction modulates protomer spacing and filament pitch. We map Fanconi anaemia-like disease-associated RAD51 mutations, clarifying potential phenotypes. We predict binding sites on the presynaptic filament for two modules present in each BRC repeat of the BRCA2 tumour suppressor, a critical HR mediator. Structural modelling suggests that changes in filament pitch mask or expose one binding site with filament-inhibitory potential, rationalizing the paradoxical ability of the BRC repeats to either stabilize or inhibit filament formation at different steps during HR. Collectively, our findings provide fresh insight into the structural mechanism of HR and its dysregulation in human disease. PMID:27596592

  17. MicroRNA-22 Gates Long-Term Heterosynaptic Plasticity in Aplysia through Presynaptic Regulation of CPEB and Downstream Targets.

    PubMed

    Fiumara, Ferdinando; Rajasethupathy, Priyamvada; Antonov, Igor; Kosmidis, Stylianos; Sossin, Wayne S; Kandel, Eric R

    2015-06-30

    The maintenance phase of memory-related long-term facilitation (LTF) of synapses between sensory and motor neurons of the gill-withdrawal reflex of Aplysia depends on a serotonin (5-HT)-triggered presynaptic upregulation of CPEB, a functional prion that regulates local protein synthesis at the synapse. The mechanisms whereby serotonin regulates CPEB levels in presynaptic sensory neurons are not known. Here, we describe a sensory neuron-specific microRNA 22 (miR-22) that has multiple binding sites on the mRNA of CPEB and inhibits it in the basal state. Serotonin triggers MAPK/Erk-dependent downregulation of miR-22, thereby upregulating the expression of CPEB, which in turn regulates, through functional CPE elements, the presynaptic expression of atypical PKC (aPKC), another candidate regulator of memory maintenance. Our findings support a model in which the neurotransmitter-triggered downregulation of miR-22 coordinates the regulation of genes contributing synergistically to the long-term maintenance of memory-related synaptic plasticity.

  18. Use-dependent control of presynaptic calcium signalling at central synapses

    PubMed Central

    Scott, Ricardo

    2007-01-01

    Voltage-gated Ca2+ channels activated by action potentials evoke Ca2+ entry into presynaptic terminals thus briefly distorting the resting Ca2+ concentration. When this happens, a number of processes are initiated to re-establish the Ca2+ equilibrium. During the post-spike period, the increased Ca2+ concentration could enhance the presynaptic Ca2+ signalling. Some of the mechanisms contributing to presynaptic Ca2+ dynamics involve endogenous Ca2+ buffers, Ca2+ stores, mitochondria, the sodium–calcium exchanger, extraterminal Ca2+ depletion and presynaptic receptors. Additionally, subthreshold presynaptic depolarization has been proposed to have an effect on release of neurotransmitters through a mechanism involving changes in resting Ca2+. Direct evidence for the role of any of these participants in shaping the presynaptic Ca2+ dynamics comes from direct recordings of giant presynaptic terminals and from fluorescent Ca2+ imaging of axonal boutons. Here, some of this evidence is presented and discussed. PMID:17523936

  19. Presynaptic α4β2 nicotinic acetylcholine receptors increase glutamate release and serotonin neuron excitability in the dorsal raphe nucleus.

    PubMed

    Garduño, Julieta; Galindo-Charles, Luis; Jiménez-Rodríguez, Javier; Galarraga, Elvira; Tapia, Dagoberto; Mihailescu, Stefan; Hernandez-Lopez, Salvador

    2012-10-24

    Several behavioral effects of nicotine are mediated by changes in serotonin (5-HT) release in brain areas that receive serotonergic afferents from the dorsal raphe nucleus (DRN). In vitro experiments have demonstrated that nicotine increases the firing activity in the majority of DRN 5-HT neurons and that DRN contains nicotinic acetylcholine receptors (nAChRs) located at both somata and presynaptic elements. One of the most common presynaptic effects of nicotine is to increase glutamate release. Although DRN receives profuse glutamatergic afferents, the effect of nicotine on glutamate release in the DRN has not been studied in detail. Using whole-cell recording techniques, we investigated the effects of nicotine on the glutamatergic input to 5-HT DRN neurons in rat midbrain slices. Low nicotine concentrations, in the presence of bicuculline and tetrodotoxin (TTX), increased the frequency but did not change the amplitude of glutamate-induced EPSCs, recorded from identified 5-HT neurons. Nicotine-induced increase of glutamatergic EPSC frequency persisted 10-20 min after drug withdrawal. This nicotinic effect was mimicked by exogenous administration of acetylcholine (ACh) or inhibition of ACh metabolism. In addition, the nicotine-induced increase in EPSC frequency was abolished by blockade of α4β2 nAChRs, voltage-gated calcium channels, or intracellular calcium signaling but not by α7 nAChR antagonists. These data suggest that both nicotine and endogenous ACh can increase glutamate release through activation of presynaptic α4β2 but not α7 nAChRs in the DRN. The effect involves long-term changes in synaptic function, and it is dependent on voltage-gated calcium channels and presynaptic calcium stores.

  20. Organization and dynamics of SNARE proteins in the presynaptic membrane

    PubMed Central

    Milovanovic, Dragomir; Jahn, Reinhard

    2015-01-01

    Our view of the lateral organization of lipids and proteins in the plasma membrane has evolved substantially in the last few decades. It is widely accepted that many, if not all, plasma membrane proteins and lipids are organized in specific domains. These domains vary widely in size, composition, and stability, and they represent platforms governing diverse cell functions. The presynaptic plasma membrane is a well-studied example of a membrane which undergoes rearrangements, especially during exo- and endocytosis. Many proteins and lipids involved in presynaptic function are known, and major efforts have been made to understand their spatial organization and dynamics. Here, we focus on the mechanisms underlying the organization of SNAREs, the key proteins of the fusion machinery, in distinct domains, and we discuss the functional significance of these clusters. PMID:25852575

  1. Advances in imaging ultrastructure yield new insights into presynaptic biology

    PubMed Central

    Bruckner, Joseph J.; Zhan, Hong; O’Connor-Giles, Kate M.

    2015-01-01

    Synapses are the fundamental functional units of neural circuits, and their dysregulation has been implicated in diverse neurological disorders. At presynaptic terminals, neurotransmitter-filled synaptic vesicles are released in response to calcium influx through voltage-gated calcium channels activated by the arrival of an action potential. Decades of electrophysiological, biochemical, and genetic studies have contributed to a growing understanding of presynaptic biology. Imaging studies are yielding new insights into how synapses are organized to carry out their critical functions. The development of techniques for rapid immobilization and preservation of neuronal tissues for electron microscopy (EM) has led to a new renaissance in ultrastructural imaging that is rapidly advancing our understanding of synapse structure and function. PMID:26052269

  2. Protocadherin 17 regulates presynaptic assembly in topographic corticobasal Ganglia circuits.

    PubMed

    Hoshina, Naosuke; Tanimura, Asami; Yamasaki, Miwako; Inoue, Takeshi; Fukabori, Ryoji; Kuroda, Teiko; Yokoyama, Kazumasa; Tezuka, Tohru; Sagara, Hiroshi; Hirano, Shinji; Kiyonari, Hiroshi; Takada, Masahiko; Kobayashi, Kazuto; Watanabe, Masahiko; Kano, Masanobu; Nakazawa, Takanobu; Yamamoto, Tadashi

    2013-06-05

    Highly topographic organization of neural circuits exists for the regulation of various brain functions in corticobasal ganglia circuits. Although neural circuit-specific refinement during synapse development is essential for the execution of particular neural functions, the molecular and cellular mechanisms for synapse refinement are largely unknown. Here, we show that protocadherin 17 (PCDH17), one of the nonclustered δ2-protocadherin family members, is enriched along corticobasal ganglia synapses in a zone-specific manner during synaptogenesis and regulates presynaptic assembly in these synapses. PCDH17 deficiency in mice causes facilitated presynaptic vesicle accumulation and enhanced synaptic transmission efficacy in corticobasal ganglia circuits. Furthermore, PCDH17(-/-) mice exhibit antidepressant-like phenotypes that are known to be regulated by corticobasal ganglia circuits. Our findings demonstrate a critical role for PCDH17 in the synaptic development of specific corticobasal ganglia circuits and suggest the involvement of PCDH17 in such circuits in depressive behaviors.

  3. Presynaptic glycine receptors on GABAergic terminals facilitate discharge of dopaminergic neurons in ventral tegmental area.

    PubMed

    Ye, Jiang-Hong; Wang, Fushun; Krnjevic, Kresimir; Wang, Weizhen; Xiong, Zhi-Gang; Zhang, Jingli

    2004-10-13

    GABA-mediated postsynaptic currents (IPSCs) were recorded from dopaminergic (DA) neurons of the ventral tegmental area (VTA) of rats, in acute brain slices, and from enzymatically or mechanically dissociated neurons. In young rats (3-10 d of age), where GABA is excitatory, glycine (1-3 microm) and taurine (10-30 microm) increased the amplitude of evoked IPSCs (eIPSCs) and the frequency of spontaneous IPSCs (sIPSCs) but had minimal postsynaptic effects. Strychnine (1 microm) blocked the action of glycine; when applied alone, it reduced the amplitude of eIPSCs and the frequency of sIPSCs, indicating a tonic facilitation of GABAergic excitation by some endogenous glycine agonist(s). In medium containing no Ca2+, or with Cd2+ or tetrodotoxin added, the amplitude and especially the frequency of sIPSCs greatly diminished. In many cells, glycine had no effect on remaining miniature IPSCs, suggesting a preterminal site of glycine receptors (GlyRs). Fura-2 fluorescent imaging showed a glycine-induced increase of [Ca2+] in nerve terminals (on DA neurons), which was suppressed by strychnine or 3 microm omega-conotoxin MVIIA. Therefore, the presynaptic GlyR-mediated facilitation of GABAergic transmission seems to be mediated by N- and/or P/Q-type Ca2+ channels. In older rats (22-30 d of age), where GABA causes inhibition, the effect of strychnine on GABAergic IPSCs was reversed to facilitation, indicating a tonic glycinergic inhibition of GABA release. Furthermore, glycine (1-3 microm) reduced the amplitude of eIPSCs and the frequency of sIPSCs. Hence, the overall effect of the presynaptic action of glycine is to enhance the firing of DA cells, both in very young and older rats.

  4. Modulation by presynaptic beta-adrenoceptors of noradrenaline release from sympathetic nerves in human dental pulp.

    PubMed

    Parker, D A; Marino, V; Ivar, P M; de la Lande, I S

    1998-12-01

    This study was undertaken to test for the presence of presynaptic beta-adrenoceptors on sympathetic nerves in human dental pulp and, if present, to investigate the subtype. Pulp was excised from freshly extracted teeth, incubated with [3H]-noradrenaline (0.6 micromol/l) and subsequently superfused with Krebs solution. Sympathetic nerves were stimulated at 5 Hz for 100 sec. The non-specific beta-adrenoceptor agonist isoprenaline (1.0 micromol/l), and the selective beta2-agonist salbutamol (10 micromol/l) facilitated the release of [3H]-noradrenaline; isoprenaline, but not salbutamol, also facilitated this release in the presence of desipramine (DMI, 0.3 micromol/l), corticosterone (10 micromol/l) and rauwolscine (0.1 micromol/l). BRL 37344 (1.0 micromol/l), a beta3-agonist, had no effect on [3H]-noradrenaline release. The facilitatory effects of isoprenaline and salbutamol were inhibited by the non-specific beta-antagonist propranolol (1.0 micromol/l), while that of salbutamol was inhibited in the presence of ICI-188,551 (1.0 micromol/l), a selective beta2-antagonist, as well. The beta1-antagonist atenolol (1.0 micromol/l) potentiated the facilitatory effects of isoprenaline in the presence of DMI and corticosterone. Neither propranolol nor ICI-188,551 alone affected the release of [3H]-noradrenaline. These results establish the presence of presynaptic beta-adrenoceptors on sympathetic nerves in human dental pulp. It is suggested that they are of the beta2-subtype, although a greater range of agonists and antagonists needs to be used to clarify the nature of the the beta-adrenoceptors.

  5. Actions of Acute and Chronic Ethanol on Presynaptic Terminals

    PubMed Central

    Roberto, Marisa; Treistman, Steven N.; Pietrzykowski, Andrzej Z.; Weiner, Jeff; Galindo, Rafael; Mameli, Manuel; Valenzuela, Fernando; Zhu, Ping Jun; Lovinger, David; Zhang, Tao A.; Hendricson, Adam H.; Morrisett, Richard; Siggins, George Robert

    2014-01-01

    This article presents the proceedings of a symposium entitled “The Tipsy Terminal: Presynaptic Effects of Ethanol” (held at the annual meeting of the Research Society on Alcoholism, in Santa Barbara, CA, June 27, 2005). The objective of this symposium was to focus on a cellular site of ethanol action underrepresented in the alcohol literature, but quickly becoming a “hot” topic. The chairs of the session were Marisa Roberto and George Robert Siggins. Our speakers were chosen on the basis of the diverse electrophysiological and other methods used to discern the effects of acute and chronic ethanol on presynaptic terminals and on the basis of significant insights that their data provide for understanding ethanol actions on neurons in general, as mechanisms underlying problematic behavioral effects of alcohol. The 5 presenters drew from their recent studies examining the effects of acute and chronic ethanol using a range of sophisticated methods from electrophysiological analysis of paired-pulse facilitation and spontaneous and miniature synaptic currents (Drs. Weiner, Valenzuela, Zhu, and Morrisett), to direct recording of ion channel activity and peptide release from acutely isolated synaptic terminals (Dr. Treistman), to direct microscopic observation of vesicular release (Dr. Morrisett). They showed that ethanol administration could both increase and decrease the probability of release of different transmitters from synaptic terminals. The effects of ethanol on synaptic terminals could often be correlated with important behavioral or developmental actions of alcohol. These and other novel findings suggest that future analyses of synaptic effects of ethanol should attempt to ascertain, in multiple brain regions, the role of presynaptic terminals, relevant presynaptic receptors and signal transduction linkages, exocytotic mechanisms, and their involvement in alcohol’s behavioral actions. Such studies could lead to new treatment strategies for alcohol

  6. Citalopram antagonizes the stimulation by lysergic acid diethylamide of presynaptic inhibitory serotonin autoreceptors in the rat hypothalamus.

    PubMed

    Langer, S Z; Moret, C

    1982-07-01

    Slices of rat hypothalamus prelabeled with [3H]-5-hydroxytryptamine ([3H]-5-HT) were superfused and the release of the labeled transmitter was elicited either by electrical stimulation or by fenfluramine. Whereas the electrically stimulated release of [3H]-5-HT was completely abolished by removing calcium from the superfusion medium, the fenfluramine-induced release of [3H]-5-HT was calcium-independent. Methiothepin increased, in a concentration-dependent manner, the [3H]-5-HT release induced by electrical stimulation but had no effect on that elicited by fenfluramine. The 3H-transmitter release elicited by electrical stimulation was inhibited by lysergic acid diethylamide (LSD) in a concentration-dependent manner, but the release induced by fenfluramine was not modified by LSD. The reduction by LSD of [3H]-5-HT overflow elicited by electrical stimulation was antagonized by methiothepin, but unaffected by phentolamine or by sulpiride. Low concentrations (10-1000 nM) of citalopram, a 5-HT uptake inhibitor, antagonized the inhibition by LSD of electrically evoked release of [3H]-5-HT. These concentrations of citalopram did not modify by themselves the overflow of [3H]-5-HT elicited by electrical stimulation. It is concluded that the modulation of [3H]-5-HT release by presynaptic serotonin autoreceptors is not operational when the neurotransmitter is released through a calcium-independent mechanism. The potent presynaptic inhibition by LSD of serotonergic neurotransmission may contribute to the central actions of this drug. The interaction between citalopram and LSD at the level of [3H]-5-HT release does not seem to involve a competitive interaction at the same receptor site. The possibility that neuronal uptake of 5-HT and the presynaptic 5-HT autoreceptor may be linked in a functional manner cannot be excluded.

  7. Dendritic position is a major determinant of presynaptic strength

    PubMed Central

    de Jong, Arthur P.H.; Schmitz, Sabine K.; Toonen, Ruud F.G.

    2012-01-01

    Different regulatory principles influence synaptic coupling between neurons, including positional principles. In dendrites of pyramidal neurons, postsynaptic sensitivity depends on synapse location, with distal synapses having the highest gain. In this paper, we investigate whether similar rules exist for presynaptic terminals in mixed networks of pyramidal and dentate gyrus (DG) neurons. Unexpectedly, distal synapses had the lowest staining intensities for vesicular proteins vGlut, vGAT, Synaptotagmin, and VAMP and for many nonvesicular proteins, including Bassoon, Munc18, and Syntaxin. Concomitantly, distal synapses displayed less vesicle release upon stimulation. This dependence of presynaptic strength on dendritic position persisted after chronically blocking action potential firing and postsynaptic receptors but was markedly reduced on DG dendrites compared with pyramidal dendrites. These data reveal a novel rule, independent of neuronal activity, which regulates presynaptic strength according to dendritic position, with the strongest terminals closest to the soma. This gradient is opposite to postsynaptic gradients observed in pyramidal dendrites, and different cell types apply this rule to a different extent. PMID:22492722

  8. Dendritic position is a major determinant of presynaptic strength.

    PubMed

    de Jong, Arthur P H; Schmitz, Sabine K; Toonen, Ruud F G; Verhage, Matthijs

    2012-04-16

    Different regulatory principles influence synaptic coupling between neurons, including positional principles. In dendrites of pyramidal neurons, postsynaptic sensitivity depends on synapse location, with distal synapses having the highest gain. In this paper, we investigate whether similar rules exist for presynaptic terminals in mixed networks of pyramidal and dentate gyrus (DG) neurons. Unexpectedly, distal synapses had the lowest staining intensities for vesicular proteins vGlut, vGAT, Synaptotagmin, and VAMP and for many nonvesicular proteins, including Bassoon, Munc18, and Syntaxin. Concomitantly, distal synapses displayed less vesicle release upon stimulation. This dependence of presynaptic strength on dendritic position persisted after chronically blocking action potential firing and postsynaptic receptors but was markedly reduced on DG dendrites compared with pyramidal dendrites. These data reveal a novel rule, independent of neuronal activity, which regulates presynaptic strength according to dendritic position, with the strongest terminals closest to the soma. This gradient is opposite to postsynaptic gradients observed in pyramidal dendrites, and different cell types apply this rule to a different extent.

  9. A Role for Presynaptic alpha(sub 2)-Adrenoceptors in Angiotensin 2-Induced Drinking in Rats

    NASA Technical Reports Server (NTRS)

    Fregly, Melvin J.; Rowland, Neil E.; Greenleaf, John E.

    1984-01-01

    Studies from this laboratory have shown that either central or peripheral administration of clonidine, the alpha(sub 2)-adrenoceptor agonist, can attenuate a variety of dipsogenic stimuli in rats. Further, yohimbine and tolazoline, alpha(sub 2)-adrenoceptor antagonists, augment the drinking response to both peripherally administered isoproterenol and angiotensin 2. Studies reported here establish a dose-inhibition relationship between the dose of clonidine administered (2 to 32 micrograms/kg) intracerebroventricularly (IVT) and inhibition of the drinking response to peripherally administered angiotensin 2 (200 micrograms/kg, SC). DI(sub 50) was approximately 4 micrograms/kg. Yohimbine (300 micrograms/kg, SC) reversed the antidipsogenic effect of centrally administered clonidine (32 micrograms/kg, IVT) on angiotensin 2-induced (200 micrograms/kg, SC) water intake. Phenylephrine, an alpha(sub 2)-adrenoceptor agonist, administered IVT (40 and 80 micrograms/kg) also inhibited angiotensin 2-induced drinking in a dose-related fashion. The antidipsogenic effect of phenylephfine (80 micrograms/kg) was blocked by administration of yohimbine (100 micrograms/kg, SC). Thus, this effect of phenylephrine most likely occurs by way of alpha(sub 2)- adrenoceptors. These results support a role for the pre-synaptic alpha(sub 2)-adrenoceptor in the mediation of drinking in rats. Activation of alpha(sub 2)-adrenoceptors is accompanied by reduced water intake while inhibition of these receptors enhances water intake.

  10. The Role of Brain-Derived Neurotrophic Factor Receptors in the Mature Hippocampus: Modulation of Long-Term Potentiation through a Presynaptic Mechanism involving TrkB

    PubMed Central

    Xu, Baoji; Gottschalk, Wolfram; Chow, Ana; Wilson, Rachel I.; Schnell, Eric; Zang, Keling; Wang, Denan; Nicoll, Roger A.; Lu, Bai; Reichardt, Louis F.

    2009-01-01

    The neurotrophin BDNF has been shown to modulate long-term potentiation (LTP) at Schaffer collateral-CA1 hippocampal synapses. Mutants in the BDNF receptor gene trkB and antibodies to its second receptor p75NTR have been used to determine the receptors and cells involved in this response. Inhibition of p75NTR does not detectably reduce LTP or affect presynaptic function, but analyses of newly generated trkB mutants implicate TrkB. One mutant has reduced expression in a normal pattern of TrkB throughout the brain. The second mutant was created by cre-loxP-mediated removal of TrkB in CA1 pyramidal neurons of this mouse. Neither mutant detectably impacts survival or morphology of hippocampal neurons. TrkB reduction, however, affects presynaptic function and reduces the ability of tetanic stimulation to induce LTP. Postsynaptic glutamate receptors are not affected by TrkB reduction, indicating that BDNF does not modulate plasticity through postsynaptic TrkB. Consistent with this, elimination of TrkB in postsynaptic neurons does not affect LTP. Moreover, normal LTP is generated in the mutant with reduced TrkB by a depolarization–low-frequency stimulation pairing protocol that puts minimal demands on presynaptic terminal function. Thus, BDNF appears to act through TrkB presynaptically, but not postsynaptically, to modulate LTP. PMID:10995833

  11. The Alzheimer's β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques.

    PubMed

    Kandalepas, Patty C; Sadleir, Katherine R; Eimer, William A; Zhao, Jie; Nicholson, Daniel A; Vassar, Robert

    2013-09-01

    β-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the β-secretase that initiates Aβ production in Alzheimer's disease (AD). BACE1 levels are increased in AD, which could contribute to pathogenesis, yet the mechanism of BACE1 elevation is unclear. Furthermore, the normal function of BACE1 is poorly understood. We localized BACE1 in the brain at both the light and electron microscopic levels to gain insight into normal and pathophysiologic roles of BACE1 in health and AD, respectively. Our findings provide the first ultrastructural evidence that BACE1 localizes to vesicles (likely endosomes) in normal hippocampal mossy fiber terminals of both non-transgenic and APP transgenic (5XFAD) mouse brains. In some instances, BACE1-positive vesicles were located near active zones, implying a function for BACE1 at the synapse. In addition, BACE1 accumulated in swollen dystrophic autophagosome-poor presynaptic terminals surrounding amyloid plaques in 5XFAD cortex and hippocampus. Importantly, accumulations of BACE1 and APP co-localized in presynaptic dystrophies, implying increased BACE1 processing of APP in peri-plaque regions. In primary cortical neuron cultures, treatment with the lysosomal protease inhibitor leupeptin caused BACE1 levels to increase; however, exposure of neurons to the autophagy inducer trehalose did not reduce BACE1 levels. This suggests that BACE1 is degraded by lysosomes but not by autophagy. Our results imply that BACE1 elevation in AD could be linked to decreased lysosomal degradation of BACE1 within dystrophic presynaptic terminals. Elevated BACE1 and APP levels in plaque-associated presynaptic dystrophies could increase local peri-plaque Aβ generation and accelerate amyloid plaque growth in AD.

  12. Nesfatin-1 modulates murine gastric vagal afferent mechanosensitivity in a nutritional state dependent manner.

    PubMed

    Kentish, Stephen J; Li, Hui; Frisby, Claudine L; Page, Amanda J

    2017-03-01

    Food intake is regulated by vagal afferent signals from the stomach. Nesfatin-1 is an anorexigenic peptide produced within the gastrointestinal tract and has well defined central effects. We aimed to determine if nesfatin-1 can modulate gastric vagal afferent signals in the periphery and further whether this is altered in different nutritional states. Female C57BL/6J mice were fed either a standard laboratory diet (SLD) or a high fat diet (HFD) for 12 weeks or fasted overnight. Plasma nucleobindin-2 (NUCB2; nesfatin-1 precursor)/nesfatin-1 levels were assayed, the expression of NUCB2 in the gastric mucosa and adipose tissue was assessed using real-time quantitative reverse-transcription polymerase chain reaction. An in vitro preparation was used to determine the effect of nesfatin-1 on gastric vagal afferent mechanosensitivity. HFD mice exhibited an increased body weight and adiposity. Plasma NUCB2/nesfatin-1 levels were unchanged between any of the groups of mice. NUCB2 mRNA was detected in the gastric mucosa and gonadal fat of SLD, HFD and fasted mice with no difference in mRNA abundance between groups in either tissue. In SLD and fasted mice nesfatin-1 potentiated mucosal receptor mechanosensitivity, an effect not observed in HFD mice. Tension receptor mechanosensitivity was unaffected by nesfatin-1 in SLD and fasted mice, but was inhibited in HFD mice. In conclusion, Nesfatin-1 modulates gastric vagal afferent mechanosensitivity in a nutritional state dependent manner.

  13. LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

    PubMed Central

    Wang, Weiwei; Townes-Anderson, Ellen

    2015-01-01

    Purpose Rod photoreceptors retract their axon terminals and develop neuritic sprouts in response to retinal detachment and reattachment, respectively. This study examines the role of LIM kinase (LIMK), a component of RhoA and Rac pathways, in the presynaptic structural remodeling of rod photoreceptors. Methods Phosphorylated LIMK (p-LIMK), the active form of LIMK, was examined in salamander retina with Western blot and confocal microscopy. Axon length within the first 7 hours and process growth after 3 days of culture were assessed in isolated rod photoreceptors treated with inhibitors of upstream regulators ROCK and p21-activated kinase (Pak) (Y27632 and IPA-3) and a direct LIMK inhibitor (BMS-5). Porcine retinal explants were also treated with BMS-5 and analyzed 24 hours after detachment. Because Ca2+ influx contributes to axonal retraction, L-type channels were blocked in some experiments with nicardipine. Results Phosphorylated LIMK is present in rod terminals during retraction and in newly formed processes. Axonal retraction over 7 hours was significantly reduced by inhibition of LIMK or its regulators, ROCK and Pak. Process growth was reduced by LIMK or Pak inhibition especially at the basal (axon-bearing) region of the rod cells. Combining Ca2+ channel and LIMK inhibition had no additional effect on retraction but did further inhibit sprouting after 3 days. In detached porcine retina, LIMK inhibition reduced rod axonal retraction and improved retinal morphology. Conclusions Thus structural remodeling, in the form of either axonal retraction or neuritic growth, requires LIMK activity. LIM kinase inhibition may have therapeutic potential for reducing pathologic rod terminal plasticity after retinal injury. PMID:26658506

  14. Salvinorin A exerts opposite presynaptic controls on neurotransmitter exocytosis from mouse brain nerve terminals.

    PubMed

    Grilli, Massimo; Neri, Elisa; Zappettini, Stefania; Massa, Francesca; Bisio, Angela; Romussi, Giovanni; Marchi, Mario; Pittaluga, Anna

    2009-01-01

    We investigated the effects of salvinorin A on the basal and the 12 mM K(+)-evoked release of preloaded [(3)H]noradenaline ([(3)H]NA) and [(3)H]serotonin ([(3)H]5-HT) from mouse hippocampal nerve terminals (synaptosomes), as well as on the basal and 12mM K(+)-evoked release of preloaded [(3)H]dopamine ([(3)H]DA) from mouse striatal and prefrontal cortex (PFc) synaptosomes. Salvinorin A (0.1-1000 nM) failed to affect the basal release of amines, but inhibited the 12 mM K(+)-evoked, Ca(2+)-dependent, exocytotic-like release of [(3)H]5-HT and [(3)H]DA. At the same concentration, salvinorin A facilitated the 12 mM K(+)-evoked, Ca(2+)-dependent, exocytotic-like release of [(3)H]NA. These effects could not be observed in pertussis toxin (PTx) entrapped synaptosomes. The broad spectrum kappa-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 1-100 nM) antagonized the inhibition of [(3)H]5-HT and [(3)H]DA exocytosis as well as the facilitation of [(3)H]NA overflow induced by 100 nM salvinorin A. The KOR agonist U69593 (1-100 nM) mimicked salvinorin A in inhibiting [(3)H]5-HT and of [(3)H]DA exocytosis, its effect being prevented by norBNI, but leaving unchanged the K(+)-evoked release of [(3)H]NA. The effects of Salvinorin A on neurotransmitter exocytosis were not prevented by the selective mu opioid (MOR) receptor antagonist CTAP (10-100 nM), whereas facilitation of [(3)H]NA exocytosis, but not inhibition of [(3)H]5-HT and [(3)H]DA K(+)-evoked release, was counteracted by the delta opioid receptor (DOR) antagonist naltrindole (1-100 nM). We conclude that salvinorin A presynaptically modulates central NA, 5-HT, and DA exocytosis evoked by a mild depolarizing stimulus by acting at presynaptic opioid receptors having different pharmacological profiles.

  15. Amyloid-β Oligomers Interact with Neurexin and Diminish Neurexin-mediated Excitatory Presynaptic Organization

    PubMed Central

    Naito, Yusuke; Tanabe, Yuko; Lee, Alfred Kihoon; Hamel, Edith; Takahashi, Hideto

    2017-01-01

    Alzheimer’s disease (AD) is characterized by excessive production and deposition of amyloid-beta (Aβ) proteins as well as synapse dysfunction and loss. While soluble Aβ oligomers (AβOs) have deleterious effects on synapse function and reduce synapse number, the underlying molecular mechanisms are not well understood. Here we screened synaptic organizer proteins for cell-surface interaction with AβOs and identified a novel interaction between neurexins (NRXs) and AβOs. AβOs bind to NRXs via the N-terminal histidine-rich domain (HRD) of β-NRX1/2/3 and alternatively-spliced inserts at splicing site 4 of NRX1/2. In artificial synapse-formation assays, AβOs diminish excitatory presynaptic differentiation induced by NRX-interacting proteins including neuroligin1/2 (NLG1/2) and the leucine-rich repeat transmembrane protein LRRTM2. Although AβOs do not interfere with the binding of NRX1β to NLG1 or LRRTM2, time-lapse imaging revealed that AβO treatment reduces surface expression of NRX1β on axons and that this reduction depends on the NRX1β HRD. In transgenic mice expressing mutated human amyloid precursor protein, synaptic expression of β-NRXs, but not α-NRXs, decreases. Thus our data indicate that AβOs interact with NRXs and that this interaction inhibits NRX-mediated presynaptic differentiation by reducing surface expression of axonal β-NRXs, providing molecular and mechanistic insights into how AβOs lead to synaptic pathology in AD. PMID:28211900

  16. Temporal variations in presynaptic release probability in the lateral habenula

    PubMed Central

    Park, Hoyong; Cheon, Myunghyun; Kim, Sungmin; Chung, ChiHye

    2017-01-01

    Rhythmicity plays an important role in a number of biological systems. The habenular complex is reported to contain an intrinsic molecular clock and to show rhythmic expression of circadian clock genes and proteins including per2/PER2. In this study, we observed that there is a temporal rhythmicity in the presynaptic efficacy of the lateral habenula (LHb) neurons. We collected a substantial number of recordings at different time points of the day during the light phase. The frequency and amplitude of spontaneous excitatory transmission were increased in the afternoon compared to recordings performed in the morning. In addition, the paired-pulse ratio and the success rate of minimal stimulation were also significantly different depending on the time of the recording. We did not see any significant differences in recordings obtained from pyramidal neurons of the hippocampus in the same brain slices. Taken together, our data indicates that the LHb exhibits intrinsic temporal oscillation in basal neurotransmission and in presynaptic release probability. Given the rapidly growing interest on the function of the LHb, more careful examination of synaptic transmission in the LHb is thus required. PMID:28106159

  17. The importance of presynaptic beta receptors in Raynaud's disease.

    PubMed

    Brotzu, G; Falchi, S; Mannu, B; Montisci, R; Petruzzo, P; Staico, R

    1989-06-01

    The purpose of the present study was to investigate the effect of atenolol, a beta 1-selective blocker, along with flunarizine, a calcium antagonist, in the management of Raynaud's disease. Forty patients with Raynaud's disease were randomized into a trial in which atenolol (50 mg daily) was given with flunarizine (10 mg daily). During the trial all patients were subjected to finger photoplethysmography and were given a diary to note daily the number and duration of the crises and presence or absence of pain and paresthesia. The association of atenolol with flunarizine caused an 80% reduction in the number of vasospastic crises, a significant increase (p less than 0.001) in the photoplethysmographic wave amplitude, and complete disappearance of pain and paresthesia. These results were not observed in patients treated with a placebo. Flunarizine reinforces the action of atenolol in causing a decrease in vasoconstriction in patients with Raynaud's disease, as observed previously by us, in that it acts directly on the beta-presynaptic receptors or on the calcium slow channels connected to the beta-receptors. The present study confirms that the principal role in the physiopathologic progression of Raynaud's disease seems to be played by a modification of the beta-presynaptic receptors in the nerve endings of the peripheral vessels.

  18. Does human presynaptic striatal dopamine function predict social conformity?

    PubMed

    Stokes, Paul R A; Benecke, Aaf; Puraite, Julita; Bloomfield, Michael A P; Shotbolt, Paul; Reeves, Suzanne J; Lingford-Hughes, Anne R; Howes, Oliver; Egerton, Alice

    2014-03-01

    Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D₂/₃ receptor availability. This may reflect an association between SDR and D₂/₃ receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [¹⁸F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [¹⁸F]-DOPA uptake, (k(i)(cer), min⁻¹), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [¹⁸F]-DOPA k(i)(cer). These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D₂/₃ receptor expression rather than with synaptic dopamine levels.

  19. SNAP-25, a Known Presynaptic Protein with Emerging Postsynaptic Functions

    PubMed Central

    Antonucci, Flavia; Corradini, Irene; Fossati, Giuliana; Tomasoni, Romana; Menna, Elisabetta; Matteoli, Michela

    2016-01-01

    A hallmark of synaptic specializations is their dependence on highly organized complexes of proteins that interact with each other. The loss or modification of key synaptic proteins directly affects the properties of such networks, ultimately impacting synaptic function. SNAP-25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis, and, by directly interacting with different calcium channels subunits, it negatively modulates neuronal voltage-gated calcium channels, thus regulating intracellular calcium dynamics. The SNAP-25 gene has been associated with distinct brain diseases, including Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia and bipolar disorder, indicating that the protein may act as a shared biological substrate among different “synaptopathies”. The mechanisms by which alterations in SNAP-25 may concur to these psychiatric diseases are still undefined, although alterations in neurotransmitter release have been indicated as potential causative processes. This review summarizes recent work showing that SNAP-25 not only controls exo/endocytic processes at the presynaptic terminal, but also regulates postsynaptic receptor trafficking, spine morphogenesis, and plasticity, thus opening the possibility that SNAP-25 defects may contribute to psychiatric diseases by impacting not only presynaptic but also postsynaptic functions. PMID:27047369

  20. Presynaptic Disorders: Lambert-Eaton Myasthenic Syndrome and Botulism.

    PubMed

    Gable, Karissa L; Massey, Janice M

    2015-08-01

    Lambert-Eaton myasthenic syndrome (LEMS) and botulism are acquired presynaptic nerve terminal disorders of the neuromuscular junction. Lambert-Eaton myasthenic syndrome is an idiopathic or paraneoplastic autoimmune syndrome in which autoantibodies of the P/Q-type voltage-gated calcium channel play a role in decreasing the release of acetylcholine, resulting in clinical symptoms of skeletal muscle weakness, diminished reflexes, and autonomic symptoms. Paraneoplastic LEMS is most often associated with small cell lung cancer. Diagnosis is confirmed by positive serologic testing and electrophysiological studies, which display characteristic features of low compound muscle action potentials, a decrement at 3Hz repetitive nerve stimulation, and facilitation with exercise or high-frequency repetitive stimulation. Treatment involves cancer monitoring and treatment, 3,4-diaminopyridine, immunosuppressive medications, and acetylcholinesterase inhibitors. Botulism is another presynaptic disorder of neuromuscular transmission. Clinical features classically involve cranial and bulbar palsies followed by descending weakness of the limbs, respiratory failure, and autonomic dysfunction. Electrodiagnostic testing is important in the evaluation and diagnosis. Treatment is supportive, and administration of antitoxin is beneficial in selected cases.

  1. State-dependent and reflex drives to the upper airway: basic physiology with clinical implications.

    PubMed

    Horner, Richard L; Hughes, Stuart W; Malhotra, Atul

    2014-02-01

    The root cause of the most common and serious of the sleep disorders is impairment of breathing, and a number of factors predispose a particular individual to hypoventilation during sleep. In turn, obstructive hypopneas and apneas are the most common of the sleep-related respiratory problems and are caused by dysfunction of the upper airway as a conduit for airflow. The overarching principle that underpins the full spectrum of clinical sleep-related breathing disorders is that the sleeping brain modifies respiratory muscle activity and control mechanisms and diminishes the ability to respond to respiratory distress. Depression of upper airway muscle activity and reflex responses, and suppression of arousal (i.e., "waking-up") responses to respiratory disturbance, can also occur with commonly used sedating agents (e.g., hypnotics and anesthetics). Growing evidence indicates that the sometimes critical problems of sleep and sedation-induced depression of breathing and arousal responses may be working through common brain pathways acting on common cellular mechanisms. To identify these state-dependent pathways and reflex mechanisms, as they affect the upper airway, is the focus of this paper. Major emphasis is on the synthesis of established and recent findings. In particular, we specifically focus on 1) the recently defined mechanism of genioglossus muscle inhibition in rapid-eye-movement sleep; 2) convergence of diverse neurotransmitters and signaling pathways onto one root mechanism that may explain pharyngeal motor suppression in sleep and drug-induced brain sedation; 3) the lateral reticular formation as a key hub of respiratory and reflex drives to the upper airway.

  2. A novel mathematical setup for fault tolerant control systems with state-dependent failure process

    NASA Astrophysics Data System (ADS)

    Chitraganti, S.; Aberkane, S.; Aubrun, C.

    2014-12-01

    In this paper, we consider a fault tolerant control system (FTCS) with state- dependent failures and provide a tractable mathematical model to handle the state-dependent failures. By assuming abrupt changes in system parameters, we use a jump process modelling of failure process and the fault detection and isolation (FDI) process. In particular, we assume that the failure rates of the failure process vary according to which set the state of the system belongs to.

  3. Synaptic Variability Introduces State-Dependent Modulation of Excitatory Spinal Cord Synapses.

    PubMed

    Parker, David

    2015-01-01

    The relevance of neuronal and synaptic variability remains unclear. Cellular and synaptic plasticity and neuromodulation are also variable. This could reflect state-dependent effects caused by the variable initial cellular or synaptic properties or direct variability in plasticity-inducing mechanisms. This study has examined state-dependent influences on synaptic plasticity at connections between excitatory interneurons (EIN) and motor neurons in the lamprey spinal cord. State-dependent effects were examined by correlating initial synaptic properties with the substance P-mediated plasticity of low frequency-evoked EPSPs and the reduction of the EPSP depression over spike trains (metaplasticity). The low frequency EPSP potentiation reflected an interaction between the potentiation of NMDA responses and the release probability. The release probability introduced a variable state-dependent subtractive influence on the postsynaptic NMDA-dependent potentiation. The metaplasticity was also state-dependent: it was greater at connections with smaller available vesicle pools and high initial release probabilities. This was supported by the significant reduction in the number of connections showing metaplasticity when the release probability was reduced by high Mg(2+) Ringer. Initial synaptic properties thus introduce state-dependent influences that affect the potential for plasticity. Understanding these conditions will be as important as understanding the subsequent changes.

  4. Dopaminergic Presynaptic Modulation of Nigral Afferents: Its Role in the Generation of Recurrent Bursting in Substantia Nigra Pars Reticulata Neurons

    PubMed Central

    de Jesús Aceves, José; Rueda-Orozco, Pavel E.; Hernández, Ricardo; Plata, Víctor; Ibañez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, José

    2011-01-01

    Previous work has shown the functions associated with activation of dopamine presynaptic receptors in some substantia nigra pars reticulata (SNr) afferents: (i) striatonigral terminals (direct pathway) posses presynaptic dopamine D1-class receptors whose action is to enhance inhibitory postsynaptic currents (IPSCs) and GABA transmission. (ii) Subthalamonigral terminals posses D1- and D2-class receptors where D1-class receptor activation enhances and D2-class receptor activation decreases excitatory postsynaptic currents. Here we report that pallidonigral afferents posses D2-class receptors (D3 and D4 types) that decrease inhibitory synaptic transmission via presynaptic modulation. No action of D1-class agonists was found on pallidonigral synapses. In contrast, administration of D1-receptor antagonists greatly decreased striatonigral IPSCs in the same preparation, suggesting that tonic dopamine levels help in maintaining the function of the striatonigral (direct) pathway. When both D3 and D4 type receptors were blocked, pallidonigral IPSCs increased in amplitude while striatonigral connections had no significant change, suggesting that tonic dopamine levels are repressing a powerful inhibition conveyed by pallidonigral synapses (a branch of the indirect pathway). We then blocked both D1- and D2-class receptors to acutely decrease direct pathway (striatonigral) and enhance indirect pathways (subthalamonigral and pallidonigral) synaptic force. The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models. These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism. PMID:21347219

  5. Presynaptic regulation of the inhibitory transmission by GluR5-containing kainate receptors in spinal substantia gelatinosa

    PubMed Central

    Xu, Hui; Wu, Long-Jun; Zhao, Ming-Gao; Toyoda, Hiroki; Vadakkan, Kunjumon I; Jia, Yongheng; Pinaud, Raphael; Zhuo, Min

    2006-01-01

    GluR5-containing kainate receptors (KARs) are known to be involved in nociceptive transmission. Our previous work has shown that the activation of presynaptic KARs regulates GABAergic and glycinergic synaptic transmission in cultured dorsal horn neurons. However, the role of GluR5-containing KARs in the modulation of inhibitory transmission in the spinal substantia gelatinosa (SG) in slices remains unknown. In the present study, pharmacological, electrophysiological and genetic methods were used to show that presynaptic GluR5 KARs are involved in the modulation of inhibitory transmission in the SG of spinal slices in vitro. The GluR5 selective agonist, ATPA, facilitated the frequency but not amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in SG neurons. ATPA increased sIPSC frequency in all neurons with different firing patterns as delayed, tonic, initial and single spike patterns. The frequency of either GABAergic or glycinergic sIPSCs was significantly increased by ATPA. ATPA could also induce inward currents in all SG neurons recorded. The frequency, but not amplitude, of action potential-independent miniature IPSCs (mIPSCs) was also facilitated by ATPA in a concentration-dependent manner. However, the effect of ATPA on the frequency of either sIPSCs or mIPSCs was abolished in GluR5-/- mice. Deletion of the GluR5 subunit gene had no effect on the frequency or amplitude of mIPSCs in SG neurons. However, GluR5 antagonist LY293558 reversibly inhibited sIPSC and mIPSC frequencies in spinal SG neurons. Taken together, these results suggest that GluR5 KARs, which may be located at presynaptic terminals, contribute to the modulation of inhibitory transmission in the SG. GluR5-containing KARs are thus important for spinal sensory transmission/modulation in the spinal cord. PMID:16948848

  6. The Roles of Microtubule-Based Transport at Presynaptic Nerve Terminals

    PubMed Central

    Yagensky, Oleksandr; Kalantary Dehaghi, Tahere; Chua, John Jia En

    2016-01-01

    Targeted intracellular movement of presynaptic proteins plays important roles during synapse formation and, later, in the homeostatic maintenance of mature synapses. Movement of these proteins, often as vesicular packages, is mediated by motor complexes travelling along intracellular cytoskeletal networks. Presynaptic protein transport by kinesin motors in particular plays important roles during synaptogenesis to bring newly synthesized proteins to establish nascent synaptic sites. Conversely, movement of proteins away from presynaptic sites by Dynein motors enables synapse-nuclear signaling and allows for synaptic renewal through degradation of unwanted or damaged proteins. Remarkably, recent data has indicated that synaptic and protein trafficking machineries can modulate each other’s functions. Here, we survey the mechanisms involved in moving presynaptic components to and away from synapses and how this process supports presynaptic function. PMID:26903856

  7. Presynaptic long-term depression mediated by Gi/o-coupled receptors

    PubMed Central

    Atwood, Brady K.; Lovinger, David M.; Mathur, Brian N.

    2014-01-01

    Long-term depression (LTD) of the efficacy of synaptic transmission is now recognized as an important mechanism for regulation of information storage and control of actions, as well as synapse, neuron, and circuit development. Studies of LTD mechanisms have focused mainly on postsynaptic AMPA receptor trafficking. However, the focus has now expanded to include presynaptically expressed plasticity; the predominant form being initiated by presynaptically expressed Gi/o-coupled metabotropic receptor (Gi/o-GPCR) activation. Several forms of LTD involving activation of different presynaptic Gi/o-GPCRs as a “common pathway” are described. Here, we review the literature on presynaptic Gi/o-GPCR-mediated LTD, discuss known mechanisms, gaps in our knowledge, and evaluate if all Gi/o-GPCR are capable of inducing presynaptic LTD. PMID:25160683

  8. Presynaptic long-term depression mediated by Gi/o-coupled receptors.

    PubMed

    Atwood, Brady K; Lovinger, David M; Mathur, Brian N

    2014-11-01

    Long-term depression (LTD) of the efficacy of synaptic transmission is now recognized as an important mechanism for the regulation of information storage and the control of actions, as well as for synapse, neuron, and circuit development. Studies of LTD mechanisms have focused mainly on postsynaptic AMPA-type glutamate receptor trafficking. However, the focus has now expanded to include presynaptically expressed plasticity, the predominant form being initiated by presynaptically expressed Gi/o-coupled metabotropic receptor (Gi/o-GPCR) activation. Several forms of LTD involving activation of different presynaptic Gi/o-GPCRs as a 'common pathway' are described. We review here the literature on presynaptic Gi/o-GPCR-mediated LTD, discuss known mechanisms, gaps in our knowledge, and evaluate whether all Gi/o-GPCRs are capable of inducing presynaptic LTD.

  9. Basolateral amygdala CB1 cannabinoid receptors are involved in cross state-dependent memory retrieval between morphine and ethanol.

    PubMed

    Ofogh, Sattar Norouzi; Rezayof, Ameneh; Sardari, Maryam; Ghasemzadeh, Zahra

    2016-09-01

    Ethanol and morphine are largely co-abused and affect memory formation. The present study intended to investigate the involvement of cannabinoid CB1 receptors of the basolateral amygdala (BLA) in cross state-dependent memory retrieval between morphine and ethanol. Adult male Wistar rats received bilateral cannulation of the BLA, and memory retrieval was measured in step-through type passive avoidance apparatus. Our results showed that post-training intraperitoneal (i.p.) administration of morphine (6mg/kg) induced amnesia. Pre-test administration of ethanol (0.5g/kg, i.p.) significantly improved morphine-induced memory impairment, suggesting that there is cross state-dependent memory retrieval between morphine and ethanol. It should be considered that pre-test administration of ethanol (0.1 and 0.5g/kg, i.p.) by itself had no effect on memory retrieval in the passive avoidance task. Interestingly, pre-test intra-BLA microinjection of different doses of WIN55,212-2 (0.1, 0.2 and 0.3μg/rat), a non-selective CB1/CB2 receptor agonist, plus an ineffective dose of ethanol (0.1g/kg, i.p.) improved morphine-induced memory impairment. Intra-BLA microinjection of AM251 (0.4-0.6ng/rat), a selective CB1 receptor antagonist, inhibited the improved effect of ethanol (0.5g/kg, i.p.) on morphine response. Pre-test intra-BLA microinjection of WIN55,212-2 or AM251 had no effect on memory retrieval or morphine-induced amnesia. Taken together, it can be concluded that morphine and ethanol can induce state-dependent memory retrieval. In addition, the BLA endocannabinoid system mediates via CB1 receptors the functional interaction of morphine and ethanol state-dependent memory retrieval which may depend on the rewarding effects of the drugs.

  10. A frequency-dependent switch from inhibition to excitation in a hippocampal unitary circuit.

    PubMed

    Mori, Masahiro; Abegg, Mathias H; Gähwiler, Beat H; Gerber, Urs

    2004-09-23

    The hippocampus, a brain structure essential for memory and cognition, is classically represented as a trisynaptic excitatory circuit. Recent findings challenge this view, particularly with regard to the mossy fibre input to CA3, the second synapse in the trisynaptic pathway. Thus, the powerful mossy fibre input to CA3 pyramidal cells might mediate both synaptic excitation and inhibition. Here we show, by recording from connected cell pairs in rat entorhinal-hippocampal slice cultures, that single action potentials in a dentate granule cell evoke a net inhibitory signal in a pyramidal cell. The hyperpolarization is due to disynaptic feedforward inhibition, which overwhelms monosynaptic excitation. Interestingly, this net inhibitory synaptic response changes to an excitatory signal when the frequency of presynaptic action potentials increases. The process responsible for this switch involves the facilitation of monosynaptic excitatory transmission coupled with rapid depression of inhibitory circuits. This ability to immediately switch the polarity of synaptic responses constitutes a novel synaptic mechanism, which might be crucial to the state-dependent processing of information in associative hippocampal networks.

  11. Presynaptic elements involved in the maintenance of the neuromuscular junction

    NASA Technical Reports Server (NTRS)

    Burrows, G. H.

    1984-01-01

    Alterations in the neuromuscular junction were observed in rats preceding loss of muscle mass. In view of the possibility that these alterations involve changes in the secretion of myotrophic agents by presynaptic motor neurons, an investigation was undertaken to characterize a neuronall factor which is thought to be involved in the initiation and maintenance of cholinergic synapses. This factor, which is secreted into the incubation medium by NG108-15 neuroblastoma x glioma hybrid cells, induces the aggregation of nicotinic acetylcholine receptors on primary cultures of rat hindlimb myotubes. Previous attempts to purify this factor failed. Extensive washing of the NG108-15 cells with hepes-buffered salt solution followed by short (4 hour) collection times resulted in the collection of incubation medium containing maximal aggregation activity with as little as 5 ug secreted protein per ml of fresh medium. A three-fold increase in specific activity was obtained after anion exchange chromatography.

  12. [Presynaptic component in the mechanism of fenibut action].

    PubMed

    Kovalev, G I; Prikhozhan, A V; Raevskiĭ, K S

    1982-11-01

    Superfusion of crude synaptosomal fractions from the rat brain cortex was used to study in vitro the effect of phenibut (beta-phenyl-GABA), a tranquilizing agent, on spontaneous and K+-stimulated release of 3H-GABA. It was found that phenibut in concentrations of 50 and 100 microM enhanced spontaneous tritium efflux by 15.9 and 30.7%, respectively. The effect of exogenous GABA in a concentration of 100 microM was 5 times more remarkable. The K+-stimulated release of the transmitter significantly increased under the effect of phenibut. Bicuculline counteracted this enhancement while picrotoxin did not effect the K+-stimulated egress of 3H-GABA. It is assumed that the presynaptic component described plays a role in the realization of the tranquilizing action of the tranquilizing action of phenibut.

  13. Presynaptic control of dopamine release by BETA-phenylethylamine

    SciTech Connect

    Zharikova, A.D.; Godukhin, O.V.

    1985-04-01

    The authors study the effect of extracellular ions (Ca/sup 2 +/, Na/sup 2 +/) on the beta-phenylethylamine (beta-PEA) releasing effect, dependence of this effect on the membrane potential of dopaminergic endings, and the participation of dopamine presynaptic autoreceptors in the realization of the effects of beta-PEA on dopamine (DA) release. Experi ments were carried out on noninbred male albino rats. By means of a microsyringe, (/sup 3/H)-DA hydrochloride was injected. The significance of the difference in levels of (/sup 3/H)-DA release during analogous periods of perfusion in the groups of animals compared was estimated by Student's test. These experiments in vivo thus demonstrated the ability of beta-PEA to regulate DA release in different directions depending on the functional state of the dopaminergic neuron.

  14. Functional presynaptic HCN channels in the rat globus pallidus.

    PubMed

    Boyes, Justin; Bolam, J Paul; Shigemoto, Ryuichi; Stanford, Ian M

    2007-04-01

    Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are expressed postsynaptically in the rodent globus pallidus (GP), where they play several important roles in controlling GP neuronal activity. To further elucidate the role of HCN channels in the GP, immunocytochemical and electrophysiological approaches were used to test the hypothesis that HCN channels are also expressed presynaptically on the local axon collaterals of GP neurons. At the electron microscopic level, immunoperoxidase labelling for HCN1 and HCN2 was localized in GP somata and dendritic processes, myelinated and unmyelinated axons, and axon terminals. One population of labelled terminals formed symmetric synapses with somata and proximal dendrites and were immunoreactive for parvalbumin, consistent with the axon collaterals of GABAergic GP projection neurons. In addition, labelling for HCN2 and, to a lesser degree, HCN1 was observed in axon terminals that formed asymmetric synapses and were immunoreactive for the vesicular glutamate transporter 2. Immunogold labelling demonstrated that HCN1 and HCN2 were located predominantly at extrasynaptic sites along the plasma membrane of both types of terminal. To determine the function of presynaptic HCN channels in the GP, we performed whole-cell recordings from GP neurons in vitro. Bath application of the HCN channel blocker ZD7288 resulted in an increase in the frequency of mIPSCs but had no effect on their amplitude, implying that HCN channels tonically regulate the release of GABA. Their presence, and predicted role in modulating transmitter release, represents a hitherto unidentified mechanism whereby HCN channels influence the activity of GP neurons.

  15. GABAergic mechanisms regulated by miR-33 encode state-dependent fear

    PubMed Central

    Jovasevic, Vladimir; Corcoran, Kevin A; Leaderbrand, Katherine; Yamawaki, Naoki; Guedea, Anita L; Chen, Helen J; Shepherd, Gordon M G; Radulovic, Jelena

    2016-01-01

    Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar. Restricted access to such memories can present a risk for psychiatric disorders and hamper their treatment. To better understand the mechanisms underlying state-dependent fear, we used a mouse model of contextual fear conditioning. We found that heightened activity of hippocampal extrasynaptic GABAA receptors, believed to impair fear and memory, actually enabled their state-dependent encoding and retrieval. This effect required protein kinase C-βII and was influenced by miR-33, a microRNA that regulates several GABA-related proteins. In the extended hippocampal circuit, extrasynaptic GABAA receptors promoted subcortical, but impaired cortical, activation during memory encoding of context fear. Moreover, suppression of retrosplenial cortical activity, which normally impairs retrieval, had an enhancing effect on the retrieval of state-dependent fear. These mechanisms can serve as treatment targets for managing access to state-dependent memories of stressful experiences. PMID:26280760

  16. Presynaptic NMDA receptors – dynamics and distribution in developing axons in vitro and in vivo

    PubMed Central

    Gill, Ishwar; Droubi, Sammy; Giovedi, Silvia; Fedder, Karlie N.; Bury, Luke A. D.; Bosco, Federica; Sceniak, Michael P.; Benfenati, Fabio; Sabo, Shasta L.

    2015-01-01

    ABSTRACT During cortical development, N-methyl-D-aspartate (NMDA) receptors (NMDARs) facilitate presynaptic terminal formation, enhance neurotransmitter release and are required in presynaptic neurons for spike-timing-dependent long-term depression (tLTD). However, the extent to which NMDARs are found within cortical presynaptic terminals has remained controversial, and the sub-synaptic localization and dynamics of axonal NMDARs are unknown. Here, using live confocal imaging and biochemical purification of presynaptic membranes, we provide strong evidence that NMDARs localize to presynaptic terminals in vitro and in vivo in a developmentally regulated manner. The NR1 and NR2B subunits (also known as GRIN1 and GRIN2B, respectively) were found within the active zone membrane, where they could respond to synaptic glutamate release. Surprisingly, NR1 also appeared in glutamatergic and GABAergic synaptic vesicles. During synaptogenesis, NR1 was mobile throughout axons – including growth cones and filopodia, structures that are involved in synaptogenesis. Upon synaptogenic contact, NMDA receptors were quickly recruited to terminals by neuroligin-1 signaling. Unlike dendrites, the trafficking and distribution of axonal NR1 were insensitive to activity changes, including NMDA exposure, local glutamate uncaging or action potential blockade. These results support the idea that presynaptic NMDARs play an early role in presynaptic development. PMID:25526735

  17. Mechanisms underlying short-term modulation of transmitter release by presynaptic depolarization

    PubMed Central

    Hori, Tetsuya; Takahashi, Tomoyuki

    2009-01-01

    Presynaptic terminal depolarization modulates the efficacy of transmitter release. Residual Ca2+ remaining after presynaptic depolarization is thought to play a critical role in facilitation of transmitter release, but its downstream mechanism remains unclear. By making simultaneous pre- and postsynaptic recordings at the rodent calyx of Held synapse, we have investigated mechanisms involved in the facilitation and depression of postsynaptic currents induced by presynaptic depolarization. In voltage-clamp experiments, cancellation of the Ca2+-dependent presynaptic Ca2+ current (IpCa) facilitation revealed that this mechanism can account for 50% of postsynaptic current facilitation, irrespective of intraterminal EGTA concentrations. Intraterminal EGTA, loaded at 10 mm, failed to block postsynaptic current facilitation, but additional BAPTA at 1 mm abolished it. Potassium-induced sustained depolarization of non-dialysed presynaptic terminals caused a facilitation of postsynaptic currents, superimposed on a depression, with the latter resulting from reductions in presynaptic action potential amplitude and number of releasable vesicles. We conclude that presynaptic depolarization bidirectionally modulates transmitter release, and that the residual Ca2+ mechanism for synaptic facilitation operates in the immediate vicinity of voltage-gated Ca2+ channels in the nerve terminal. PMID:19403620

  18. Structural organization of the presynaptic density at identified synapses in the locust central nervous system.

    PubMed

    Leitinger, Gerd; Masich, Sergej; Neumüller, Josef; Pabst, Maria Anna; Pavelka, Margit; Rind, F Claire; Shupliakov, Oleg; Simmons, Peter J; Kolb, Dagmar

    2012-02-01

    In a synaptic active zone, vesicles aggregate around a densely staining structure called the presynaptic density. We focus on its three-dimensional architecture and a major molecular component in the locust. We used electron tomography to study the presynaptic density in synapses made in the brain by identified second-order neuron of the ocelli. Here, vesicles close to the active zone are organized in two rows on either side of the presynaptic density, a level of organization not previously reported in insect central synapses. The row of vesicles that is closest to the density's base includes vesicles docked with the presynaptic membrane and thus presumably ready for release, whereas the outer row of vesicles does not include any that are docked. We show that a locust ortholog of the Drosophila protein Bruchpilot is localized to the presynaptic density, both in the ocellar pathway and compound eye visual neurons. An antibody recognizing the C-terminus of the Bruchpilot ortholog selectively labels filamentous extensions of the presynaptic density that reach out toward vesicles. Previous studies on Bruchpilot have focused on its role in neuromuscular junctions in Drosophila, and our study shows it is also a major functional component of presynaptic densities in the central nervous system of an evolutionarily distant insect. Our study thus reveals Bruchpilot executes similar functions in synapses that can sustain transmission of small graded potentials as well as those relaying large, spike-evoked signals.

  19. Cortical Presynaptic Control of Dorsal Horn C–Afferents in the Rat

    PubMed Central

    Martínez-Lorenzana, Guadalupe; Condés-Lara, Miguel; Rojas-Piloni, Gerardo

    2013-01-01

    Lamina 5 sensorimotor cortex pyramidal neurons project to the spinal cord, participating in the modulation of several modalities of information transmission. A well-studied mechanism by which the corticospinal projection modulates sensory information is primary afferent depolarization, which has been characterized in fast muscular and cutaneous, but not in slow-conducting nociceptive skin afferents. Here we investigated whether the inhibition of nociceptive sensory information, produced by activation of the sensorimotor cortex, involves a direct presynaptic modulation of C primary afferents. In anaesthetized male Wistar rats, we analyzed the effects of sensorimotor cortex activation on post tetanic potentiation (PTP) and the paired pulse ratio (PPR) of dorsal horn field potentials evoked by C–fiber stimulation in the sural (SU) and sciatic (SC) nerves. We also explored the time course of the excitability changes in nociceptive afferents produced by cortical stimulation. We observed that the development of PTP was completely blocked when C-fiber tetanic stimulation was paired with cortex stimulation. In addition, sensorimotor cortex activation by topical administration of bicuculline (BIC) produced a reduction in the amplitude of C–fiber responses, as well as an increase in the PPR. Furthermore, increases in the intraspinal excitability of slow-conducting fiber terminals, produced by sensorimotor cortex stimulation, were indicative of primary afferent depolarization. Topical administration of BIC in the spinal cord blocked the inhibition of C–fiber neuronal responses produced by cortical stimulation. Dorsal horn neurons responding to sensorimotor cortex stimulation also exhibited a peripheral receptive field and responded to stimulation of fast cutaneous myelinated fibers. Our results suggest that corticospinal inhibition of nociceptive responses is due in part to a modulation of the excitability of primary C–fibers by means of GABAergic inhibitory

  20. Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain

    PubMed Central

    Hirasawa, Michiru; Schwab, Yannick; Natah, Sirajedin; Hillard, Cecilia J; Mackie, Ken; Sharkey, Keith A; Pittman, Quentin J

    2004-01-01

    Oxytocin is released from supraoptic magnocellular neurones and is thought to act at presynaptic receptors to inhibit transmitter release. We now show that this effect is mediated by endocannabinoids, but that oxytocin nonetheless plays an important role in endocannabinoid signalling. WIN55,212-2, a cannabinoid receptor agonist, mimicked the action of oxytocin and occluded oxytocin-induced presynaptic inhibition. The cannabinoid action is at the presynaptic terminal as shown by alteration in paired pulse ratio, a reduction in miniature EPSC frequency and immunohistochemical localization of CB1 receptors on presynaptic terminals. AM251, a CB1 receptor antagonist, blocked both the WIN55,212-2 and the oxytocin-induced presynaptic inhibition of EPSCs. Depolarization of postsynaptic magnocellular neurones (which contain fatty acid amide hydrolase, a cannabinoid catabolic enzyme) caused a transient inhibition of EPSCs that could be blocked by both the AM251 and Manning compound, an oxytocin/vasopressin receptor antagonist. This indicates that somatodendritic peptide release and action on previously identified autoreceptors facilitates the release of endocannabinoids that act as mediators of presynaptic inhibition. PMID:15254151

  1. Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain.

    PubMed

    Hirasawa, Michiru; Schwab, Yannick; Natah, Sirajedin; Hillard, Cecilia J; Mackie, Ken; Sharkey, Keith A; Pittman, Quentin J

    2004-09-01

    Oxytocin is released from supraoptic magnocellular neurones and is thought to act at presynaptic receptors to inhibit transmitter release. We now show that this effect is mediated by endocannabinoids, but that oxytocin nonetheless plays an important role in endocannabinoid signalling. WIN55,212-2, a cannabinoid receptor agonist, mimicked the action of oxytocin and occluded oxytocin-induced presynaptic inhibition. The cannabinoid action is at the presynaptic terminal as shown by alteration in paired pulse ratio, a reduction in miniature EPSC frequency and immunohistochemical localization of CB1 receptors on presynaptic terminals. AM251, a CB1 receptor antagonist, blocked both the WIN55,212-2 and the oxytocin-induced presynaptic inhibition of EPSCs. Depolarization of postsynaptic magnocellular neurones (which contain fatty acid amide hydrolase, a cannabinoid catabolic enzyme) caused a transient inhibition of EPSCs that could be blocked by both the AM251 and Manning compound, an oxytocin/vasopressin receptor antagonist. This indicates that somatodendritic peptide release and action on previously identified autoreceptors facilitates the release of endocannabinoids that act as mediators of presynaptic inhibition.

  2. Nicotine regulates activity of lateral habenula neurons via presynaptic and postsynaptic mechanisms

    PubMed Central

    Zuo, Wanhong; Xiao, Cheng; Gao, Ming; Hopf, F. Woodward; Krnjević, Krešimir; McIntosh, J. Michael; Fu, Rao; Wu, Jie; Bekker, Alex; Ye, Jiang-Hong

    2016-01-01

    There is much interest in brain regions that drive nicotine intake in smokers. Interestingly, both the rewarding and aversive effects of nicotine are probably critical for sustaining nicotine addiction. The medial and lateral habenular (LHb) nuclei play important roles in processing aversion, and recent work has focused on the critical involvement of the LHb in encoding and responding to aversive stimuli. Several neurotransmitter systems are implicated in nicotine’s actions, but very little is known about how nicotinic acetylcholine receptors (nAChRs) regulate LHb activity. Here we report in brain slices that activation of nAChRs depolarizes LHb cells and robustly increases firing, and also potentiates glutamate release in LHb. These effects were blocked by selective antagonists of α6-containing (α6*) nAChRs, and were absent in α6*-nAChR knockout mice. In addition, nicotine activates GABAergic inputs to LHb via α4β2-nAChRs, at lower concentrations but with more rapid desensitization relative to α6*-nAChRs. These results demonstrate the existence of diverse functional nAChR subtypes at presynaptic and postsynaptic sites in LHb, through which nicotine could facilitate or inhibit LHb neuronal activity and thus contribute to nicotine aversion or reward. PMID:27596561

  3. Presynaptic Inhibitory Terminals Are Functionally Abnormal in a Rat Model of Posttraumatic Epilepsy

    PubMed Central

    Faria, Leonardo C.

    2010-01-01

    Partially isolated “undercut” neocortex with intact pial circulation is a well-established model of posttraumatic epileptogenesis. Results of previous experiments showed a decreased frequency of miniature inhibitory postsynaptic currents (mIPSCs) in layer V pyramidal (Pyr) neurons of undercuts. We further examined possible functional abnormalities in GABAergic inhibition in rat epileptogenic neocortical slices in vitro by recording whole cell monosynaptic IPSCs in layer V Pyr cells and fast-spiking (FS) GABAergic interneurons using a paired pulse paradigm. Compared with controls, IPSCs in Pyr neurons of injured slices showed increased threshold and decreased peak amplitude at threshold, decreased input/output slopes, increased failure rates, and a shift from paired pulse depression toward paired pulse facilitation (increased paired pulse ratio or PPR). Increasing [Ca2+]o from 2 to 4 mM partially reversed these abnormalities in Pyr cells of the epileptogenic tissue. IPSCs onto FS cells also had an increased PPR and failures. Blockade of GABAB receptors did not affect the paired results. These findings suggest that there are functional alterations in GABAergic presynaptic terminals onto both Pyr and FS cells in this model of posttraumatic epileptogenesis. PMID:20484536

  4. Involvement of dorsal hippocampal and medial septal nicotinic receptors in cross state-dependent memory between WIN55, 212-2 and nicotine or ethanol in mice.

    PubMed

    Alijanpour, S; Rezayof, A

    2013-08-15

    The present study examined whether nicotinic acetylcholine receptors (nAChRs) of the CA1 regions of the dorsal hippocampus and medial septum (MS) are involved in cross state-dependent memory retrieval between WIN55, 212-2 (WIN, a non-selective CB1/CB2 receptor agonist) and nicotine or ethanol. Memory retrieval was measured in one-trial step-down type passive avoidance apparatus in male adult mice. Pre-training intraperitoneal administration of WIN (0.1-1mg/kg) dose-dependently impaired memory retrieval when it was tested 24h later. Pre-test systemic administration of nicotine (0.6 and 0.7mg/kg, s.c.) or ethanol (0.5g/kg, i.p.) improved WIN-induced memory impairment, suggesting a cross state-dependent memory retrieval between the drugs. Pre-test intra-CA1 microinjection of nicotine (1 and 2μg/mouse) before systemic administration of an ineffective dose of nicotine (0.5mg/kg, s.c.) or ethanol (0.25g/kg) significantly reversed WIN-induced memory impairment. Pre-test intra-CA1 microinjection of mecamylamine (1 and 3μg/mouse) inhibited cross state-dependent memory between WIN and nicotine or ethanol. Moreover, pre-test intra-MS microinjection of nicotine (1 and 2μg/mouse) in combination with systemic administration of a lower dose of nicotine (0.5mg/kg), but not ethanol (0.25g/kg), improved memory impairment induced by pre-training administration of WIN. On the other hand, in the animals that received pre-training WIN and pre-test systemic administration of nicotine (0.7mg/kg), but not ethanol (0.5g/kg), pre-test intra-MS microinjection of mecamylamine (1-5μg/mouse) inhibited WIN-nicotine state-dependent memory retrieval. It should be noted that pre-test intra-CA1 or intra-MS microinjection of nicotine or mecamylamine by itself had no effect on memory retrieval and also could not reverse memory impairment induced by pre-training administration of WIN. It can be concluded that WIN and nicotine or WIN and ethanol can induce state-dependent memory retrieval. In

  5. State-dependent doubly weighted stochastic simulation algorithm for automatic characterization of stochastic biochemical rare events

    NASA Astrophysics Data System (ADS)

    Roh, Min K.; Daigle, Bernie J.; Gillespie, Dan T.; Petzold, Linda R.

    2011-12-01

    In recent years there has been substantial growth in the development of algorithms for characterizing rare events in stochastic biochemical systems. Two such algorithms, the state-dependent weighted stochastic simulation algorithm (swSSA) and the doubly weighted SSA (dwSSA) are extensions of the weighted SSA (wSSA) by H. Kuwahara and I. Mura [J. Chem. Phys. 129, 165101 (2008)], 10.1063/1.2987701. The swSSA substantially reduces estimator variance by implementing system state-dependent importance sampling (IS) parameters, but lacks an automatic parameter identification strategy. In contrast, the dwSSA provides for the automatic determination of state-independent IS parameters, thus it is inefficient for systems whose states vary widely in time. We present a novel modification of the dwSSA—the state-dependent doubly weighted SSA (sdwSSA)—that combines the strengths of the swSSA and the dwSSA without inheriting their weaknesses. The sdwSSA automatically computes state-dependent IS parameters via the multilevel cross-entropy method. We apply the method to three examples: a reversible isomerization process, a yeast polarization model, and a lac operon model. Our results demonstrate that the sdwSSA offers substantial improvements over previous methods in terms of both accuracy and efficiency.

  6. State Dependence and Trait Stability of Perfectionism: A Short-Term Longitudinal Study

    ERIC Educational Resources Information Center

    Rice, Kenneth G.; Aldea, Mirela A.

    2006-01-01

    The authors examined state dependency on depression, trait stability, and state-trait characteristics of perfectionism in a short-term longitudinal study of university students. Relative stability of perfectionism was assessed with test-retest correlations across 3 time points, and results showed higher rank order and relative stability for…

  7. Role of hippocampal CA1 area gap junction channels on morphine state-dependent learning.

    PubMed

    Beheshti, Siamak; Hosseini, Seyyed Akbar Mir Seyyed; Noorbakhshnia, Maryam; Eivani, Mehdi

    2014-12-15

    Morphine produces a state dependent learning. The hippocampus is involved in this kind of learning. Gap junctions (GJs) are involved in some of the effects of morphine and exist in different areas of the hippocampus. We investigated the effects of blocking GJ channels of the hippocampal CA1 area, by means of pre-test bilateral injection of carbenoxolone (CBX), on morphine state dependent learning, using a passive avoidance task. Post-training subcutaneous administrations of morphine (0.5, 2.5, 5 and 7.5 mg/kg) dose-dependently impaired memory retrieval. Pre-test administration of morphine (0.5, 2.5, 5 and 7.5 mg/kg) induced a state-dependent retrieval of the memory acquired under post-training morphine influence. Pre-test injections of CBX (25, 75 and 150 nM) dose dependently prevented memory retrieval by post-training (7.5 mg/kg) and pre-test (0.5, 2.5, 5, 7.5 mg/kg) injections of morphine. The results suggest that intercellular coupling via GJ channels of the hippocampal CA1 area modulates morphine state dependent learning.

  8. Role of state-dependent learning in the cognitive effects of caffeine in mice.

    PubMed

    Sanday, Leandro; Zanin, Karina A; Patti, Camilla L; Fernandes-Santos, Luciano; Oliveira, Larissa C; Longo, Beatriz M; Andersen, Monica L; Tufik, Sergio; Frussa-Filho, Roberto

    2013-08-01

    Caffeine is the most widely used psychoactive substance in the world and it is generally believed that it promotes beneficial effects on cognitive performance. However, there is also evidence suggesting that caffeine has inhibitory effects on learning and memory. Considering that caffeine may have anxiogenic effects, thus changing the emotional state of the subjects, state-dependent learning may play a role in caffeine-induced cognitive alterations. Mice were administered 20 mg/kg caffeine before training and/or before testing both in the plus-maze discriminative avoidance task (an animal model that concomitantly evaluates learning, memory, anxiety-like behaviour and general activity) and in the inhibitory avoidance task, a classic paradigm for evaluating memory in rodents. Pre-training caffeine administration did not modify learning, but produced an anxiogenic effect and impaired memory retention. While pre-test administration of caffeine did not modify retrieval on its own, the pre-test administration counteracted the memory deficit induced by the pre-training caffeine injection in both the plus-maze discriminative and inhibitory avoidance tasks. Our data demonstrate that caffeine-induced memory deficits are critically related to state-dependent learning, reinforcing the importance of considering the participation of state-dependency on the interpretation of the cognitive effects of caffeine. The possible participation of caffeine-induced anxiety alterations in state-dependent memory deficits is discussed.

  9. Presynaptic GABA Receptors Mediate Temporal Contrast Enhancement in Drosophila Olfactory Sensory Neurons and Modulate Odor-Driven Behavioral Kinetics

    PubMed Central

    Demir, Mahmut; Gorur-Shandilya, Srinivas; Kunst, Michael; Nitabach, Michael N.

    2016-01-01

    Contrast enhancement mediated by lateral inhibition within the nervous system enhances the detection of salient features of visual and auditory stimuli, such as spatial and temporal edges. However, it remains unclear how mechanisms for temporal contrast enhancement in the olfactory system can enhance the detection of odor plume edges during navigation. To address this question, we delivered to Drosophila melanogaster flies pulses of high odor intensity that induce sustained peripheral responses in olfactory sensory neurons (OSNs). We use optical electrophysiology to directly measure electrical responses in presynaptic terminals and demonstrate that sustained peripheral responses are temporally sharpened by the combined activity of two types of inhibitory GABA receptors to generate contrast-enhanced voltage responses in central OSN axon terminals. Furthermore, we show how these GABA receptors modulate the time course of innate behavioral responses after odor pulse termination, demonstrating an important role for temporal contrast enhancement in odor-guided navigation. PMID:27588305

  10. The Presynaptic Active Zone Protein RIM1α Is Critical for Normal Learning and Memory

    PubMed Central

    Powell, Craig M.; Schoch, Susanne; Monteggia, Lisa; Barrot, Michel; Matos, Maria F.; Feldmann, Nicole; Südhof, Thomas C.; Nestler, Eric J.

    2014-01-01

    Summary The active zone protein RIM1α is required both for maintaining normal probability of neurotransmitter release and for long-term presynaptic potentiation at brain synapses. We now demonstrate that RIM1α−/− mice exhibit normal coordination and anxiety-related behaviors but display severely impaired learning and memory. Mice with a synaptotagmin 1 mutation, which selectively lowers release probability, and mice with Rab3A deletion, which selectively abolishes presynaptic long-term potentiation, do not exhibit this abnormality. Our data suggest that a decrease in release probability or a loss of presynaptic LTP alone is not sufficient to cause major behavioral alterations, but the combination of presynaptic abnormalities in RIM1α−/− mice severely alters learning and memory. PMID:15066271

  11. Presynaptic c-Jun N-terminal Kinase 2 regulates NMDA receptor-dependent glutamate release

    PubMed Central

    Nisticò, Robert; Florenzano, Fulvio; Mango, Dalila; Ferraina, Caterina; Grilli, Massimo; Di Prisco, Silvia; Nobili, Annalisa; Saccucci, Stefania; D'Amelio, Marcello; Morbin, Michela; Marchi, Mario; Mercuri, Nicola B.; Davis, Roger J.; Pittaluga, Anna; Feligioni, Marco

    2015-01-01

    Activation of c-Jun N-terminal kinase (JNK) signaling pathway is a critical step for neuronal death occurring in several neurological conditions. JNKs can be activated via receptor tyrosine kinases, cytokine receptors, G-protein coupled receptors and ligand-gated ion channels, including the NMDA glutamate receptors. While JNK has been generally associated with postsynaptic NMDA receptors, its presynaptic role remains largely unexplored. Here, by means of biochemical, morphological and functional approaches, we demonstrate that JNK and its scaffold protein JIP1 are also expressed at the presynaptic level and that the NMDA-evoked glutamate release is controlled by presynaptic JNK-JIP1 interaction. Moreover, using knockout mice for single JNK isoforms, we proved that JNK2 is the essential isoform in mediating this presynaptic event. Overall the present findings unveil a novel JNK2 localization and function, which is likely to play a role in different physiological and pathological conditions. PMID:25762148

  12. Increased Presynaptic and Postsynaptic α2-Adrenoceptor Activity in the Spinal Dorsal Horn in Painful Diabetic Neuropathy

    PubMed Central

    Chen, Hong; Yuan, Wei-Xiu; Pan, Hui-Lin

    2011-01-01

    Diabetic neuropathy is a common cause of chronic pain that is not adequately relieved by conventional analgesics. The α2-adrenoceptors are involved in the regulation of glutamatergic input and nociceptive transmission in the spinal dorsal horn, but their functional changes in diabetic neuropathy are not clear. The purpose of the present study was to determine the plasticity of presynaptic and postsynaptic α2-adrenoceptors in the control of spinal glutamatergic synaptic transmission in painful diabetic neuropathy. Whole-cell voltage-clamp recordings of lamina II neurons were performed in spinal cord slices from streptozotocin-induced diabetic rats. The amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) evoked from the dorsal root and the frequency of spontaneous EPSCs (sEPSCs) were significantly higher in diabetic than vehicle-control rats. The specific α2-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK-14304) (0.1–2 μM) inhibited the frequency of sEPSCs more in diabetic than vehicle-treated rats. UK-14304 also inhibited the amplitude of evoked monosynaptic and polysynaptic EPSCs more in diabetic than control rats. Furthermore, the amplitude of postsynaptic G protein-coupled inwardly rectifying K+ channel (GIRK) currents elicited by UK-14304 was significantly larger in the diabetic group than in the control group. In addition, intrathecal administration of UK-14304 increased the nociceptive threshold more in diabetic than vehicle-control rats. Our findings suggest that diabetic neuropathy increases the activity of presynaptic and postsynaptic α2-adrenoceptors to attenuate glutamatergic transmission in the spinal dorsal horn, which accounts for the potentiated antinociceptive effect of α2-adrenoceptor activation in diabetic neuropathic pain. PMID:21248068

  13. Isolation and characterization of a presynaptic neurotoxin, P-elapitoxin-Bf1a from Malaysian Bungarus fasciatus venom.

    PubMed

    Rusmili, Muhamad Rusdi Ahmad; Yee, Tee Ting; Mustafa, Mohd Rais; Hodgson, Wayne C; Othman, Iekhsan

    2014-10-01

    Presynaptic neurotoxins are one of the major components in Bungarus venom. Unlike other Bungarus species that have been studied, β-bungarotoxin has never been isolated from Bungarus fasciatus venom. It was hypothesized that the absence of β-bungarotoxin in this species was due to divergence during evolution prior to evolution of β-bungarotoxin. In this study, we have isolated a β-bungarotoxin isoform we named P-elapitoxin-Bf1a by using gel filtration, cation-exchange and reverse-phase chromatography from Malaysian B. fasciatus venom. The toxin consists of two heterogeneous subunits, subunit A and subunit B. LCMS/MS data showed that subunit A was homologous to acidic phospholipase A2 subunit A3 from Bungarus candidus and B. multicinctus venoms, whereas subunit B was homologous with subunit B1 from B. fasciatus venom that was previously detected by cDNA cloning. The toxin showed concentration- and time-dependent reduction of indirect-twitches without affecting contractile responses to ACh, CCh or KCl at the end of experiment in the chick biventer preparation. Toxin modification with 4-BPB inhibited the neurotoxic effect suggesting the importance of His-48. Tissue pre-incubation with monovalent B. fasciatus (BFAV) or neuro-polyvalent antivenom (NPV), at the recommended titer, was unable to inhibit the twitch reduction induced by the toxin. This study indicates that Malaysian B. fasciatus venom has a unique β-bungarotoxin isoform which was not neutralized by antivenoms. This suggests that there might be other presynaptic neurotoxins present in the venom and there is a variation in the enzymatic neurotoxin composition in venoms from different localities.

  14. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons.

    PubMed

    Katona, I; Sperlágh, B; Sík, A; Käfalvi, A; Vizi, E S; Mackie, K; Freund, T F

    1999-06-01

    To understand the functional significance and mechanisms of action in the CNS of endogenous and exogenous cannabinoids, it is crucial to identify the neural elements that serve as the structural substrate of these actions. We used a recently developed antibody against the CB1 cannabinoid receptor to study this question in hippocampal networks. Interneurons with features typical of basket cells showed a selective, intense staining for CB1 in all hippocampal subfields and layers. Most of them (85.6%) contained cholecystokinin (CCK), which corresponded to 96.9% of all CCK-positive interneurons, whereas only 4.6% of the parvalbumin (PV)-containing basket cells expressed CB1. Accordingly, electron microscopy revealed that CB1-immunoreactive axon terminals of CCK-containing basket cells surrounded the somata and proximal dendrites of pyramidal neurons, whereas PV-positive basket cell terminals in similar locations were negative for CB1. The synthetic cannabinoid agonist WIN 55,212-2 (0.01-3 microM) reduced dose-dependently the electrical field stimulation-induced [3H]GABA release from superfused hippocampal slices, with an EC50 value of 0. 041 microM. Inhibition of GABA release by WIN 55,212-2 was not mediated by inhibition of glutamatergic transmission because the WIN 55,212-2 effect was not reduced by the glutamate blockers AP5 and CNQX. In contrast, the CB1 cannabinoid receptor antagonist SR 141716A (1 microM) prevented this effect, whereas by itself it did not change the outflow of [3H]GABA. These results suggest that cannabinoid-mediated modulation of hippocampal interneuron networks operate largely via presynaptic receptors on CCK-immunoreactive basket cell terminals. Reduction of GABA release from these terminals is the likely mechanism by which both endogenous and exogenous CB1 ligands interfere with hippocampal network oscillations and associated cognitive functions.

  15. Presynaptic CB(1) cannabinoid receptors control frontocortical serotonin and glutamate release--species differences.

    PubMed

    Ferreira, Samira G; Teixeira, Filipe M; Garção, Pedro; Agostinho, Paula; Ledent, Catherine; Cortes, Luísa; Mackie, Ken; Köfalvi, Attila

    2012-07-01

    Both the serotonergic and endocannabinoid systems modulate frontocortical glutamate release; thus they are well positioned to participate in the pathogenesis of psychiatric disorders. With the help of fluorescent and confocal microscopy, we localized the CB(1) cannabinoid receptor (CB(1)R) in VGLUT1- and 2- (i.e. glutamatergic) and serotonin transporter- (i.e. serotonergic) -positive fibers and nerve terminals in the mouse and rat frontal cortex. CB(1)R activation by the synthetic agonists, WIN55212-2 (1 μM) and R-methanandamide (1 μM) inhibited the simultaneously measured evoked Ca(2+)-dependent release of [(14)C]glutamate and [(3)H]serotonin from frontocortical nerve terminals of Wistar rats, in a fashion sensitive to the CB(1)R antagonists, O-2050 (1 μM) and LY320135 (5 μM). CB(1)R agonists also inhibited the evoked release of [(14)C]glutamate in C57BL/6J mice in a reversible fashion upon washout. Interestingly, the evoked release of [(14)C]glutamate and [(3)H]serotonin was significantly greater in the CB(1)R knockout CD-1 mice. Furthermore, CB(1)R binding experiments revealed similar frontocortical CB(1)R density in the rat and the CD-1 mouse. Still, the evoked release of [(3)H]serotonin was modulated by neither CB(1)R agonists nor antagonists in wild-type CD-1 or C57BL/6J mice. Altogether, this is the first study to demonstrate functional presynaptic CB(1)Rs in frontocortical glutamatergic and serotonergic terminals, revealing species differences.

  16. Presynaptic pH and vesicle fusion in Drosophila larvae neurones.

    PubMed

    Caldwell, Lesley; Harries, Peter; Sydlik, Sebastian; Schwiening, Christof J

    2013-11-01

    Both intracellular pH (pHi) and synaptic cleft pH change during neuronal activity yet little is known about how these pH shifts might affect synaptic transmission by influencing vesicle fusion. To address this we imaged pH- and Ca(2+) -sensitive fluorescent indicators (HPTS, Oregon green) in boutons at neuromuscular junctions. Electrical stimulation of motor nerves evoked presynaptic Ca(2+) i rises and pHi falls (∼0.1 pH units) followed by recovery of both Ca(2+) i and pHi. The plasma-membrane calcium ATPase (PMCA) inhibitor, 5(6)-carboxyeosin diacetate, slowed both the calcium recovery and the acidification. To investigate a possible calcium-independent role for the pHi shifts in modulating vesicle fusion we recorded post-synaptic miniature end-plate potential (mEPP) and current (mEPC) frequency in Ca(2+) -free solution. Acidification by propionate superfusion, NH(4)(+) withdrawal, or the inhibition of acid extrusion on the Na(+)/H(+) exchanger (NHE) induced a rise in miniature frequency. Furthermore, the inhibition of acid extrusion enhanced the rise induced by propionate addition and NH(4)(+) removal. In the presence of NH(4)(+), 10 out of 23 cells showed, after a delay, one or more rises in miniature frequency. These findings suggest that Ca(2+) -dependent pHi shifts, caused by the PMCA and regulated by NHE, may stimulate vesicle release. Furthermore, in the presence of membrane permeant buffers, exocytosed acid or its equivalents may enhance release through positive feedback. This hitherto neglected pH signalling, and the potential feedback role of vesicular acid, could explain some important neuronal excitability changes associated with altered pH and its buffering.

  17. Modeling of twitch fade based on slow interaction of nondepolarizing muscle relaxants with the presynaptic receptors.

    PubMed

    Bhatt, Shashi B; Amann, Anton; Nigrovic, Vladimir

    2006-08-01

    Nondepolarizing muscle relaxants (MRs) diminish the indirectly evoked single twitch due to their binding to the postsynaptic receptors. Additionally, the MRs produce progressive diminution of successive twitches upon repetitive stimulation (fade). Our study addresses the generation of fade as observed under clinical situation. The study was conducted in two phases. In the clinical part, we have evaluated the time course of twitch depression and fade following the administration of several doses of three MRs (rocuronium, pancuronium, and cisatracurium). In the second part, we have modified our model of neuromuscular transmission to simulate the time course of twitch depression and fade. The MR was assumed to bind to a single site on the presynaptic receptor to produce fade. The rates of interaction with the presynaptic receptors were characterized in terms of the arbitrarily assigned equilibrium dissociation constant and the half-life for dissociation of the presynaptic complex. A method was developed to relate the release of acetylcholine to the occupancy of the presynaptic receptors. The strength of the first and the fourth twitch was calculated from the peak concentration of the activated postsynaptic receptors, i.e., of those receptors with both sites occupied by acetylcholine. Our results indicate that, while the affinity of the MR for the presynaptic receptor plays little role in the time course of fade, the rate of dissociation of the complex between the presynaptic receptors and the muscle relaxant may be critical in determining the time course of fade. Tentative estimates of this parameter are offered.

  18. Presynaptic imaging of projection fibers by in vivo injection of dextran-conjugated calcium indicators.

    PubMed

    Brenowitz, Stephan D; Regehr, Wade G

    2012-04-01

    Dextran-conjugated calcium indicators are stably retained within neurons. As a result, they are well suited to measuring presynaptic calcium at physiological temperatures. In addition, dextran indicators can be used to label neurons and their presynaptic boutons in vivo. This has allowed measurements of calcium in the presynaptic boutons of projection fibers that cannot be stably loaded with other types of indicators. This protocol describes a technique for in vivo loading of the climbing fiber projection to the cerebellum with dextran-conjugated indicators for subsequent presynaptic calcium imaging in brain slices. This technique is applicable to studies of projection fibers in many species from which brain slices can be prepared. The dextran indicator is injected into the inferior olive using a stereotaxic device. After a period of 1-3 d, cerebellar slices are prepared and presynaptic calcium transients are measured at physiological temperature in labeled climbing fibers. The protocol also discusses important considerations for using dextran-conjugated indicators to measure presynaptic calcium.

  19. Presynaptic localization of histamine H3-receptors in rat brain

    SciTech Connect

    Fujimoto, K.; Mizuguchi, H.; Fukui, H.; Wada, H. )

    1991-06-28

    The localization of histamine H3-receptors in subcellular fractions from the rat brain was examined in a (3H) (R) alpha-methylhistamine binding assay and compared with those of histamine H1- and adrenaline alpha 1- and alpha 2-receptors. Major (3H)(R) alpha-methylhistamine binding sites with increased specific activities ((3H)ligand binding vs. protein amount) were recovered from the P2 fraction by differential centrifugation. Minor (3H)(R)alpha-methylhistamine binding sites with increased specific activities were also detected in the P3 fraction. Further subfractionation of the P2 fraction by discontinuous sucrose density gradient centrifugation showed major recoveries of (3H)(R)alpha-methylhistamine binding in myelin (MYE) and synaptic plasma membrane (SPM) fractions. A further increase in specific activity was observed in the MYE fraction, but the SPM fraction showed no significant increase in specific activity. Adrenaline alpha 2-receptors, the pre-synaptic autoreceptors, in a (3H) yohimbine binding assay showed distribution patterns similar to histamine H3-receptors. On the other hand, post-synaptic histamine H1- and adrenaline alpha 1-receptors were closely localized and distributed mainly in the SPM fraction with increased specific activity. Only a negligible amount was recovered in the MYE fraction, unlike the histamine H3- and adrenaline alpha 2-receptors.

  20. Early presynaptic changes during plasticity in cultured hippocampal neurons.

    PubMed

    Ninan, Ipe; Liu, Shumin; Rabinowitz, Daniel; Arancio, Ottavio

    2006-09-20

    Long-lasting increase in synaptic strength is thought to underlie learning. An explosion of data has characterized changes in postsynaptic (pstS) AMPA receptor cycling during potentiation. However, changes occurring within the presynaptic (prS) terminal remain largely unknown. We show that appearance of new release sites during potentiation between cultured hippocampal neurons is due to (a) conversion of nonrecycling sites to recycling sites, (b) formation of new releasing sites from areas containing diffuse staining for the prS marker Vesicle-Associated Membrane Protein-2 and (c) budding of new recycling sites from previously existing recycling sites. In addition, potentiation is accompanied by a release probability increase in pre-existing boutons depending upon their individual probability. These prS changes precede and regulate fluorescence increase for pstS GFP-tagged-AMPA-receptor subunit GluR1. These results suggest that potentiation involves early changes in the prS terminal including remodeling and release probability increase of pre-existing synapses.

  1. Effect of blockade of postsynaptic H1 or H2 receptors or activation of presynaptic H3 receptors on catecholamine-induced stimulation of ACTH and prolactin secretion.

    PubMed

    Willems, E; Knigge, U; Jorgensen, H; Kjaer, A; Warberg, J

    2000-06-01

    The effect of inhibition of the neuronal histaminergic system by blockade of postsynaptic H1 or H2 receptors or activation of presynaptic H3 autoreceptors on the ACTH and prolactin responses to the catecholamines epinephrine and norepinephrine was investigated in conscious male rats. Intracerebroventricular infusion of epinephrine and norepinephrine stimulated ACTH and prolactin secretion. Prior intracerebroventricular infusion of the H1 receptor antagonist, mepyramine, or the H2 receptor antagonist, cimetidine, had no effect on the ACTH response to epinephrine or norepinephrine, while these responses were inhibited by pretreatment with the H3 receptor agonist, imetit. The prolactin response to norepinephrine was significantly inhibited by pretreatment with mepyramine, cimetidine or imetit whereas the three histaminergic compounds had no effect on the prolactin response to epinephrine. The findings suggest that the histaminergic system exerts a mediating or permissive action on the norepinephrine-induced stimulation of prolactin secretion, whereas an intact histaminergic system may not be required for catecholamines to stimulate ACTH secretion. The inhibitory effect of imetit on catecholamine-induced release of ACTH may be due to an activation of H3 receptors located presynaptically on non-histaminergic neurons, e.g. aminergic neurons. The study further indicates an important role of histamine in the neuroendocrine regulation of prolactin secretion.

  2. Effects of intracerebroventricular administration of ultra low doses of histaminergic drugs on morphine state-dependent memory of passive avoidance in mice.

    PubMed

    Khalilzadeh, Azita; Zarrindast, Mohammad-Reza; Djahanguiri, Bijan

    2006-01-06

    The effects of intracerebroventricular (i.c.v.) administration of ultra low doses (ULDs) of histamine, clobenpropit and pyrilamine are studied on morphine state-dependent (STD) memory in mice. Although pre-test administration of different doses of histamine and clobenpropit showed no effect on impairment of memory induced by pre-training morphine, when the above drugs were co-administered with morphine, they inhibited the restoration of memory by morphine. These effects were opposite to microgram doses of the same drugs.

  3. State-Dependent Riccati Equation Regulation of Systems with State and Control Nonlinearities

    NASA Technical Reports Server (NTRS)

    Beeler, Scott C.; Cox, David E. (Technical Monitor)

    2004-01-01

    The state-dependent Riccati equations (SDRE) is the basis of a technique for suboptimal feedback control of a nonlinear quadratic regulator (NQR) problem. It is an extension of the Riccati equation used for feedback control of linear problems, with the addition of nonlinearities in the state dynamics of the system resulting in a state-dependent gain matrix as the solution of the equation. In this paper several variations on the SDRE-based method will be considered for the feedback control problem with control nonlinearities. The control nonlinearities may result in complications in the numerical implementation of the control, which the different versions of the SDRE method must try to overcome. The control methods will be applied to three test problems and their resulting performance analyzed.

  4. Estimation of time- and state-dependent delays and other parameters in functional differential equations

    NASA Technical Reports Server (NTRS)

    Murphy, K. A.

    1988-01-01

    A parameter estimation algorithm is developed which can be used to estimate unknown time- or state-dependent delays and other parameters (e.g., initial condition) appearing within a nonlinear nonautonomous functional differential equation. The original infinite dimensional differential equation is approximated using linear splines, which are allowed to move with the variable delay. The variable delays are approximated using linear splines as well. The approximation scheme produces a system of ordinary differential equations with nice computational properties. The unknown parameters are estimated within the approximating systems by minimizing a least-squares fit-to-data criterion. Convergence theorems are proved for time-dependent delays and state-dependent delays within two classes, which say essentially that fitting the data by using approximations will, in the limit, provide a fit to the data using the original system. Numerical test examples are presented which illustrate the method for all types of delay.

  5. Estimation of time- and state-dependent delays and other parameters in functional differential equations

    NASA Technical Reports Server (NTRS)

    Murphy, K. A.

    1990-01-01

    A parameter estimation algorithm is developed which can be used to estimate unknown time- or state-dependent delays and other parameters (e.g., initial condition) appearing within a nonlinear nonautonomous functional differential equation. The original infinite dimensional differential equation is approximated using linear splines, which are allowed to move with the variable delay. The variable delays are approximated using linear splines as well. The approximation scheme produces a system of ordinary differential equations with nice computational properties. The unknown parameters are estimated within the approximating systems by minimizing a least-squares fit-to-data criterion. Convergence theorems are proved for time-dependent delays and state-dependent delays within two classes, which say essentially that fitting the data by using approximations will, in the limit, provide a fit to the data using the original system. Numerical test examples are presented which illustrate the method for all types of delay.

  6. Charge-state-dependent energy loss of slow ions. II. Statistical atom model

    NASA Astrophysics Data System (ADS)

    Wilhelm, Richard A.; Möller, Wolfhard

    2016-05-01

    A model for charge-dependent energy loss of slow ions is developed based on the Thomas-Fermi statistical model of atoms. Using a modified electrostatic potential which takes the ionic charge into account, nuclear and electronic energy transfers are calculated, the latter by an extension of the Firsov model. To evaluate the importance of multiple collisions even in nanometer-thick target materials we use the charge-state-dependent potentials in a Monte Carlo simulation in the binary collision approximation and compare the results to experiment. The Monte Carlo results reproduce the incident charge-state dependence of measured data well [see R. A. Wilhelm et al., Phys. Rev. A 93, 052708 (2016), 10.1103/PhysRevA.93.052708], even though the experimentally observed charge exchange dependence is not included in the model.

  7. Whereas Short-Term Facilitation Is Presynaptic, Intermediate-Term Facilitation Involves Both Presynaptic and Postsynaptic Protein Kinases and Protein Synthesis

    ERIC Educational Resources Information Center

    Jin, Iksung; Kandel, Eric R.; Hawkins, Robert D.

    2011-01-01

    Whereas short-term plasticity involves covalent modifications that are generally restricted to either presynaptic or postsynaptic structures, long-term plasticity involves the growth of new synapses, which by its nature involves both pre- and postsynaptic alterations. In addition, an intermediate-term stage of plasticity has been identified that…

  8. The dynamics of a delayed predator-prey model with state dependent feedback control

    NASA Astrophysics Data System (ADS)

    Singh, Anuraj; Gakkhar, Sunita

    2011-11-01

    A delayed prey-predator model with state-dependent impulses is investigated. The sufficient conditions of existence and stability of semi-trivial solution and positive period-1 solution are obtained by using the Poincare map and analogue of the Poincare Criterion. The qualitative analysis shows that the positive period-one solution bifurcates from the semi-trivial solution through a fold bifurcation. The complex dynamics including chaos is obtained and numerical simulations substantiate the analytical results.

  9. The dynamics of a delayed predator-prey model with state dependent feedback control

    SciTech Connect

    Singh, Anuraj; Gakkhar, Sunita

    2011-11-30

    A delayed prey-predator model with state-dependent impulses is investigated. The sufficient conditions of existence and stability of semi-trivial solution and positive period-1 solution are obtained by using the Poincare map and analogue of the Poincare Criterion. The qualitative analysis shows that the positive period-one solution bifurcates from the semi-trivial solution through a fold bifurcation. The complex dynamics including chaos is obtained and numerical simulations substantiate the analytical results.

  10. Stability and Bifurcation in a State-Dependent Delayed Predator-Prey System

    NASA Astrophysics Data System (ADS)

    Hou, Aiyu; Guo, Shangjiang

    In this paper, we consider a class of predator-prey equations with state-dependent delayed feedback. Firstly, we investigate the local stability of the positive equilibrium and the existence of the Hopf bifurcation. Then we use perturbation methods to determine the sub/supercriticality of Hopf bifurcation and hence the stability of Hopf bifurcating periodic solutions. Finally, numerical simulations supporting our theoretical results are also provided.

  11. Proteome Analysis of Rat Hippocampus Following Morphine-induced Amnesia and State-dependent Learning.

    PubMed

    Jafarinejad-Farsangi, Saeideh; Farazmand, Ali; Rezayof, Ameneh; Darbandi, Niloufar

    2015-01-01

    Morphine's effects on learning and memory processes are well known to depend on synaptic plasticity in the hippocampus. Whereas the role of the hippocampus in morphine-induced amnesia and state-dependent learning is established, the biochemical and molecular mechanisms underlying these processes are poorly understood. The present study intended to investigate whether administration of morphine can change the expression level of rat hippocampal proteins during learning of a passive avoidance task. A step-through type passive avoidance task was used for the assessment of memory retention. To identify the complex pattern of protein expression induced by morphine, we compared rat hippocampal proteome either in morphine-induced amnesia or in state-dependent learning by two-dimensional gel electerophoresis and combined mass spectrometry (MS and MS/MS). Post-training administration of morphine decreased step-through latency. Pre-test administration of morphine induced state-dependent retrieval of the memory acquired under post-training morphine influence. In the hippocampus, a total of 18 proteins were identified whose MASCOT (Modular Approach to Software Construction Operation and Test) scores were inside 95% confidence level. Of these, five hippocampal proteins altered in morphine-induced amnesia and ten proteins were found to change in the hippocampus of animals that had received post-training and pre-test morphine. These proteins show known functions in cytoskeletal architecture, cell metabolism, neurotransmitter secretion and neuroprotection. The findings indicate that the effect of morphine on memory formation in passive avoidance learning has a morphological correlate on the hippocampal proteome level. In addition, our proteomicscreensuggests that morphine induces memory impairment and state-dependent learning through modulating neuronal plasticity.

  12. Anti-periodic solutions of Liénard equations with state dependent impulses

    NASA Astrophysics Data System (ADS)

    Belley, J.-M.; Bondo, É.

    2016-10-01

    Subject to a priori bounds, Liénard equations with state dependent impulsive forcing are shown to admit a unique absolutely continuous anti-periodic solution with first derivative of bounded variation on finite intervals. The point-wise convergence of a sequence of iterates to the solution is obtained, along with a bound for the rate of convergence. The results are applied to Josephson's and van der Pol's equations.

  13. Operational constraints on state-dependent formulations of quantum error-disturbance trade-off relations

    NASA Astrophysics Data System (ADS)

    Korzekwa, Kamil; Jennings, David; Rudolph, Terry

    2014-05-01

    We argue for an operational requirement that all state-dependent measures of disturbance should satisfy. Motivated by this natural criterion, we prove that in any d-dimensional Hilbert space and for any pair of noncommuting operators, A and B, there exists a set of at least 2d -1 zero-noise, zero-disturbance (ZNZD) states, for which the first observable can be measured without noise and the second will not be disturbed. Moreover, we show that it is possible to construct such ZNZD states for which the expectation value of the commutator [A,B] does not vanish. Therefore any state-dependent error-disturbance relation, based on the expectation value of the commutator as a lower bound, must violate the operational requirement. We also discuss Ozawa's state-dependent error-disturbance relation in light of our results and show that the disturbance measure used in this relation exhibits unphysical properties. We conclude that the trade-off is inevitable only between state-independent measures of error and disturbance.

  14. Breeding matters: Natal experience influences population state-dependent host acceptance by an eruptive insect herbivore

    PubMed Central

    2017-01-01

    Eruptive forest insects are highly influential agents of change in forest ecosystems, and their effects have increased with recent climate change. State-dependent life histories contribute significantly to the population dynamics of eruptive forest insect herbivores; however, the proximate mechanisms by which these species shift between states is poorly understood. Laboratory bioassays were conducted using the mountain pine beetle (Dendroctonus ponderosae) to determine the effect of maternal host selection on offspring host preferences, as they apply to population state-dependent behaviors. Female mountain pine beetles exhibited state-dependent preference for artificial host material amended with monoterpenes in the absence of other cues, such that individuals reared in high-density epidemic-state simulations rejected low monoterpene conditions, while low-density endemic-state beetles accepted low monoterpene conditions. State-specific behavior in offspring was dependent on rearing conditions, as a function of maternal host selection, and these effects were observed within one generation. Density-dependent host selection behaviors exhibited by female mountain pine beetle offspring is reinforced by context-dependent maternal effects arising from parental host selection, and in situ exposure to conspecifics. These results demonstrate potential proximate mechanisms that control population dynamics in eruptive forest insects, and will allow for more accurate predictions of continued impact and spread of these species. PMID:28207862

  15. The translational regulator Cup controls NMJ presynaptic terminal morphology

    PubMed Central

    Menon, Kaushiki P.; Carrillo, Robert A.; Zinn, Kai

    2015-01-01

    During oogenesis and early embryonic development in Drosophila, translation of proteins from maternally deposited mRNAs is tightly controlled. We and others have previously shown that translational regulatory proteins that function during oogenesis also have essential roles in the nervous system. Here we examine the role of Cup in neuromuscular system development. Maternal Cup controls translation of localized mRNAs encoding the Oskar and Nanos proteins and binds to the general translation initiation factor eIF4E. In this paper, we show that zygotic Cup protein is localized to presynaptic terminals at larval neuromuscular junctions (NMJs). cup mutant NMJs have strong phenotypes characterized by the presence of small clustered boutons called satellite boutons. They also exhibit an increase in the frequency of spontaneous glutamate release events (mEPSPs). Reduction of eIF4E expression synergizes with partial loss of Cup expression to produce satellite bouton phenotypes. The presence of satellite boutons is often associated with increases in retrograde bone morphogenetic protein (BMP) signaling, and we show that synaptic BMP signaling is elevated in cup mutants. cup genetically interacts with four genes (EndoA, WASp, Dap160, and Synj) encoding proteins involved in endocytosis that are also neuronal modulators of the BMP pathway. Endophilin protein, encoded by the EndoA gene, is downregulated in a cup mutant. Our results are consistent with a model in which Cup and eIF4E work together to ensure efficient localization and translation of endocytosis proteins in motor neurons and control the strength of the retrograde BMP signal. PMID:26102195

  16. Some properties of the presynaptic nerve terminals in a mammalian sympathetic ganglion

    PubMed Central

    Dunant, Y.

    1972-01-01

    1. Superior cervical ganglia of adult rats were excised and maintained in vitro in stable conditions. Potentials were recorded with external electrodes. After transmission was blocked by mecamylamine, a small potential change was recorded from the rostral area of the ganglion in response to preganglionic stimulation. 2. This electrical response was identified as the presynaptic action potential recorded from the nerve terminals by a number of criteria based on histological and physiological considerations including the disappearance of the spike in a glucose free solution. As shown by Nicolescu, Dolivo, Rouiller & Foroglou-Kerameus (1966) on the same preparation this condition causes an irreversible and selective lesion of the presynaptic nerve endings. 3. A suitable concentration of mecamylamine permitted the presynaptic response and the excitatory post-synaptic potential (EPSP) to be recorded simultaneously. As the stimulus was increased, the EPSP increased linearly with the amplitude of the presynaptic response. 4. After replacement of potassium ions in the bathing solution by caesium and during the early phase of post-tetanic facilitation there was an increase in the presynaptic response accompanied by a disproportionate increase in the EPSP. 5. No changes in the presynaptic response were found in the presence of the following drugs, all of which depressed the EPSP: acetylcholine, hemicholinium, curare, further doses of ganglion-blocking agents, and high Mg2+ and low Ca2+ concentrations. 6. Ouabain (4·5 × 10-4 M) reversibly decreased the amplitude of the presynaptic response and increased the spontaneous release of transmitter. The EPSP was at first enhanced and then depressed. PMID:4335802

  17. Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment.

    PubMed

    Lawrence, James L M; Tong, Mei; Alfulaij, Naghum; Sherrin, Tessi; Contarino, Mark; White, Michael M; Bellinger, Frederick P; Todorovic, Cedomir; Nichols, Robert A

    2014-10-22

    Soluble β-amyloid has been shown to regulate presynaptic Ca(2+) and synaptic plasticity. In particular, picomolar β-amyloid was found to have an agonist-like action on presynaptic nicotinic receptors and to augment long-term potentiation (LTP) in a manner dependent upon nicotinic receptors. Here, we report that a functional N-terminal domain exists within β-amyloid for its agonist-like activity. This sequence corresponds to a N-terminal fragment generated by the combined action of α- and β-secretases, and resident carboxypeptidase. The N-terminal β-amyloid fragment is present in the brains and CSF of healthy adults as well as in Alzheimer's patients. Unlike full-length β-amyloid, the N-terminal β-amyloid fragment is monomeric and nontoxic. In Ca(2+) imaging studies using a model reconstituted rodent neuroblastoma cell line and isolated mouse nerve terminals, the N-terminal β-amyloid fragment proved to be highly potent and more effective than full-length β-amyloid in its agonist-like action on nicotinic receptors. In addition, the N-terminal β-amyloid fragment augmented theta burst-induced post-tetanic potentiation and LTP in mouse hippocampal slices. The N-terminal fragment also rescued LTP inhibited by elevated levels of full-length β-amyloid. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal β-amyloid fragment into the dorsal hippocampi of intact mice. The fragment-induced augmentation of fear conditioning was attenuated by coadministration of nicotinic antagonist. The activity of the N-terminal β-amyloid fragment appears to reside largely in a sequence surrounding a putative metal binding site, YEVHHQ. These findings suggest that the N-terminal β-amyloid fragment may serve as a potent and effective endogenous neuromodulator.

  18. Presynaptic Localization and Possible Function of Calcium-Activated Chloride Channel Anoctamin 1 in the Mammalian Retina

    PubMed Central

    Chun, Myung-Hoon; Oh, Uhtaek; Kim, In-Beom

    2013-01-01

    Calcium (Ca2+)-activated chloride (Cl−) channels (CaCCs) play a role in the modulation of action potentials and synaptic responses in the somatodendritic regions of central neurons. In the vertebrate retina, large Ca2+-activated Cl− currents (ICl(Ca)) regulate synaptic transmission at photoreceptor terminals; however, the molecular identity of CaCCs that mediate ICl(Ca) remains unclear. The transmembrane protein, TMEM16A, also called anoctamin 1 (ANO1), has been recently validated as a CaCC and is widely expressed in various secretory epithelia and nervous tissues. Despite the fact that tmem16a was first cloned in the retina, there is little information on its cellular localization and function in the mammalian retina. In this study, we found that ANO1 was abundantly expressed as puncta in 2 synaptic layers. More specifically, ANO1 immunoreactivity was observed in the presynaptic terminals of various retinal neurons, including photoreceptors. ICl(Ca) was first detected in dissociated rod bipolar cells expressing ANO1. ICl(Ca) was abolished by treatment with the Ca2+ channel blocker Co2+, the L-type Ca2+ channel blocker nifedipine, and the Cl− channel blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and niflumic acid (NFA). More specifically, a recently discovered ANO1-selective inhibitor, T16Ainh-A01, and a neutralizing antibody against ANO1 inhibited ICl(Ca) in rod bipolar cells. Under a current-clamping mode, the suppression of ICl(Ca) by using NPPB and T16Ainh-A01 caused a prolonged Ca2+ spike-like depolarization evoked by current injection in dissociated rod bipolar cells. These results suggest that ANO1 confers ICl(Ca) in retinal neurons and acts as an intrinsic regulator of the presynaptic membrane potential during synaptic transmission. PMID:23840801

  19. Presynaptically mediated effects of cholecystokinin-8 on the excitability of area postrema neurons in rat brain slices.

    PubMed

    Sugeta, Shingo; Hirai, Yoshiyuki; Maezawa, Hitoshi; Inoue, Nobuo; Yamazaki, Yutaka; Funahashi, Makoto

    2015-08-27

    Cholecystokinin (CCK) is a well-known gut hormone that shows anorexigenic effects via action at peripheral and central receptors. CCK is also widely distributed throughout the mammalian brain and appears to function as a neurotransmitter and neuromodulator. The area postrema is one of the circumventricular organs, located on the dorsal surface of the medulla oblongata at the caudal end of the fourth ventricle. Blood vessels in the area postrema lack a blood brain barrier, offering specific central neural elements unique access to circulating substances. Immunohistochemical studies show CCK-A receptors in the area postrema, and we reported CCK-sensitive area postrema neurons. However, the receptive mechanism of CCK in area postrema neurons still remains unexplained. We investigated the responses of area postrema neurons to agonists and antagonists of CCK receptors using whole cell and perforated patch-clamp recordings in rat brain slices. The application of CCK-8 elicited excitatory responses, such as increases in the frequency of mEPSCs (miniature excitatory postsynaptic currents), a shift toward larger amplitude mEPSCs, and increases in the frequency of action potentials. These changes were found mostly in cells not displaying the hyperpolarization-activated cation current (Ih), except for small excitatory changes in a minority of Ih-positive neurons. Tonic inward currents or an inhibitory response to CCK-8 were never seen. Analysis of the amplitude of mEPSCs before and after the administration of CCK-8 indicated the responses mediated via the presynaptic receptors. The effect of CCK-8 was abolished in the presence of CNQX (AMPA type glutamate receptor antagonist). In the presence of lorglumide (a selective CCK-A receptor antagonist), CCK-8-induced excitatory responses were inhibited. No cells responded to the administration of non-sulfated CCK-8 (CCK-8NS, a selective CCK-B receptor agonist). We conclude that CCK-8 exerts its action via presynaptic CCK-A receptors

  20. Presynaptic modulation of spinal nociceptive transmission by glial cell line-derived neurotrophic factor (GDNF).

    PubMed

    Salio, Chiara; Ferrini, Francesco; Muthuraju, Sangu; Merighi, Adalberto

    2014-10-08

    The role of glial cell line-derived neurotrophic factor (GDNF) in nociceptive pathways is still controversial, as both pronociceptive and antinociceptive actions have been reported. To elucidate this role in the mouse, we performed combined structural and functional studies in vivo and in acute spinal cord slices where C-fiber activation was mimicked by capsaicin challenge. Nociceptors and their terminals in superficial dorsal horn (SDH; laminae I-II) constitute two separate subpopulations: the peptidergic CGRP/somatostatin+ cells expressing GDNF and the nonpeptidergic IB4+ neurons expressing the GFRα1-RET GDNF receptor complex. Ultrastructurally the dorsal part of inner lamina II (LIIid) harbors a mix of glomeruli that either display GDNF/somatostatin (GIb)-IR or GFRα1/IB4 labeling (GIa). LIIid thus represents the preferential site for ligand-receptor interactions. Functionally, endogenous GDNF released from peptidergic CGRP/somatostatin+ nociceptors upon capsaicin stimulation exert a tonic inhibitory control on the glutamate excitatory drive of SDH neurons as measured after ERK1/2 phosphorylation assay. Real-time Ca(2+) imaging and patch-clamp experiments with bath-applied GDNF (100 nM) confirm the presynaptic inhibition of SDH neurons after stimulation of capsaicin-sensitive, nociceptive primary afferent fibers. Accordingly, the reduction of the capsaicin-evoked [Ca(2+)]i rise and of the frequency of mEPSCs in SDH neurons is specifically abolished after enzymatic ablation of GFRα1. Therefore, GDNF released from peptidergic CGRP/somatostatin+ nociceptors acutely depresses neuronal transmission in SDH signaling to nonpeptidergic IB4+ nociceptors at glomeruli in LIIid. These observations are of potential pharmacological interest as they highlight a novel modality of cross talk between nociceptors that may be relevant for discrimination of pain modalities.

  1. A functionally active presynaptic high-affinity kainate receptor in the rat hippocampal CA3 subregion.

    PubMed

    Malva, J O; Ambrósio, A F; Cunha, R A; Ribeiro, J A; Carvalho, A P; Carvalho, C M

    1995-02-09

    We studied the modulation of the intracellular free calcium concentrations ([Ca2+]i) by kainate/AMPA receptor activation in synaptosomes isolated from whole rat hippocampus, or from its CA1, CA3 or dentate gyrus subregions. The receptor was activated either by 100 microM S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid (AMPA) (EC50 = 26.6 +/- 4.9 microM) or by 100 microM kainate (EC50 = 0.81 +/- 0.1 microM), but the effects of these agonists were not additive. The response to either AMPA or kainate was competitively inhibited by 10 microM 6-cyano-7-nitroquinoxaline-2,3-dioxine. Higher [Ca2+]i responses to 100 microM AMPA or to 100 microM kainate were observed in the CA3 subregion (43.2 +/- 2.5 nM or 42.8 +/- 2.3 nM, respectively) than in the whole hippocampus (22.4 +/- 1.1 nM or 22.4 +/- 1.6, respectively), in the CA1 subregion (26.4 +/- 1.1 nM or 26.6 +/- 2.6 nM, respectively) or in dentate gyrus (24.6 +/- 1.4 nM or 21.5 +/- 1.0 nM, respectively). These results indicate that the CA3 subregion of the hippocampus is enriched in a presynaptic high-affinity kainate receptor which modulates the [Ca2+]i in nerve terminals.

  2. Evidence for sympathetic neurotransmission through presynaptic N-type calcium channels in human saphenous vein.

    PubMed Central

    Fabi, F.; Chiavarelli, M.; Argiolas, L.; Chiavarelli, R.; del Basso, P.

    1993-01-01

    1. The specific type(s) of voltage-sensitive calcium channels (VSCCs) involved in sympathetic neurotransmission have not yet been characterized in human vascular tissues. We therefore examined the functional role of the N- and L-type VSCCs in human saphenous veins. 2. Contractile response curves for transmural nerve stimulation (TNS) and for exogenously administered noradrenaline (NA) were obtained in superfused saphenous vein rings. The contractions induced by TNS, but not by NA, were inhibited by 1 microM tetrodotoxin and by 10 microM guanethidine. Both responses were substantially reduced by 1 microM phentolamine, indicating that the contractions evoked by TNS were mediated by endogenous NA released from noradrenergic nerves. 3. In the presence of 2 microM omega-conotoxin GVIA (omega Conus Geographus toxin, fraction VI A; omega-CgTx), a polypeptide with specific inhibitory activity on N- and L-type calcium channels, the neurally evoked contractions were almost completely abolished. In contrast, the responses induced by exogenous NA were not affected by the neurotoxin, thus providing evidence of the exclusive presynaptic action of omega-CgTx. 4. In the presence of the calcium antagonist verapamil (10 microM), which selectively blocks L-type VSCCs, the contractions induced by both TNS and NA were diminished to the same extent, suggesting that the organic calcium blocker is active only at the postjunctional level. 5. It is concluded that N-type calcium channels are the main pathway of calcium entry controlling the functional responses induced by activating sympathetic nerves; the role of L-type channels appears to be limited to the postjunctional level, modulating smooth muscle contractions. PMID:8220895

  3. Presynaptic alpha2-adrenoceptors control excitatory, but not inhibitory, transmission at rat hippocampal synapses.

    PubMed

    Boehm, S

    1999-09-01

    affect K+ currents and failed to alter the frequency of miniature excitatory postsynaptic currents measured in mass cultures of hippocampal neurons. 5. These results show that noradrenaline regulates transmission at glutamatergic, but not at GABAergic, hippocampal synapses via presynaptic alpha2-adrenoceptors of the alpha2A/D subtype. This inhibitory action involves an inhibition of voltage-activated Ca2+ currents, but no modulation of spontaneous vesicle exocytosis or of voltage-activated K+ currents.

  4. The amino-terminal domain of glutamate receptor {delta}2 triggers presynaptic differentiation

    SciTech Connect

    Uemura, Takeshi; Mishina, Masayoshi

    2008-12-26

    Glutamate receptor (GluR) {delta}2 selectively expressed in cerebellar Purkinje cells plays key roles in synapse formation, long-term depression and motor learning. We propose that GluR{delta}2 regulates synapse formation by making a physical linkage between the active zone and postsynaptic density. To examine the issue, GluR{delta}2-transfected 293T cells were cultured with cerebellar neurons. We found numerous punctate signals for presynaptic markers on the surface of 293T cells expressing GluR{delta}2. The presynaptic specializations induced by GluR{delta}2 were capable of exo- and endocytosis as indicated by FM1-43 dye labeling. Replacement of the extracellular N-terminal domain (NTD) of GluR{delta}2 with that of the AMPA receptor GluR{alpha}1 abolished the inducing activity. The NTD of GluR{delta}2 fused to the immunoglobulin constant region successfully induced the accumulation of presynaptic specializations on the surface of beads bearing the fusion protein. These results suggest that GluR{delta}2 triggers presynaptic differentiation by direct interaction with presynaptic components through the NTD.

  5. Role of the Wnt receptor Frizzled-1 in presynaptic differentiation and function

    PubMed Central

    2009-01-01

    Background The Wnt signaling pathway regulates several fundamental developmental processes and recently has been shown to be involved in different aspects of synaptic differentiation and plasticity. Some Wnt signaling components are localized at central synapses, and it is thus possible that this pathway could be activated at the synapse. Results We examined the distribution of the Wnt receptor Frizzled-1 in cultured hippocampal neurons and determined that this receptor is located at synaptic contacts co-localizing with presynaptic proteins. Frizzled-1 was found in functional synapses detected with FM1-43 staining and in synaptic terminals from adult rat brain. Interestingly, overexpression of Frizzled-1 increased the number of clusters of Bassoon, a component of the active zone, while treatment with the extracellular cysteine-rich domain (CRD) of Frizzled-1 decreased Bassoon clustering, suggesting a role for this receptor in presynaptic differentiation. Consistent with this, treatment with the Frizzled-1 ligand Wnt-3a induced presynaptic protein clustering and increased functional presynaptic recycling sites, and these effects were prevented by co-treatment with the CRD of Frizzled-1. Moreover, in synaptically mature neurons Wnt-3a was able to modulate the kinetics of neurotransmitter release. Conclusion Our results indicate that the activation of the Wnt pathway through Frizzled-1 occurs at the presynaptic level, and suggest that the synaptic effects of the Wnt signaling pathway could be modulated by local activation through synaptic Frizzled receptors. PMID:19883499

  6. RIM determines Ca2+ channel density and vesicle docking at the presynaptic active zone

    PubMed Central

    Han, Yunyun; Kaeser, Pascal S.; Südhof, Thomas C.; Schneggenburger, Ralf

    2012-01-01

    At presynaptic active zones, neurotransmitter release is initiated by the opening of voltage-gated Ca2+ channels close to docked vesicles. The mechanisms that enrich Ca2+ channels at active zones are, however, largely unknown, possibly because of the limited presynaptic accessibility of most synapses. Here, we have established a Cre-lox based conditional knock-out approach at a presynaptically accessible CNS synapse, the calyx of Held, to directly study the functions of RIM proteins. Removal of all RIM1/2 isoforms strongly reduced the presynaptic Ca2+ channel density, revealing a new role of RIM proteins in Ca2+ channel targeting. Removal of RIMs also reduced the readily-releasable pool, paralleled by a similar reduction of the number of docked vesicles, and the Ca2+ channel - vesicle coupling was decreased. Thus, RIM proteins co-ordinately regulate key functions for fast transmitter release: enabling a high presynaptic Ca2+ channel density, and vesicle docking at the active zone. PMID:21262468

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

    PubMed

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

    1990-09-01

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

  8. Evidence of Presynaptic Localization and Function of the c-Jun N-Terminal Kinase

    PubMed Central

    Biggi, Silvia; Buccarello, Lucia; Sclip, Alessandra; Lippiello, Pellegrino; Rumio, Cristiano; Di Marino, Daniele

    2017-01-01

    The c-Jun N-terminal kinase (JNK) is part of a stress signalling pathway strongly activated by NMDA-stimulation and involved in synaptic plasticity. Many studies have been focused on the post-synaptic mechanism of JNK action, and less is known about JNK presynaptic localization and its physiological role at this site. Here we examined whether JNK is present at the presynaptic site and its activity after presynaptic NMDA receptors stimulation. By using N-SIM Structured Super Resolution Microscopy as well as biochemical approaches, we demonstrated that presynaptic fractions contained significant amount of JNK protein and its activated form. By means of modelling design, we found that JNK, via the JBD domain, acts as a physiological effector on T-SNARE proteins; then using biochemical approaches we demonstrated the interaction between Syntaxin-1-JNK, Syntaxin-2-JNK, and Snap25-JNK. In addition, taking advance of the specific JNK inhibitor peptide, D-JNKI1, we defined JNK action on the SNARE complex formation. Finally, electrophysiological recordings confirmed the role of JNK in the presynaptic modulation of vesicle release. These data suggest that JNK-dependent phosphorylation of T-SNARE proteins may have an important functional role in synaptic plasticity. PMID:28367336

  9. GABA-Mediated Presynaptic Inhibition Is Required for Precision of Long-Term Memory

    ERIC Educational Resources Information Center

    Cullen, Patrick K.; Dulka, Brooke N.; Ortiz, Samantha; Riccio, David C.; Jasnow, Aaron M.

    2014-01-01

    Though much attention has been given to the neural structures that underlie the long-term consolidation of contextual memories, little is known about the mechanisms responsible for the maintenance of memory precision. Here, we demonstrate a rapid time-dependent decline in memory precision in GABA [subscript B(1a)] receptor knockout mice. First, we…

  10. Investigations into neuropeptide Y-mediated presynaptic inhibition in cultured hippocampal neurones of the rat.

    PubMed Central

    Bleakman, D.; Harrison, N. L.; Colmers, W. F.; Miller, R. J.

    1992-01-01

    1. We have examined the effects of neuropeptide Y (NPY) on synaptic transmission and [Ca2+]i signals in rat hippocampal neurones grown in culture. [Ca2+]i in individual neurones displayed frequent spontaneous fluctuations often resulting in an elevated plateau [Ca2+]i. These fluctuations were reduced by tetrodotoxin (1 microM) or combinations of the excitatory amino acid antagonists 6-cyano-7-dinitro-quinoxaline (CNQX) (10 microM) and aminophosphonovalerate (APV) (50 microM), indicating that they were the result of glutamatergic transmission occurring between hippocampal neurones. 2. [Ca2+]i fluctuations were also prevented by Ni2+ (200 microM), by the GABAB receptor agonist, baclofen (10 microM) and by NPY (100 nM) or Y2 receptor-selective NPY agonists. Following treatment of cells with pertussis toxin, NPY produced only a brief decrease in [Ca2+]i fluctuations which rapidly recovered. 3. Perfusion of hippocampal neurones with 50 mM K+ produced a large rapid increase in [Ca2+]i. This increase was slightly reduced by NPY or by a combination of CNQX and APV. The effects of CNQX/APV occluded those of NPY. NPY had no effect on Ba2+ currents measured in hippocampal neurones under whole cell voltage-clamp even in the presence of intracellular GTP-gamma-S. On the other hand, Ba2+ currents were reduced by both Cd2+ (200 microM) and baclofen (10 microM). 4. Current clamp recordings from hippocampal neurones demonstrated the occurrence of spontaneous e.p.s.ps and action potential firing which were accompanied by increases in [Ca2+]i. This spontaneous activity and the accompanying [Ca2+]i signals were prevented by application of NPY (100 nM).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1358389

  11. Noradrenergic inhibition of presynaptic TRPV1 channels: a new pathway of pain control.

    PubMed

    Carbone, Emilio

    2017-02-16

    Chronic pain is a major health problem that heavily conditions life quality and results in a huge socio-economic cost. Currently available drugs and therapies are often inadequate for treating pain in many patients, particularly when "acute" pain converts to a "chronic" state This article is protected by copyright. All rights reserved.

  12. Electrophysiological characterization of activation state-dependent Cav2 channel antagonist TROX-1 in spinal nerve injured rats

    PubMed Central

    Patel, R.; Rutten, K.; Valdor, M.; Schiene, K.; Wigge, S.; Schunk, S.; Damann, N.; Christoph, T.; Dickenson, A.H.

    2015-01-01

    Prialt, a synthetic version of Cav2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Cav2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Cav2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury. PMID:25839150

  13. Electrophysiological characterization of activation state-dependent Ca(v)2 channel antagonist TROX-1 in spinal nerve injured rats.

    PubMed

    Patel, R; Rutten, K; Valdor, M; Schiene, K; Wigge, S; Schunk, S; Damann, N; Christoph, T; Dickenson, A H

    2015-06-25

    Prialt, a synthetic version of Ca(v)2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Ca(v)2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Ca(v)2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury.

  14. Characterization of the substituted N-triazole oxindole TROX-1, a small-molecule, state-dependent inhibitor of Ca(V)2 calcium channels.

    PubMed

    Swensen, Andrew M; Herrington, James; Bugianesi, Randal M; Dai, Ge; Haedo, Rodolfo J; Ratliff, Kevin S; Smith, McHardy M; Warren, Vivien A; Arneric, Stephen P; Eduljee, Cyrus; Parker, David; Snutch, Terrance P; Hoyt, Scott B; London, Clare; Duffy, Joseph L; Kaczorowski, Gregory J; McManus, Owen B

    2012-03-01

    Biological, genetic, and clinical evidence provide validation for N-type calcium channels (Ca(V)2.2) as therapeutic targets for chronic pain. A state-dependent Ca(V)2.2 inhibitor may provide an improved therapeutic window over ziconotide, the peptidyl Ca(V)2.2 inhibitor used clinically. Supporting this notion, we recently reported that in preclinical models, the state-dependent Ca(V)2 inhibitor (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1) has an improved therapeutic window compared with ziconotide. Here we characterize TROX-1 inhibition of Cav2.2 channels in more detail. When channels are biased toward open/inactivated states by depolarizing the membrane potential under voltage-clamp electrophysiology, TROX-1 inhibits Ca(V)2.2 channels with an IC(50) of 0.11 μM. The voltage dependence of Ca(V)2.2 inhibition was examined using automated electrophysiology. TROX-1 IC(50) values were 4.2, 0.90, and 0.36 μM at -110, -90, and -70 mV, respectively. TROX-1 displayed use-dependent inhibition of Ca(V)2.2 with a 10-fold IC(50) separation between first (27 μM) and last (2.7 μM) pulses in a train. In a fluorescence-based calcium influx assay, TROX-1 inhibited Ca(V)2.2 channels with an IC(50) of 9.5 μM under hyperpolarized conditions and 0.69 μM under depolarized conditions. Finally, TROX-1 potency was examined across the Ca(V)2 subfamily. Depolarized IC(50) values were 0.29, 0.19, and 0.28 μM by manual electrophysiology using matched conditions and 1.8, 0.69, and 1.1 μM by calcium influx for Ca(V)2.1, Ca(V)2.2, and Ca(V)2.3, respectively. Together, these in vitro data support the idea that a state-dependent, non-subtype-selective Ca(V)2 channel inhibitor can achieve an improved therapeutic window over the relatively state-independent Ca(V)2.2-selective inhibitor ziconotide in preclinical models of chronic pain.

  15. Postsynaptic, not presynaptic NMDA receptors are required for spike timing dependent LTD induction

    PubMed Central

    Carter, Brett C.; Jahr, Craig E.

    2016-01-01

    Long-term depression (LTD) between cortical layer 4 spiny stellate cells and layer 2/3 pyramidal cells requires the activation of NMDA receptors (NMDARs). In young rodents, this form of LTD has been repeatedly reported to require presynaptic NMDARs for its induction. Here we show that at this synapse in the somatosensory cortex of 2 to 3 week old rats and mice, postsynaptic, not presynaptic NMDARs are required for LTD induction. First, we find no evidence for functional NMDARs in L4 neuron axons using 2 photon laser scanning microscopy and 2 photon glutamate uncaging. Second, we find that genetic deletion of postsynaptic, but not presynaptic NMDARs prevents LTD induction. Finally, the pharmacology of the NMDAR requirement is consistent with a non-ionic signaling mechanism. PMID:27399842

  16. Presynaptic potentials and facilitation of transmitter release in the squid giant synapse

    PubMed Central

    1978-01-01

    Presynaptic potentials were studied during facilitation of transmitter release in the squid giant synapse. Changes in action potentials were found to cause some, but not all, of the facilitation during twin-pulse stimulation. During trains of action potentials, there were no progressive changes in presynaptic action potentials which could account for the growth of facilitation. Facilitation could still be detected in terminals which had undergone conditioning depolarization or hyperpolarization. Facilitation could be produced by small action potentials in low [Ca++]o and by small depolarizations in the presence of tetrodotoxin. Although the production of facilitation varied somewhat with presynaptic depolarization, nevertheless, approximately equal amounts of facilitation could be produced by depolarizations which caused the release of very different amounts of transmitter. PMID:31412

  17. Control and Plasticity of the Presynaptic Action Potential Waveform at Small CNS Nerve Terminals

    PubMed Central

    Hoppa, Michael B.; Gouzer, Geraldine; Armbruster, Moritz; Ryan, Timothy A.

    2014-01-01

    SUMMARY The steep dependence of exocytosis on Ca2+ entry at nerve terminals implies that voltage control of both Ca2+ channel opening and the driving force for Ca2+ entry are powerful levers in sculpting synaptic efficacy. Using fast, genetically encoded voltage indicators in dissociated primary neurons, we show that at small nerve terminals K+ channels constrain the peak voltage of the presynaptic action potential (APSYN) to values much lower than those at cell somas. This key APSYN property additionally shows adaptive plasticity: manipulations that increase presynaptic Ca2+ channel abundance and release probability result in a commensurate lowering of the APSYN peak and narrowing of the waveform, while manipulations that decrease presynaptic Ca2+ channel abundance do the opposite. This modulation is eliminated upon blockade of Kv3.1 and Kv1 channels. Our studies thus reveal that adaptive plasticity in the APSYN waveform serves as an important regulator of synaptic function. PMID:25447742

  18. Presynaptic Excitation via GABAB Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression.

    PubMed

    Zhang, Juen; Tan, Lubin; Ren, Yuqi; Liang, Jingwen; Lin, Rui; Feng, Qiru; Zhou, Jingfeng; Hu, Fei; Ren, Jing; Wei, Chao; Yu, Tao; Zhuang, Yinghua; Bettler, Bernhard; Wang, Fengchao; Luo, Minmin

    2016-07-28

    Fear behaviors are regulated by adaptive mechanisms that dampen their expression in the absence of danger. By studying circuits and the molecular mechanisms underlying this adaptive response, we show that cholinergic neurons of the medial habenula reduce fear memory expression through GABAB presynaptic excitation. Ablating these neurons or inactivating their GABAB receptors impairs fear extinction in mice, whereas activating the neurons or their axonal GABAB receptors reduces conditioned fear. Although considered exclusively inhibitory, here, GABAB mediates excitation by amplifying presynaptic Ca(2+) entry through Cav2.3 channels and potentiating co-release of glutamate, acetylcholine, and neurokinin B to excite interpeduncular neurons. Activating the receptors for these neurotransmitters or enhancing neurotransmission with a phosphodiesterase inhibitor reduces fear responses of both wild-type and GABAB mutant mice. We identify the role of an extra-amygdalar circuit and presynaptic GABAB receptors in fear control, suggesting that boosting neurotransmission in this pathway might ameliorate some fear disorders.

  19. NFAT regulates pre-synaptic development and activity-dependent plasticity in Drosophila

    PubMed Central

    Freeman, Amanda; Franciscovich, Amy; Bowers, Mallory; Sandstrom, David J.; Sanyal, Subhabrata

    2010-01-01

    The calcium-regulated transcription factor NFAT is emerging as a key regulator of neuronal development and plasticity but precise cellular consequences of NFAT function remain poorly understood. Here, we report that the single Drosophila NFAT homolog is widely expressed in the nervous system including motor neurons and unexpectedly controls neural excitability. Likely due to this effect on excitability, NFAT regulates overall larval locomotion and both chronic and acute forms of activity-dependent plasticity at the larval glutamatergic neuro-muscular synapse. Specifically, NFAT-dependent synaptic phenotypes include changes in the number of pre-synaptic boutons, stable modifications in synaptic microtubule architecture and pre-synaptic transmitter release, while no evidence is found for synaptic retraction or alterations in the level of the synaptic cell adhesion molecule FasII. We propose that NFAT regulates pre-synaptic development and constraints long-term plasticity by dampening neuronal excitability. PMID:21185939

  20. Induction of excitatory and inhibitory presynaptic differentiation by GluD1.

    PubMed

    Ryu, Kyounghee; Yokoyama, Marie; Yamashita, Manami; Hirano, Tomoo

    2012-01-06

    The δ subfamily of ionotropic glutamate receptor subunits consists of GluD1 and GluD2. GluD2, which is selectively expressed in cerebellar Purkinje neurons, has been shown to contribute to the formation of synapses between granule neurons and Purkinje neurons through interaction with Cbln1 (cerebellin precursor protein1) and presynaptic Neurexin. On the other hand, the synaptogenic activity of GluD1, which is expressed not in the cerebellum but in the hippocampus, remains to be characterized. Here, we report that GluD1 expressed in non-neuronal HEK cells, induced presynaptic differentiation of granule neurons through its N-terminal domain in co-cultures with cerebellar neurons, similarly to GluD2. We also show that GluD1 rescued the defect of synapse formation in GluD2-knockout Purkinje neurons, indicating the functional similarity of GluD1 and GluD2. In contrast, GluD1 expression alone did not induce presynaptic differentiation in co-cultures of HEK cells with hippocampal neurons. However, when Cbln1 was exogenously added to the culture medium, GluD1 induced presynaptic differentiation of not only glutamatergic presynaptic terminals but also GABAergic ones. Cbln1 is not expressed in hippocampal neurons but is expressed in entorhinal cortical neurons projecting to the hippocampus. In co-cultures of HEK cells expressing GluD1 and entorhinal cortical neurons, both glutamatergic and GABAergic presynaptic terminals were formed on the HEK cells without exogenous application of Cbln1. These results suggest that GluD1 might contribute to the formation of specific synapses in the hippocampus such as those formed by the projecting neurons of the entorhinal cortex.

  1. Presynaptic kainate receptors impart an associative property to hippocampal mossy fiber long-term potentiation.

    PubMed

    Schmitz, Dietmar; Mellor, Jack; Breustedt, Joerg; Nicoll, Roger A

    2003-10-01

    Hippocampal mossy fiber synapses show an unusual form of long-term potentiation (LTP) that is independent of NMDA receptor activation and is expressed presynaptically. Using receptor antagonists, as well as receptor knockout mice, we found that presynaptic kainate receptors facilitate the induction of mossy fiber long-term potentiation (LTP), although they are not required for this form of LTP. Most importantly, these receptors impart an associativity to mossy fiber LTP such that activity in neighboring mossy fiber synapses, or even associational/commissural synapses, influences the threshold for inducing mossy fiber LTP. Such a mechanism greatly increases the computational power of this form of plasticity.

  2. Effects of carbamazepine, phenytoin, valproic acid, oxcarbazepine, lamotrigine, topiramate and vinpocetine on the presynaptic Ca2+ channel-mediated release of [3H]glutamate: comparison with the Na+ channel-mediated release.

    PubMed

    Sitges, María; Guarneros, Araceli; Nekrassov, Vladimir

    2007-12-01

    The effect of carbamazepine, phenytoin, valproate, oxcarbazepine, lamotrigine and topiramate, that are among the most widely used antiepileptic drugs (AEDs), and of the new putative AED vinpocetine on the Ca(2+) channel-mediated release of [(3)H]Glu evoked by high K(+) in hippocampal isolated nerve endings was investigated. Results show that carbamazepine, oxcarbazepine and phenytoin reduced [(3)H]Glu release to high K(+) to about 30% and 55% at concentrations of 500 microM and 1500 microM, respectively; lamotrigine and topiramate to about 27% at 1500 microM; while valproate failed to modify it. Vinpocetine was the most potent and effective; 50 microM vinpocetine practically abolished the high K(+) evoked release of [(3)H]Glu. Comparison of the inhibition exerted by the AEDs on [(3)H]Glu release evoked by high K(+) with the inhibition exerted by the AEDs on [(3)H]Glu release evoked by the Na(+) channel opener, veratridine, shows that all the AEDs are in general more effective blockers of the presynaptic Na(+) than of the presynaptic Ca(2+) channel-mediated response. The high doses of AEDs required to control seizures are frequently accompanied by adverse secondary effects. Therefore, the higher potency and efficacy of vinpocetine to reduce the permeability of presynaptic ionic channels controlling the release of the most important excitatory neurotransmitter in the brain must be advantageous in the treatment of epilepsy.

  3. Deficit of state-dependent risk attitude modulation in gambling disorder.

    PubMed

    Fujimoto, A; Tsurumi, K; Kawada, R; Murao, T; Takeuchi, H; Murai, T; Takahashi, H

    2017-04-04

    Gambling disorder (GD) is often considered as a problem of trait-like risk preference. However, the symptoms of GD cannot be fully understood by this trait view. In the present study, we hypothesized that GD patients also had problem with a flexible control of risk attitude (state-dependent strategy optimization), and aimed to investigate the mechanisms underlying abnormal risk-taking of GD. To address this issue, we tested GD patients without comorbidity (GD group: n=21) and age-matched healthy control participants (HC group: n=29) in a multi-step gambling task, in which participants needed to clear 'block quota' (required units to clear a block, 1000-7000 units) in 20 choices, and conducted a task-functional magnetic resonance imaging (fMRI) experiment. Behavioral analysis indeed revealed a less flexible risk-attitude change in the GD group; the GD group failed to avoid risky choice in a specific quota range (low-quota condition), in which risky strategy was not optimal to solve the quota. Accordingly, fMRI analysis highlighted diminished functioning of the dorsolateral prefrontal cortex (dlPFC), which has been heavily implicated in cognitive flexibility. To our knowledge, the present study provided the first empirical evidence of a deficit of state-dependent strategy optimization in GD. Focusing on flexible control of risk attitude under quota may contribute to a better understanding of the psychopathology of GDs.

  4. Predicting behavioural responses to novel organisms: state-dependent detection theory.

    PubMed

    Trimmer, Pete C; Ehlman, Sean M; Sih, Andrew

    2017-01-25

    Human activity alters natural habitats for many species. Understanding variation in animals' behavioural responses to these changing environments is critical. We show how signal detection theory can be used within a wider framework of state-dependent modelling to predict behavioural responses to a major environmental change: novel, exotic species. We allow thresholds for action to be a function of reserves, and demonstrate how optimal thresholds can be calculated. We term this framework 'state-dependent detection theory' (SDDT). We focus on behavioural and fitness outcomes when animals continue to use formerly adaptive thresholds following environmental change. In a simple example, we show that exposure to novel animals which appear dangerous-but are actually safe-(e.g. ecotourists) can have catastrophic consequences for 'prey' (organisms that respond as if the new organisms are predators), significantly increasing mortality even when the novel species is not predatory. SDDT also reveals that the effect on reproduction can be greater than the effect on lifespan. We investigate factors that influence the effect of novel organisms, and address the potential for behavioural adjustments (via evolution or learning) to recover otherwise reduced fitness. Although effects of environmental change are often difficult to predict, we suggest that SDDT provides a useful route ahead.

  5. Stochastic modeling of biochemical systems with multistep reactions using state-dependent time delay

    PubMed Central

    Wu, Qianqian; Tian, Tianhai

    2016-01-01

    To deal with the growing scale of molecular systems, sophisticated modelling techniques have been designed in recent years to reduce the complexity of mathematical models. Among them, a widely used approach is delayed reaction for simplifying multistep reactions. However, recent research results suggest that a delayed reaction with constant time delay is unable to describe multistep reactions accurately. To address this issue, we propose a novel approach using state-dependent time delay to approximate multistep reactions. We first use stochastic simulations to calculate time delay arising from multistep reactions exactly. Then we design algorithms to calculate time delay based on system dynamics precisely. To demonstrate the power of proposed method, two processes of mRNA degradation are used to investigate the function of time delay in determining system dynamics. In addition, a multistep pathway of metabolic synthesis is used to explore the potential of the proposed method to simplify multistep reactions with nonlinear reaction rates. Simulation results suggest that the state-dependent time delay is a promising and accurate approach to reduce model complexity and decrease the number of unknown parameters in the models. PMID:27553753

  6. Rotorcraft Trajectory Tracking Using the State-Dependent Riccati Equation Controller

    NASA Astrophysics Data System (ADS)

    Kim, Chang-Joo; Sung, Sang Kyung; Yang, Chang Deok; Yu, Yung Hoon

    This paper deals with the State-Dependent Riccati Equation (SDRE) method for designing a rotorcraft flight controller. It focuses on the design of the SDRE controller when a highly complex rotorcraft mathematical model is used. The requirements of the rotorcraft model are investigated to design the SDRE controller and to validate the final designs. Since the SDRE method can be applied to a deterministic system, adequate fidelity in the rotorcraft mathematical model is crucial to guarantee controller performance. However, a complex mathematical model generally prevents us from analytically deriving the State Dependent Coefficient (SDC) form of the system equations, which conforms to the basic structure of the SDRE method. This paper proposes a pure numerical procedure for SDC factorization of the motion equation. The numerical methods available to solve the algebraic Riccati equation are selected to cope with the inherent system instability and are applied to the trajectory tracking problems. The overall feature of the present approach is highlighted through analysis of a bob-up and turn maneuver. The results can be utilized as a guide for appropriate selection of rotorcraft mathematical models and numerical methods in designing a robust SDRE controller.

  7. Postsynaptic inositol 1,4,5-trisphosphate signaling maintains presynaptic function of parallel fiber–Purkinje cell synapses via BDNF

    PubMed Central

    Furutani, Kazuharu; Okubo, Yohei; Kakizawa, Sho; Iino, Masamitsu

    2006-01-01

    The maintenance of synaptic functions is essential for neuronal information processing, but cellular mechanisms that maintain synapses in the adult brain are not well understood. Here, we report an activity-dependent maintenance mechanism of parallel fiber (PF)–Purkinje cell (PC) synapses in the cerebellum. When postsynaptic metabotropic glutamate receptor (mGluR) or inositol 1,4,5-trisphosphate (IP3) signaling was chronically inhibited in vivo, PF–PC synaptic strength decreased because of a decreased transmitter release probability. The same effects were observed when PF activity was inhibited in vivo by the suppression of NMDA receptor-mediated inputs to granule cells. PF–PC synaptic strength similarly decreased after the in vivo application of an antibody against brain-derived neurotrophic factor (BDNF). Furthermore, the weakening of synaptic connection caused by the blockade of mGluR–IP3 signaling was reversed by the in vivo application of BDNF. These results indicate that a signaling cascade comprising PF activity, postsynaptic mGluR–IP3 signaling and subsequent BDNF signaling maintains presynaptic functions in the mature cerebellum. PMID:16709674

  8. α-Synuclein Membrane Association Is Regulated by the Rab3a Recycling Machinery and Presynaptic Activity*♦

    PubMed Central

    Chen, Robert H. C.; Wislet-Gendebien, Sabine; Samuel, Filsy; Visanji, Naomi P.; Zhang, Gang; Marsilio, Diana; Langman, Tammy; Fraser, Paul E.; Tandon, Anurag

    2013-01-01

    α-Synuclein is an abundant presynaptic protein and a primary component of Lewy bodies in Parkinson disease. Although its pathogenic role remains unclear, in healthy nerve terminals α-synuclein undergoes a cycle of membrane binding and dissociation. An α-synuclein binding assay was used to screen for vesicle proteins involved in α-synuclein membrane interactions and showed that antibodies directed to the Ras-related GTPase Rab3a and its chaperone RabGDI abrogated α-synuclein membrane binding. Biochemical analyses, including density gradient sedimentation and co-immunoprecipitation, suggested that α-synuclein interacts with membrane-associated GTP-bound Rab3a but not to cytosolic GDP-Rab3a. Accumulation of membrane-bound α-synuclein was induced by the expression of a GTPase-deficient Rab3a mutant, by a dominant-negative GDP dissociation inhibitor mutant unable to recycle Rab3a off membranes, and by Hsp90 inhibitors, radicicol and geldanamycin, which are known to inhibit Rab3a dissociation from membranes. Thus, all treatments that inhibited Rab3a recycling also increased α-synuclein sequestration on intracellular membranes. Our results suggest that membrane-bound GTP-Rab3a stabilizes α-synuclein on synaptic vesicles and that the GDP dissociation inhibitor·Hsp90 complex that controls Rab3a membrane dissociation also regulates α-synuclein dissociation during synaptic activity. PMID:23344955

  9. Posttetanic potentiation critically depends on an enhanced Ca2+ sensitivity of vesicle fusion mediated by presynaptic PKC

    PubMed Central

    Korogod, Natalya; Lou, Xuelin; Schneggenburger, Ralf

    2007-01-01

    Activity-dependent enhancement of transmitter release is a common form of presynaptic plasticity, but the underlying signaling mechanisms have remained largely unknown, perhaps because of the inaccessibility of most CNS nerve terminals. Here we investigated the signaling steps that underlie posttetanic potentiation (PTP), a form of presynaptic plasticity found at many CNS synapses. Direct whole-cell recordings from the large calyx of Held nerve terminals with the perforated patch-clamp technique showed that PTP was not mediated by changes in the presynaptic action potential waveform. Ca2+ imaging revealed a slight increase of the presynaptic Ca2+ transient during PTP (≈15%), which, however, was too small to explain a large part of PTP. The presynaptic PKC pathway was critically involved in PTP because (i) PTP was occluded by activation of PKC with phorbol esters, and (ii) PTP was largely (by approximately two-thirds) blocked by the PKC inhibitors, Ro31-8220 or bisindolylmaleimide. Activation of PKC during PTP most likely acts directly on the presynaptic release machinery, because in presynaptic Ca2+ uncaging experiments, activation of PKC by phorbol ester greatly increased the Ca2+ sensitivity of vesicle fusion in a Ro31-8220-sensitive manner (≈300% with small Ca2+ uncaging stimuli), but only slightly increased presynaptic voltage-gated Ca2+ currents (≈15%). We conclude that a PKC-dependent increase in the Ca2+ sensitivity of vesicle fusion is a key step in the enhancement of transmitter release during PTP. PMID:17884983

  10. The systematic study of the stability of forecasts in the rate- and state-dependent model.

    NASA Astrophysics Data System (ADS)

    De Gaetano, D.; McCloskey, J.; Nalbant, S.

    2012-04-01

    Numerous observations have shown a general spatial correlation between positive Coulomb failure stress changes due to an earthquake and the locations of aftershocks. However this correlation does not give any indication of the rate from which we can infer the magnitude using the Gutenberg-Richter law. Dieterich's rate- and state-dependent model can be used to obtain a forecast of the observed aftershock rate for the space and time evolution of seismicity caused by stress changes applied to an infinite population of nucleating patches. The seismicity rate changes on this model depend on eight parameters: the stressing rate, the amplitude of the stress perturbation, the physical constitutive properties of faults, the spatial parameters (location and radii of the cells), the start and duration of each of the temporal windows as well as the background seismicity rate. The background seismicity is obtained from the epidemic type aftershock sequence model. We use the 1992 Landers earthquake as a case study, using the Southern California Earthquake Data Centre (SCEDC) catalogue, to examine if Dieterich's rate- and state-dependent model can forecast the aftershock seismicity rate. A systematic study is performed on a range of values on all the parameters to test the forecasting ability of this model. The results obtained suggest variable success in forecasting, when varying the values for the parameters, with the spatial and temporal parameters being the most sensitive. Dieterich's rate- and state-dependent model is compared with a well studied null hypothesis, the Omori-Utsu law. This law describes the aftershock rate as a power law in time following the main shock and depends on only three parameters: the aftershock productivity, the elapsed time since the main shock and the constant time shift, all of which can be estimated in the early part of the aftershock sequence and then extrapolated to give a long term rate forecast. All parameters are estimated using maximum

  11. AMPA receptor inhibition by synaptically released zinc

    PubMed Central

    Kalappa, Bopanna I.; Anderson, Charles T.; Lippard, Stephen J.; Tzounopoulos, Thanos

    2015-01-01

    The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses. PMID:26647187

  12. Dynamic control of presynaptic Ca(2+) inflow by fast-inactivating K(+) channels in hippocampal mossy fiber boutons.

    PubMed

    Geiger, J R; Jonas, P

    2000-12-01

    Analysis of presynaptic determinants of synaptic strength has been difficult at cortical synapses, mainly due to the lack of direct access to presynaptic elements. Here we report patch-clamp recordings from mossy fiber boutons (MFBs) in rat hippocampal slices. The presynaptic action potential is very short during low-frequency stimulation but is prolonged up to 3-fold during high-frequency stimulation. Voltage-gated K(+) channels in MFBs inactivate rapidly but recover from inactivation very slowly, suggesting that cumulative K(+) channel inactivation mediates activity-dependent spike broadening. Prolongation of the presynaptic voltage waveform leads to an increase in the number of Ca(2+) ions entering the terminal per action potential and to a consecutive potentiation of evoked excitatory postsynaptic currents at MFB-CA3 pyramidal cell synapses. Thus, inactivation of presynaptic K(+) channels contributes to the control of efficacy of a glutamatergic synapse in the cortex.

  13. N-methyl-D-aspartate (NMDA)-stimulated noradrenaline (NA) release in rat brain cortex is modulated by presynaptic H3-receptors.

    PubMed

    Fink, K; Schlicker, E; Göthert, M

    1994-02-01

    In superfused rat brain cortex slices and synaptosomes preincubated with [3H]noradrenaline the effect of agonists or antagonists at presynaptic H3 receptors on NMDA-evoked [3H]noradrenaline release was investigated. In experiments on slices, histamine and the preferential H3 receptor agonist R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow (IC20 values 0.27 mumol/l or 0.032 mumol/l, respectively); S-(+)-alpha-methylhistamine (up to 10 mumol/l) as well as the selective H1 receptor agonist (2-(2-thiazolyl)ethylamine and the selective H2 receptor agonist dimaprit (each up to 10 mumol/l) were ineffective. The H3 receptor antagonist thioperamide abolished the inhibitory effect of histamine whereas the preferential H1 receptor antagonist dimetindene and the preferential H2 receptor antagonist ranitidine were ineffective. In experiments on synaptosomes, histamine and R-(-)-alpha-methylhistamine inhibited NMDA-evoked tritium overflow, whereas 2-(2-thiazolyl)ethylamine or dimaprit had no effect. The inhibitory effect of histamine was abolished by thioperamide. When tritium overflow was stimulated by NMDA in the presence of omega-conotoxin GVIA (which by itself decreased the response to NMDA by about 55%), R-(-)-alpha-methylhistamine did not inhibit NMDA-evoked overflow. It is concluded that NMDA-evoked noradrenaline release in the cerebral cortex can be modulated by inhibitory H3 receptors. NMDA receptors and H3 receptors are both located presynaptically and may interact at the same noradrenergic varicosity. An unimpaired function of the N-type voltage-sensitive calcium channel probably is a prerequisite for the inhibition of NMDA-evoked noradrenaline release by H3 receptor stimulation.

  14. A Presynaptic Role for FMRP during Protein Synthesis-Dependent Long-Term Plasticity in "Aplysia"

    ERIC Educational Resources Information Center

    Till, Sally M.; Li, Hsiu-Ling; Miniaci, Maria Concetta; Kandel, Eric R.; Choi, Yun-Beom

    2011-01-01

    Loss of the Fragile X mental retardation protein (FMRP) is associated with presumed postsynaptic deficits in mouse models of Fragile X syndrome. However, the possible presynaptic roles of FMRP in learning-related plasticity have received little attention. As a result, the mechanisms whereby FMRP influences synaptic function remain poorly…

  15. Perlecan antagonizes collagen IV and ADAMTS9/GON-1 in restricting the growth of presynaptic boutons.

    PubMed

    Qin, Jianzhen; Liang, Jingjing; Ding, Mei

    2014-07-30

    In the mature nervous system, a significant fraction of synapses are structurally stable over a long time scale. However, the mechanisms that restrict synaptic growth within a confined region are poorly understood. Here, we identified that in the C. elegans neuromuscular junction, collagens Type IV and XVIII, and the secreted metalloprotease ADAMTS/GON-1 are critical for growth restriction of presynaptic boutons. Without these components, ectopic boutons progressively invade into the nonsynaptic region. Perlecan/UNC-52 promotes the growth of ectopic boutons and functions antagonistically to collagen Type IV and GON-1 but not to collagen XVIII. The growth constraint of presynaptic boutons correlates with the integrity of the extracellular matrix basal lamina or basement membrane (BM), which surrounds chemical synapses. Fragmented BM appears in the region where ectopic boutons emerge. Further removal of UNC-52 improves the BM integrity and the tight association between BM and presynaptic boutons. Together, our results unravel the complex role of the BM in restricting the growth of presynaptic boutons and reveal the antagonistic function of perlecan on Type IV collagen and ADAMTS protein.

  16. Presynaptic Alpha-Synuclein Aggregation in a Mouse Model of Parkinson's Disease

    PubMed Central

    Spinelli, Kateri J.; Taylor, Jonathan K.; Osterberg, Valerie R.; Churchill, Madeline J.; Pollock, Eden; Moore, Cynthia; Meshul, Charles K.

    2014-01-01

    Parkinson's disease and dementia with Lewy bodies are associated with abnormal neuronal aggregation of α-synuclein. However, the mechanisms of aggregation and their relationship to disease are poorly understood. We developed an in vivo multiphoton imaging paradigm to study α-synuclein aggregation in mouse cortex with subcellular resolution. We used a green fluorescent protein-tagged human α-synuclein mouse line that has moderate overexpression levels mimicking human disease. Fluorescence recovery after photobleaching (FRAP) of labeled protein demonstrated that somatic α-synuclein existed primarily in an unbound, soluble pool. In contrast, α-synuclein in presynaptic terminals was in at least three different pools: (1) as unbound, soluble protein; (2) bound to presynaptic vesicles; and (3) as microaggregates. Serial imaging of microaggregates over 1 week demonstrated a heterogeneous population with differing α-synuclein exchange rates. The microaggregate species were resistant to proteinase K, phosphorylated at serine-129, oxidized, and associated with a decrease in the presynaptic vesicle protein synapsin and glutamate immunogold labeling. Multiphoton FRAP provided the specific binding constants for α-synuclein's binding to synaptic vesicles and its effective diffusion coefficient in the soma and axon, setting the stage for future studies targeting synuclein modifications and their effects. Our in vivo results suggest that, under moderate overexpression conditions, α-synuclein aggregates are selectively found in presynaptic terminals. PMID:24501346

  17. Flap loop of GluD2 binds to Cbln1 and induces presynaptic differentiation.

    PubMed

    Kuroyanagi, Tomoaki; Hirano, Tomoo

    2010-07-30

    Glutamate receptor delta2 (GluD2) is selectively expressed on the postsynaptic spines at parallel-fiber (PF)-Purkinje neuron (PN) synapses. GluD2 knockout mice show a reduced number of PF-PN synapses, suggesting that GluD2 is involved in synapse formation. Recent studies revealed that GluD2 induces presynaptic differentiation in a manner dependent on its N-terminal domain (NTD) through binding of Cbln1 secreted from cerebellar granule neurons. However, the underlying mechanism of the specific binding of the NTD to Cbln1 remains elusive. Here, we have identified the flap loop (Arg321-Trp339) in the NTD of GluD2 (GluD2-NTD) as a crucial region for the binding to Cbln1 and the induction of presynaptic differentiation. Both induction of presynaptic differentiation and binding of Cbln1 were abolished in the HEK cells expressing not wild-type GluD2 but GluD2 with mutations in the flap loop. Especially, single amino acid substitution of either Arg321 or Trp323 to alanine was sufficient to disable the GluD2 function. Finally, a homology model of GluD2-NTD suggested that the flap loop is located at the distal end, which appears consistent with an interaction with Cbln1 and a presynaptic varicosity.

  18. G-protein-coupled inward rectifier potassium channels involved in corticostriatal presynaptic modulation.

    PubMed

    Meneses, David; Mateos, Verónica; Islas, Gustavo; Barral, Jaime

    2015-09-01

    Presynaptic modulation has been associated mainly with calcium channels but recent data suggests that inward rectifier potassium channels (K(IR)) also play a role. In this work we set to characterize the role of presynaptic K(IR) channels in corticostriatal synaptic transmission. We elicited synaptic potentials in striatum by stimulating cortical areas and then determined the synaptic responses of corticostriatal synapsis by using paired pulse ratio (PPR) in the presence and absence of several potassium channel blockers. Unspecific potassium channels blockers Ba(2+) and Cs(+) reduced the PPR, suggesting that these channels are presynaptically located. Further pharmacological characterization showed that application of tertiapin-Q, a specific K(IR)3 channel family blocker, also induced a reduction of PPR, suggesting that K(IR)3 channels are present at corticostriatal terminals. In contrast, exposure to Lq2, a specific K(IR)1.1 inward rectifier potassium channel, did not induce any change in PPR suggesting the absence of these channels in the presynaptic corticostriatal terminals. Our results indicate that K(IR)3 channels are functionally expressed at the corticostriatal synapses, since blockage of these channels result in PPR decrease. Our results also help to explain how synaptic activity may become sensitive to extracellular signals mediated by G-protein coupled receptors. A vast repertoire of receptors may influence neurotransmitter release in an indirect manner through regulation of K(IR)3 channels.

  19. Loss of Saltation and Presynaptic Action Potential Failure in Demyelinated Axons

    PubMed Central

    Hamada, Mustafa S.; Popovic, Marko A.; Kole, Maarten H. P.

    2017-01-01

    In cortical pyramidal neurons the presynaptic terminals controlling transmitter release are located along unmyelinated axon collaterals, far from the original action potential (AP) initiation site, the axon initial segment (AIS). Once initiated, APs will need to reliably propagate over long distances and regions of geometrical inhomogeneity like branch points (BPs) to rapidly depolarize the presynaptic terminals and confer temporally precise synaptic transmission. While axon pathologies such as demyelinating diseases are well established to impede the fidelity of AP propagation along internodes, to which extent myelin loss affects propagation along BPs and axon collaterals is not well understood. Here, using the cuprizone demyelination model, we performed optical voltage-sensitive dye (VSD) imaging from control and demyelinated layer 5 pyramidal neuron axons. In the main axon, we find that myelin loss switches the modality of AP propagation from rapid saltation towards a slow continuous wave. The duration of single AP waveforms at BPs or nodes was, however, only slightly briefer. In contrast, by using two-photon microscopy-guided loose-seal patch recordings from axon collaterals we revealed a presynaptic AP broadening in combination with a reduced velocity and frequency-dependent failure. Finally, internodal myelin loss was also associated with de novo sprouting of axon collaterals starting from the primary (demyelinated) axon. Thus, the loss of oligodendrocytes and myelin sheaths bears functional consequences beyond the main axon, impeding the temporal fidelity of presynaptic APs and affecting the functional and structural organization of synaptic connectivity within the neocortex. PMID:28289377

  20. Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers FGF22 and FGF7

    PubMed Central

    Terauchi, Akiko; Timmons, Kendall M.; Kikuma, Koto; Pechmann, Yvonne; Kneussel, Matthias; Umemori, Hisashi

    2015-01-01

    ABSTRACT Specific formation of excitatory and inhibitory synapses is crucial for proper functioning of the brain. Fibroblast growth factor 22 (FGF22) and FGF7 are postsynaptic-cell-derived presynaptic organizers necessary for excitatory and inhibitory presynaptic differentiation, respectively, in the hippocampus. For the establishment of specific synaptic networks, these FGFs must localize to appropriate synaptic locations – FGF22 to excitatory and FGF7 to inhibitory postsynaptic sites. Here, we show that distinct motor and adaptor proteins contribute to intracellular microtubule transport of FGF22 and FGF7. Excitatory synaptic targeting of FGF22 requires the motor proteins KIF3A and KIF17 and the adaptor protein SAP102 (also known as DLG3). By contrast, inhibitory synaptic targeting of FGF7 requires the motor KIF5 and the adaptor gephyrin. Time-lapse imaging shows that FGF22 moves with SAP102, whereas FGF7 moves with gephyrin. These results reveal the basis of selective targeting of the excitatory and inhibitory presynaptic organizers that supports their different synaptogenic functions. Finally, we found that knockdown of SAP102 or PSD95 (also known as DLG4), which impairs the differentiation of excitatory synapses, alters FGF7 localization, suggesting that signals from excitatory synapses might regulate inhibitory synapse formation by controlling the distribution of the inhibitory presynaptic organizer. PMID:25431136

  1. Differential presynaptic effects of hexachlorocyclohexane isomers on noradrenaline release in cerebral cortex

    SciTech Connect

    Cristofol, R.M.; Rodriguez-Farre, E. )

    1991-01-01

    To investigate presynaptic effects of hexachlorocyclohexane (HCH) isomers, the release of noradrenaline (NA) in brain tissue was analyzed using rat cerebral cortical slices preloaded with ({sup 3}H)-NA. {gamma}-HCH (lindane) 50 {mu}M significantly enhanced the ({sup 3}H)-NA release evoked by 15-25 mM K{sup +}. {alpha}- and {beta}-HCH did not produce any significant effect on K{sup +}-evoked ({sup 3}H)-NA release. {delta}-HCH induced a significant decrease of the 25 mM K{sup +}-evoked release of ({sup 3}H)-NA. The effect of the {gamma}- and {delta}-HCH isomers on the presynaptic action of the {alpha}{sub 2}-agonist clonidine and the {alpha}{sub 2}-antagonist yohimbine was also studied. The presynaptic inhibitory effect of clonidine and the stimulatory effect of yohimbine on ({sup 3}H)-NA release was attenuated by lindane and {delta}-HCH, respectively. These results are consistent with a presynaptic action of the HCH isomers on noradrenergic release processes.

  2. Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications.

    PubMed

    Cenci, M Angela

    2014-01-01

    The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson's disease (PD) for over 40 years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.

  3. ATM protein is located on presynaptic vesicles and its deficit leads to failures in synaptic plasticity.

    PubMed

    Vail, Graham; Cheng, Aifang; Han, Yu Ray; Zhao, Teng; Du, Shengwang; Loy, Michael M T; Herrup, Karl; Plummer, Mark R

    2016-07-01

    Ataxia telangiectasia is a multisystemic disorder that includes a devastating neurodegeneration phenotype. The ATM (ataxia-telangiectasia mutated) protein is well-known for its role in the DNA damage response, yet ATM is also found in association with cytoplasmic vesicular structures: endosomes and lysosomes, as well as neuronal synaptic vesicles. In keeping with this latter association, electrical stimulation of the Schaffer collateral pathway in hippocampal slices from ATM-deficient mice does not elicit normal long-term potentiation (LTP). The current study was undertaken to assess the nature of this deficit. Theta burst-induced LTP was reduced in Atm(-/-) animals, with the reduction most pronounced at burst stimuli that included 6 or greater trains. To assess whether the deficit was associated with a pre- or postsynaptic failure, we analyzed paired-pulse facilitation and found that it too was significantly reduced in Atm(-/-) mice. This indicates a deficit in presynaptic function. As further evidence that these synaptic effects of ATM deficiency were presynaptic, we used stochastic optical reconstruction microscopy. Three-dimensional reconstruction revealed that ATM is significantly more closely associated with Piccolo (a presynaptic marker) than with Homer1 (a postsynaptic marker). These results underline how, in addition to its nuclear functions, ATM plays an important functional role in the neuronal synapse where it participates in the regulation of presynaptic vesicle physiology.

  4. Presynaptic Protein Synthesis Is Required for Long-Term Plasticity of GABA Release.

    PubMed

    Younts, Thomas J; Monday, Hannah R; Dudok, Barna; Klein, Matthew E; Jordan, Bryen A; Katona, István; Castillo, Pablo E

    2016-10-19

    Long-term changes of neurotransmitter release are critical for proper brain function. However, the molecular mechanisms underlying these changes are poorly understood. While protein synthesis is crucial for the consolidation of postsynaptic plasticity, whether and how protein synthesis regulates presynaptic plasticity in the mature mammalian brain remain unclear. Here, using paired whole-cell recordings in rodent hippocampal slices, we report that presynaptic protein synthesis is required for long-term, but not short-term, plasticity of GABA release from type 1 cannabinoid receptor (CB1)-expressing axons. This long-term depression of inhibitory transmission (iLTD) involves cap-dependent protein synthesis in presynaptic interneuron axons, but not somata. Translation is required during the induction, but not maintenance, of iLTD. Mechanistically, CB1 activation enhances protein synthesis via the mTOR pathway. Furthermore, using super-resolution STORM microscopy, we revealed eukaryotic ribosomes in CB1-expressing axon terminals. These findings suggest that presynaptic local protein synthesis controls neurotransmitter release during long-term plasticity in the mature mammalian brain.

  5. Redox state dependence of axial ligand dynamics in Nitrosomonas europaea cytochrome c552.

    PubMed

    Kaur, Ravinder; Bren, Kara L

    2013-12-12

    Analysis of NMR spectra reveals that the heme axial Met ligand orientation and dynamics in Nitrosomonas europaea cytochrome c552 (Ne cyt c) are dependent on the heme redox state. In the oxidized state, the heme axial Met is fluxional, interconverting between two conformers related to each other by inversion through the Met δS atom. In the reduced state, there is no evidence of fluxionality, with the Met occupying one conformation similar to that seen in the homologous Pseudomonas aeruginosa cytochrome c551. Comparison of the observed and calculated pseudocontact shifts for oxidized Ne cyt c using the reduced protein structure as a reference structure reveals a redox-dependent change in the structure of the loop bearing the axial Met (loop 3). Analysis of nuclear Overhauser effects (NOEs) and existing structural data provides further support for the redox state dependence of the loop 3 structure. Implications for electron transfer function are discussed.

  6. Dynamical properties induced by state-dependent delays in photonic systems

    PubMed Central

    Martínez-Llinàs, Jade; Porte, Xavier; Soriano, Miguel C.; Colet, Pere; Fischer, Ingo

    2015-01-01

    In many dynamical systems and complex networks time delays appear naturally in feedback loops or coupling connections of individual elements. Moreover, in a whole class of systems, these delay times can depend on the state of the system. Nevertheless, so far the understanding of the impact of such state-dependent delays remains poor with a particular lack of systematic experimental studies. Here we fill this gap by introducing a conceptually simple photonic system that exhibits dynamics of self-organised switching between two loops with two different delay times, depending on the state of the system. On the basis of experiments and modelling on semiconductor lasers with frequency-selective feedback mirrors, we characterize the switching between the states defined by the individual delays. Our approach opens new perspectives for the study of this class of dynamical systems and enables applications in which the self-organized switching can be exploited. PMID:26081000

  7. Boundary control of bidomain equations with state-dependent switching source functions in the ionic model

    NASA Astrophysics Data System (ADS)

    Chamakuri, Nagaiah; Engwer, Christian; Kunisch, Karl

    2014-09-01

    Optimal control for cardiac electrophysiology based on the bidomain equations in conjunction with the Fenton-Karma ionic model is considered. This generic ventricular model approximates well the restitution properties and spiral wave behavior of more complex ionic models of cardiac action potentials. However, it is challenging due to the appearance of state-dependent discontinuities in the source terms. A computational framework for the numerical realization of optimal control problems is presented. Essential ingredients are a shape calculus based treatment of the sensitivities of the discontinuous source terms and a marching cubes algorithm to track iso-surface of excitation wavefronts. Numerical results exhibit successful defibrillation by applying an optimally controlled extracellular stimulus.

  8. Synchronization Control of Neural Networks With State-Dependent Coefficient Matrices.

    PubMed

    Zhang, Junfeng; Zhao, Xudong; Huang, Jun

    2016-11-01

    This brief is concerned with synchronization control of a class of neural networks with state-dependent coefficient matrices. Being different from the existing drive-response neural networks in the literature, a novel model of drive-response neural networks is established. The concepts of uniformly ultimately bounded (UUB) synchronization and convex hull Lyapunov function are introduced. Then, by using the convex hull Lyapunov function approach, the UUB synchronization design of the drive-response neural networks is proposed, and a delay-independent control law guaranteeing the bounded synchronization of the neural networks is constructed. All present conditions are formulated in terms of bilinear matrix inequalities. By comparison, it is shown that the neural networks obtained in this brief are less conservative than those ones in the literature, and the bounded synchronization is suitable for the novel drive-response neural networks. Finally, an illustrative example is given to verify the validity of the obtained results.

  9. Dynamical properties induced by state-dependent delays in photonic systems

    NASA Astrophysics Data System (ADS)

    Martínez-Llinàs, Jade; Porte, Xavier; Soriano, Miguel C.; Colet, Pere; Fischer, Ingo

    2015-06-01

    In many dynamical systems and complex networks time delays appear naturally in feedback loops or coupling connections of individual elements. Moreover, in a whole class of systems, these delay times can depend on the state of the system. Nevertheless, so far the understanding of the impact of such state-dependent delays remains poor with a particular lack of systematic experimental studies. Here we fill this gap by introducing a conceptually simple photonic system that exhibits dynamics of self-organised switching between two loops with two different delay times, depending on the state of the system. On the basis of experiments and modelling on semiconductor lasers with frequency-selective feedback mirrors, we characterize the switching between the states defined by the individual delays. Our approach opens new perspectives for the study of this class of dynamical systems and enables applications in which the self-organized switching can be exploited.

  10. Earthquake nucleation on faults with rate-and state-dependent strength

    USGS Publications Warehouse

    Dieterich, J.H.

    1992-01-01

    Dieterich, J.H., 1992. Earthquake nucleation on faults with rate- and state-dependent strength. In: T. Mikumo, K. Aki, M. Ohnaka, L.J. Ruff and P.K.P. Spudich (Editors), Earthquake Source Physics and Earthquake Precursors. Tectonophysics, 211: 115-134. Faults with rate- and state-dependent constitutive properties reproduce a range of observed fault slip phenomena including spontaneous nucleation of slip instabilities at stresses above some critical stress level and recovery of strength following slip instability. Calculations with a plane-strain fault model with spatially varying properties demonstrate that accelerating slip precedes instability and becomes localized to a fault patch. The dimensions of the fault patch follow scaling relations for the minimum critical length for unstable fault slip. The critical length is a function of normal stress, loading conditions and constitutive parameters which include Dc, the characteristic slip distance. If slip starts on a patch that exceeds the critical size, the length of the rapidly accelerating zone tends to shrink to the characteristic size as the time of instability approaches. Solutions have been obtained for a uniform, fixed-patch model that are in good agreement with results from the plane-strain model. Over a wide range of conditions, above the steady-state stress, the logarithm of the time to instability linearly decreases as the initial stress increases. Because nucleation patch length and premonitory displacement are proportional to Dc, the moment of premonitory slip scales by D3c. The scaling of Dc is currently an open question. Unless Dc for earthquake faults is significantly greater than that observed on laboratory faults, premonitory strain arising from the nucleation process for earthquakes may by too small to detect using current observation methods. Excluding the possibility that Dc in the nucleation zone controls the magnitude of the subsequent earthquake, then the source dimensions of the smallest

  11. Extinction-induced neuroplasticity attenuates stress-induced cocaine seeking: a state-dependent learning hypothesis.

    PubMed

    Self, David W; Choi, Kwang-Ho

    2004-09-01

    Chronic drug use weakens excitatory neocortical input to the nucleus accumbens (NAc). We previously reported that extinction training, a form of inhibitory learning that progressively reduces cocaine-seeking behaviour when reward is withheld, reverses this deficit by up-regulating GluR1 and GluR2/3 subunits of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptors in the NAc. The level of GluR1 up-regulation is positively associated with a reduction in cocaine seeking, suggesting that extinction-induced up-regulation in AMPA receptors in the NAc opposes motivational influences that maintain cocaine seeking. This hypothesis is supported by the finding that over-expression of GluR1 and GluR2 in the NAc facilitates extinction of cocaine self-administration. Furthermore, a single extinction training session conducted during GluR1 and GluR2 over-expression strongly and selectively attenuates the ability of an environmental stressor to trigger relapse to cocaine seeking long after GluR1 and GluR2 over-expression declines. These results could suggest that excitatory input to the NAc promotes extinction learning, but only when memory is recalled under stressful situations. Recent studies indicate that both environmental stress and the frustrative stress of withholding reward during extinction of drug self-administration induce similar neurochemical events in the NAc. These neurochemical events could impose a "state-dependency" on extinction learning such that subsequent exposure to stress acts as a cue to enhance retrieval of extinction memory. Our results suggest that extinction-induced up-regulation in NAc AMPA receptors acts reciprocally to facilitate state-dependent extinction learning, as stressful situations evoke extinction memories that exert powerful inhibitory control over drug-seeking behaviour. These results may have important therapeutic implications for behaviour-based approaches aimed at treating drug addiction.

  12. State-dependent block of Na+ channels by articaine via the local anesthetic receptor.

    PubMed

    Wang, Ging Kuo; Calderon, Joanna; Jaw, Shiow-Jiin; Wang, Sho-Ya

    2009-05-01

    Articaine is widely used as a local anesthetic (LA) in dentistry, but little is known regarding its blocking actions on Na+ channels. We therefore examined the state-dependent block of articaine first in rat skeletal muscle rNav1.4 Na+ channels expressed in Hek293t cells. Articaine exhibited a weak block of resting rNav1.4 Na+ channels at -140 mV with a 50% inhibitory concentration (IC(50)) of 378 +/- 26 microM (n = 5). The affinity was higher for inactivated Na+ channels measured at -70 mV with an IC50 value of 40.6 +/- 2.7 microM (n = 5). The open-channel block by articaine was measured using inactivation-deficient rNav1.4 Na+ channels with an IC50 value of 15.8 +/- 1.5 microM (n = 5). Receptor mapping demonstrated that articaine interacted strongly with a D4S6 phenylalanine residue, which is known to form a part of the LA receptor. Thus the block of rNav1.4 Na+ channels by articaine is via the conserved LA receptor in a highly state-dependent manner, with a ranking order of open (23.9x) > inactivated (9.3x) > resting (1x) state. Finally, the open-channel block by articaine was likewise measured in inactivation-deficient hNav1.7 and rNav1.8 Na+ channels, with IC(50) values of 8.8 +/- 0.1 and 22.0 +/- 0.5 microM, respectively (n = 5), indicating that the high-affinity open-channel block by articaine is indeed preserved in neuronal Na+ channel isoforms.

  13. Phosphorylation state-dependent interaction between AKAP7δ/γ and phospholamban increases phospholamban phosphorylation

    PubMed Central

    Rigatti, Marc; Le, Andrew V.; Gerber, Claire; Moraru, Ion I.; Dodge-Kafka, Kimberly L.

    2016-01-01

    Changes in heart rate and contractility in response to sympathetic stimulation occur via activation of cAMP dependent protein kinase A (PKA), leading to phosphorylation of numerous substrates that alter Ca2+ cycling. Phosphorylation of these substrates is coordinated by A-kinase anchoring proteins (AKAPs), which recruit PKA to specific substrates [1]. Phosphorylation of the PKA substrate phospholamban (PLB) is a critical determinant of Ca2+ re-entry into the sarcoplasmic reticulum and is coordinated by AKAP7δ/γ [2,3]. Here, we further these findings by showing that phosphorylation of PLB requires interaction with AKAP7δ/γ and that this interaction occurs only when PLB is unphosphorylated. Additionally, we find that two mutants of PLB (R9C and Δ14), which are associated with dilated cardiomyopathy in humans, prevent association with AKAP7δ/γ and display reduced phosphorylation in vitro. This finding implicates the AKAP7δ/γ-PLB interaction in the pathology of the disease phenotype. Further exploration of the AKAP7δ/γ-PLB association demonstrated a phosphorylation state-dependence of the interaction. Computational modeling revealed that this mode of interaction allows for small amounts of AKAP and PKA (100–200nM) to regulate the phosphorylation of large quantities of PLB (50µM). Our results confirm that AKAP7γ/δ binding to PLB is important for phosphorylation of PLB, and describe a novel phosphorylation state-dependent binding mechanism that explains how phosphorylation of highly abundant PKA substrates can be regulated by AKAPs present at ~100–200 fold lower concentrations. PMID:26027516

  14. In silico assessment of kinetics and state dependent binding properties of drugs causing acquired LQTS.

    PubMed

    Lee, William; Mann, Stefan A; Windley, Monique J; Imtiaz, Mohammad S; Vandenberg, Jamie I; Hill, Adam P

    2016-01-01

    The Kv11.1 or hERG potassium channel is responsible for one of the major repolarising currents (IKr) in cardiac myocytes. Drug binding to hERG can result in reduction in IKr, action potential prolongation, acquired long QT syndrome and fatal cardiac arrhythmias. The current guidelines for pre-clinical assessment of drugs in development is based on the measurement of the drug concentration that causes 50% current block, i.e., IC50. However, drugs with the same apparent IC50 may have very different kinetics of binding and unbinding, as well as different affinities for the open and inactivated states of Kv11.1. Therefore, IC50 measurements may not reflect the true risk of drug induced arrhythmias. Here we have used an in silico approach to test the hypothesis that drug binding kinetics and differences in state-dependent affinity will influence the extent of cardiac action potential prolongation independent of apparent IC50 values. We found, in general that drugs with faster overall kinetics and drugs with higher affinity for the open state relative to the inactivated state cause more action potential prolongation. These characteristics of drug-hERG interaction are likely to be more arrhythmogenic but cannot be predicted by IC50 measurement alone. Our results suggest that the pre-clinical assessment of Kv11.1-drug interactions should include descriptions of the kinetics and state dependence of drug binding. Further, incorporation of this information into sophisticated in silico models should be able to better predict arrhythmia risk and therefore more accurately assess safety of new drugs in development.

  15. Morphine and DAMGO produce an opposite effect on presynaptic glutamate release via different downstream pathways of μ opioid receptors in the basolateral amygdala.

    PubMed

    Yang, Jinhui; Yang, Hualan; Du, Xiaowei; Ma, Qianqian; Song, Jiaojiao; Chen, Ming; Dong, Yi; Ma, Lan; Zheng, Ping

    2014-11-01

    Increasing evidence demonstrates that different opioids, while acting μ opioid receptors, can activate distinct downstream responses, a phenomenon termed functional selectivity or biased agonism. The present study designed experiments to test whether the μ receptor agonist morphine and D-Ala(2), N-Me-Phe(4), Gly(5)-ol-enkephalin (DAMGO) had a different effect on presynaptic glutamate release in the basolateral amygdala (BLA) and whether this difference was due to their biased agonism at μ receptors. The results showed that DAMGO markedly decreased the frequency of sEPSCs in pyramidal cells of BLA. The concentration-dependence experiment showed that DAMGO dose-dependently decreased the frequency of sEPSCs. Morphine markedly increased the frequency of sEPSCs in pyramidal cells of BLA. The concentration-dependence experiment showed that morphine dose-dependently increased the frequency of sEPSCs. We also used PPF of EPSC as another indicator of presynaptic glutamate release to confirm the opposite effect of morphine and DAMGO on the glutamate release. Further mechanism studies showed that the opposite effect of morphine and DAMGO on the glutamate release was via the activation of μ receptors, but the downstream signaling pathways of μ receptors were different: DAMGO inhibited the glutamate release via μ receptor-Gi protein- PLA2-AA signaling pathway, whereas morphine promoted the glutamate release via μ receptor-Gi protein-PKC-ERK1/2-synapsin I signaling pathway.

  16. Visualizing K48 Ubiquitination during Presynaptic Formation By Ubiquitination-Induced Fluorescence Complementation (UiFC)

    PubMed Central

    Pinto, Maria J.; Pedro, Joana R.; Costa, Rui O.; Almeida, Ramiro D.

    2016-01-01

    In recent years, signaling through ubiquitin has been shown to be of great importance for normal brain development. Indeed, fluctuations in ubiquitin levels and spontaneous mutations in (de)ubiquitination enzymes greatly perturb synapse formation and neuronal transmission. In the brain, expression of lysine (K) 48-linked ubiquitin chains is higher at a developmental stage coincident with synaptogenesis. Nevertheless, no studies have so far delved into the involvement of this type of polyubiquitin chains in synapse formation. We have recently proposed a role for polyubiquitinated conjugates as triggering signals for presynaptic assembly. Herein, we aimed at characterizing the axonal distribution of K48 polyubiquitin and its dynamics throughout the course of presynaptic formation. To accomplish so, we used an ubiquitination-induced fluorescence complementation (UiFC) strategy for the visualization of K48 polyubiquitin in live hippocampal neurons. We first validated its use in neurons by analyzing changing levels of polyubiquitin. UiFC signal is diffusely distributed with distinct aggregates in somas, dendrites and axons, which perfectly colocalize with staining for a K48-specific antibody. Axonal UiFC aggregates are relatively stable and new aggregates are formed as an axon grows. Approximately 65% of UiFC aggregates colocalize with synaptic vesicle clusters and they preferentially appear in the axonal domains of axo-somatodendritic synapses when compared to isolated axons. We then evaluated axonal accumulation of K48 ubiquitinated signals in bead-induced synapses. We observed rapid accumulation of UiFC signal and endogenous K48 ubiquitin at the sites of newly formed presynapses. Lastly, we show by means of a microfluidic platform, for the isolation of axons, that presynaptic clustering on beads is dependent on E1-mediated ubiquitination at the axonal level. Altogether, these results indicate that enrichment of K48 polyubiquitin at the site of nascent presynaptic

  17. Dopamine D1 Receptors Are Not Critical for Opiate Reward but Can Mediate Opiate Memory Retrieval in a State-Dependent Manner

    PubMed Central

    Vargas-Perez, Hector; George, Susan R.; van der Kooy, Derek

    2013-01-01

    Although D1 receptor knockout mice demonstrate normal morphine place preferences, antagonism of basolateral amygdala (BLA) D1 receptors only during drug-naive rat conditioning has been reported to inhibit the expression of a morphine place preference. One possible explanation for this result is state-dependent learning. That is, the omission of the intra-BLA infusion cue during testing — which acts as a potent discriminative stimulus — may have prevented the recall of a morphine-environment association and therefore, the consequent expression of a morphine place preference. To examine this possibility, we tested whether intra-BLA infusion of the D1-receptor antagonist SCH23390 during both training and testing might reveal a morphine place preference. Our results suggest that in previously drug-naive animals, D1 receptor antagonism during testing restores the opiate conditioned place preference that is normally absent when D1 receptors are blocked only during training, suggesting that BLA D1 receptors can mediate state-dependent memory retrieval. PMID:23538064

  18. The Presynaptic Microtubule Cytoskeleton in Physiological and Pathological Conditions: Lessons from Drosophila Fragile X Syndrome and Hereditary Spastic Paraplegias

    PubMed Central

    Bodaleo, Felipe J.; Gonzalez-Billault, Christian

    2016-01-01

    The capacity of the nervous system to generate neuronal networks relies on the establishment and maintenance of synaptic contacts. Synapses are composed of functionally different presynaptic and postsynaptic compartments. An appropriate synaptic architecture is required to provide the structural basis that supports synaptic transmission, a process involving changes in cytoskeletal dynamics. Actin microfilaments are the main cytoskeletal components present at both presynaptic and postsynaptic terminals in glutamatergic synapses. However, in the last few years it has been demonstrated that microtubules (MTs) transiently invade dendritic spines, promoting their maturation. Nevertheless, the presence and functions of MTs at the presynaptic site are still a matter of debate. Early electron microscopy (EM) studies revealed that MTs are present in the presynaptic terminals of the central nervous system (CNS) where they interact with synaptic vesicles (SVs) and reach the active zone. These observations have been reproduced by several EM protocols; however, there is empirical heterogeneity in detecting presynaptic MTs, since they appear to be both labile and unstable. Moreover, increasing evidence derived from studies in the fruit fly neuromuscular junction proposes different roles for MTs in regulating presynaptic function in physiological and pathological conditions. In this review, we summarize the main findings that support the presence and roles of MTs at presynaptic terminals, integrating descriptive and biochemical analyses, and studies performed in invertebrate genetic models. PMID:27504085

  19. Calcium-activated potassium channels in isolated presynaptic nerve terminals from rat brain.

    PubMed Central

    Bartschat, D K; Blaustein, M P

    1985-01-01

    86Rb efflux was examined in isolated presynaptic nerve terminals (synaptosomes) from rat brain in a study designed to assess K permeability (PK) changes sensitive to alterations in internal Ca activity. Rb efflux from 86Rb-loaded synaptosomes into nominally Ca-free physiological saline (PSS) containing 5 mM-K was about 0.3-0.4%/s. Raising extracellular K concentration [( K]o), to depolarize the synaptosomes, stimulated the 86Rb efflux. Addition of Ca to the 5 mM-K PSS had no effect, but Ca did further stimulate 86Rb efflux into K-rich solutions. The effect of Ca was graded, with apparent half-maximal activation, KA approximately equal to 0.5 mM-Ca. These data fit the view that, during depolarization, Ca enters the terminals through voltage-regulated Ca channels, and that the rise in intracellular Ca concentration opens certain (Ca-activated) K channels. The Ca-dependent stimulation of 86Rb efflux was greatest during the initial seconds of incubation (component CT), and then declined to a much lower rate (component CS). Much of this change in rate could be attributed to inactivation of voltage-regulated Ca channels and reduced entry of Ca. The Ca-dependent increase in 86Rb efflux was completely inhibited by 100 microM-La. In the presence of Ca, but not in its absence, the Ca ionophore A23187 stimulated 86Rb efflux both in 5 and 100 mM-K PSS. The effect in 100 mM-K was quantitatively greater, perhaps because of the increased outward driving force on Rb in depolarized synaptosomes. When synaptosomes were suspended in media containing the voltage-sensitive fluorescent dye, DiS-C3-(5) (1,1'-dipentyl-2,2'-thiocarbocyanine), the addition of Ca+ A23187 decreased the fluorescence intensity (= synaptosome hyperpolarization) when the media contained 5 mM-K but not 100 mM-K. This implies that in the presence of Ca + A23187, PK was increased, and the membrane potential moved closer to the K equilibrium potential, EK. Quinine sulphate, a blocker of Ca-activated K channels

  20. Autoradiographic localization of voltage-dependent sodium channels on the mouse neuromuscular junction using /sup 125/I-alpha scorpion toxin. I. Preferential labeling of glial cells on the presynaptic side

    SciTech Connect

    Boudier, J.L.; Jover, E.; Cau, P.

    1988-05-01

    Alpha-scorpion toxins bind specifically to the voltage-sensitive sodium channel in excitable membranes, and binding is potential-dependent. The radioiodinated toxin II from the scorpion Androctonus australis Hector (alpha ScTx) was used to localize voltage-sensitive sodium channels on the presynaptic side of mouse neuromuscular junctions (NMJ) by autoradiography using both light and electron microscopy. Silver grain localization was analyzed by the cross-fire method. At the light-microscopic level, grain density over NMJ appeared 6-8x higher than over nonjunctional muscle membrane. The specificity of labeling was verified by competition/displacement with an excess of native alpha ScTx. Labeling was also inhibited by incubation in depolarizing conditions, showing its potential-dependence. At the electron-microscopic level, analysis showed that voltage-sensitive sodium channels labeled with alpha ScTx were almost exclusively localized on membranes, as expected. Due to washout after incubation, appreciable numbers of binding sites were not found on the postsynaptic membranes. However, on the presynaptic side, alpha ScTx-labeled voltage-sensitive sodium channels were localized on the membrane of non-myelin-forming Schwann cells covering NMJ. The axonal presynaptic membrane was not labeled. These results show that voltage-sensitive sodium channels are present on glial cells in vivo, as already demonstrated in vitro. It is proposed that these glial channels could be indirectly involved in the ionic homeostasis of the axonal environment.

  1. Individual Differences and State-Dependent Responses in Transcranial Direct Current Stimulation

    PubMed Central

    Hsu, Tzu-Yu; Juan, Chi-Hung; Tseng, Philip

    2016-01-01

    Transcranial direct current stimulation (tDCS) has been extensively used to examine whether neural activities can be selectively increased or decreased with manipulations of current polarity. Recently, the field has reevaluated the traditional anodal-increase and cathodal-decrease assumption due to the growing number of mixed findings that report the effects of the opposite directions. Therefore, the directionality of tDCS polarities and how it affects each individual still remain unclear. In this study, we used a visual working memory (VWM) paradigm and systematically manipulated tDCS polarities, types of different independent baseline measures, and task difficulty to investigate how these factors interact to determine the outcome effect of tDCS. We observed that only low-performers, as defined by their no-tDCS corsi block tapping (CBT) performance, persistently showed a decrement in VWM performance after anodal stimulation, whereas no tDCS effect was found when participants were divided by their performance in digit span. In addition, only the optimal level of task difficulty revealed any significant tDCS effect. All these findings were consistent across different blocks, suggesting that the tDCS effect was stable across a short period of time. Lastly, there was a high degree of intra-individual consistency in one’s responsiveness to tDCS, namely that participants who showed positive or negative effect to anodal stimulation are also more likely to show the same direction of effects for cathodal stimulation. Together, these findings imply that tDCS effect is interactive and state dependent: task difficulty and consistent individual differences modulate one’s responsiveness to tDCS, while researchers’ choices of independent behavioral baseline measures can also critically affect how the effect of tDCS is evaluated. These factors together are likely the key contributors to the wide range of “noises” in tDCS effects between individuals, between stimulation

  2. On the state dependency of the equilibrium climate sensitivity during the last 5 million years

    NASA Astrophysics Data System (ADS)

    Köhler, P.; de Boer, B.; von der Heydt, A. S.; Stap, L. B.; van de Wal, R. S. W.

    2015-12-01

    It is still an open question how equilibrium warming in response to increasing radiative forcing - the specific equilibrium climate sensitivity S - depends on background climate. We here present palaeodata-based evidence on the state dependency of S, by using CO2 proxy data together with a 3-D ice-sheet-model-based reconstruction of land ice albedo over the last 5 million years (Myr). We find that the land ice albedo forcing depends non-linearly on the background climate, while any non-linearity of CO2 radiative forcing depends on the CO2 data set used. This non-linearity has not, so far, been accounted for in similar approaches due to previously more simplistic approximations, in which land ice albedo radiative forcing was a linear function of sea level change. The latitudinal dependency of ice-sheet area changes is important for the non-linearity between land ice albedo and sea level. In our set-up, in which the radiative forcing of CO2 and of the land ice albedo (LI) is combined, we find a state dependence in the calculated specific equilibrium climate sensitivity, S[CO2,LI], for most of the Pleistocene (last 2.1 Myr). During Pleistocene intermediate glaciated climates and interglacial periods, S[CO2,LI] is on average ~ 45 % larger than during Pleistocene full glacial conditions. In the Pliocene part of our analysis (2.6-5 Myr BP) the CO2 data uncertainties prevent a well-supported calculation for S[CO2,LI], but our analysis suggests that during times without a large land ice area in the Northern Hemisphere (e.g. before 2.82 Myr BP), the specific equilibrium climate sensitivity, S[CO2,LI], was smaller than during interglacials of the Pleistocene. We thus find support for a previously proposed state change in the climate system with the widespread appearance of northern hemispheric ice sheets. This study points for the first time to a so far overlooked non-linearity in the land ice albedo radiative forcing, which is important for similar palaeodata

  3. On the state-dependency of the equilibrium climate sensitivity during the last 5 million years

    NASA Astrophysics Data System (ADS)

    Köhler, P.; de Boer, B.; von der Heydt, A. S.; Stap, L. B.; van de Wal, R. S. W.

    2015-07-01

    A still open question is how equilibrium warming in response to increasing radiative forcing - the specific equilibrium climate sensitivity S - is depending on background climate. We here present paleo-data based evidence on the state-dependency of S, by using CO2 proxy data together with 3-D ice-sheet model-based reconstruction of land ice albedo over the last 5 million years (Myr). We find that the land-ice albedo forcing depends non-linearly on the background climate, while any non-linearity of CO2 radiative forcing depends on the CO2 data set used. This non-linearity was in similar approaches not accounted for due to previously more simplistic approximations of land-ice albedo radiative forcing being a linear function of sea level change. Important for the non-linearity between land-ice albedo and sea level is a latitudinal dependency in ice sheet area changes.In our setup, in which the radiative forcing of CO2 and of the land-ice albedo (LI) is combined, we find a state-dependency in the calculated specific equilibrium climate sensitivity S[CO2,LI] for most of the Pleistocene (last 2.1 Myr). During Pleistocene intermediate glaciated climates and interglacial periods S[CO2,LI] is on average ∼ 45 % larger than during Pleistocene full glacial conditions. In the Pliocene part of our analysis (2.6-5 Myr BP) the CO2 data uncertainties prevents a well-supported calculation for S[CO2,LI], but our analysis suggests that during times without a large land-ice area in the Northern Hemisphere (e.g. before 2.82 Myr BP) the specific equilibrium climate sensitivity S[CO2,LI] was smaller than during interglacials of the Pleistocene. We thus find support for a previously proposed state-change in the climate system with the wide appearance of northern hemispheric ice sheets. This study points for the first time to a so far overlooked non-linearity in the land-ice albedo radiative forcing, which is important for similar paleo data-based approaches to calculate climate

  4. Individual Differences and State-Dependent Responses in Transcranial Direct Current Stimulation.

    PubMed

    Hsu, Tzu-Yu; Juan, Chi-Hung; Tseng, Philip

    2016-01-01

    Transcranial direct current stimulation (tDCS) has been extensively used to examine whether neural activities can be selectively increased or decreased with manipulations of current polarity. Recently, the field has reevaluated the traditional anodal-increase and cathodal-decrease assumption due to the growing number of mixed findings that report the effects of the opposite directions. Therefore, the directionality of tDCS polarities and how it affects each individual still remain unclear. In this study, we used a visual working memory (VWM) paradigm and systematically manipulated tDCS polarities, types of different independent baseline measures, and task difficulty to investigate how these factors interact to determine the outcome effect of tDCS. We observed that only low-performers, as defined by their no-tDCS corsi block tapping (CBT) performance, persistently showed a decrement in VWM performance after anodal stimulation, whereas no tDCS effect was found when participants were divided by their performance in digit span. In addition, only the optimal level of task difficulty revealed any significant tDCS effect. All these findings were consistent across different blocks, suggesting that the tDCS effect was stable across a short period of time. Lastly, there was a high degree of intra-individual consistency in one's responsiveness to tDCS, namely that participants who showed positive or negative effect to anodal stimulation are also more likely to show the same direction of effects for cathodal stimulation. Together, these findings imply that tDCS effect is interactive and state dependent: task difficulty and consistent individual differences modulate one's responsiveness to tDCS, while researchers' choices of independent behavioral baseline measures can also critically affect how the effect of tDCS is evaluated. These factors together are likely the key contributors to the wide range of "noises" in tDCS effects between individuals, between stimulation protocols

  5. State-dependent climate sensitivity of the last 5 million years

    NASA Astrophysics Data System (ADS)

    Köhler, Peter; de Boer, Bas; von der Heydt, Anna; Stap, Lennert; van de Wal, Roderik

    2015-04-01

    Equilibrium temperature rise in response to increase in radiative forcing is called equilibrium climate sensitivity, an important quantity calculated by climate models to project future warming. For model validation comparisons with estimates based on paleo reconstructions are necessary. Here we use an energy balance model (Köhler et al., 2010) to estimate climate sensitivity using CO2 proxy data together with model-based reconstruction of land ice (de Boer et al., 2014) over the last 5 million years. We find that equilibrium climate sensitivity containing the radiative forcing of CO2 and land ice albedo depends on the background climate. This state-dependency is mainly contained in the non-linearity of the land-ice forcing. Results differ in detail if based on ice core CO2 of the last 800,000 years covering mainly colder than present climates (von der Heydt et al., 2014) or on CO2 proxies of the last 5 million years. Nevertheless, the climate sensitivity of the warm Pliocene, a paleo-analogy for a warmer future, is at least about a third higher than for preindustrial background climates. References: de Boer, B., Lourens, L. J. & van de Wal, R. S. Persistent 400,000-year variability of Antarctic ice volume and the carbon cycle is revealed throughout the Plio-Pleistocene. Nature Communications 5, 2999 (2014). doi: 10.1038/ncomms3999. Köhler, P. Bintanja, R., Fischer, H., Joos, F., Knutti, R., Lohmann, G. & Masson-Delmotte, V. What caused Earth's temperature variations during the last 800,000 years? Data-based evidences on radiative forcing and constraints on climate sensitivity. Quaternary Science Reviews 29, 129-145 (2010). doi: 10.1016/j.quascirev.2009.09.026. von der Heydt, A. S., Köhler, P., van de Wal, R. S. & Dijkstra, H. A. On the state dependency of fast feedback processes in (paleo) climate sensitivity. Geophysical Research Letters 41, 6484-6492 (2014). doi: 10.1002/2014GL061121.

  6. The systematic study of the stability of forecasts in the rate- and state-dependent model

    NASA Astrophysics Data System (ADS)

    De Gaetano, D.; McCloskey, J.; Nalbant, S. S.

    2011-12-01

    Numerous observations have shown a general spatial correlation between positive Coulomb failure stress changes due to an earthquake and the locations of aftershocks. However this correlation does not give any indication of the rate from which we can infer the magnitude using the Gutenberg-Richter law. Dieterich's rate- and state-dependent model can be used to obtain a forecast of the observed aftershock rate for the space and time evolution of seismicity caused by stress changes applied to an infinite population of nucleating patches. The seismicity rate changes on this model depend on eight parameters: the stressing rate, the amplitude of the stress perturbation, the physical constitutive properties of faults, the spatial parameters (location and radii of the cells), the start and duration of each of the temporal windows as well as the background seismicity rate. The background seismicity is declustered using the epidemic type aftershock sequence model. We use the 1992 Landers earthquake as a case study, using the Southern California Earthquake Data Centre (SCEDC) catalogue, to examine if Dieterich's rate- and state-dependent model can forecast the aftershock seismicity rate. We perform a systematic study on a range of values on all the parameters to test the forecasting ability of this model. The results obtained suggest variable success in forecasting, when varying the values for the parameters, with the spatial and temporal parameters being the most sensitive. The Omori-Utsu law describes the aftershock rate as a power law in time following the main shock and depends on only three parameters: the aftershock productivity, the elapsed time since the main shock and the constant time shift, all of which can be estimated in the early part of the aftershock sequence and then extrapolated to give a long term rate forecast. All parameters are estimated using maximum likelihood methods. We compare the Dieterich and the Omori-Utsu forecasts using the Akaike information

  7. Electrophysiological identification of the functional presynaptic nerve terminals on an isolated single vasopressin neurone of the rat supraoptic nucleus.

    PubMed

    Ohbuchi, T; Yokoyama, T; Fujihara, H; Suzuki, H; Ueta, Y

    2010-05-01

    Release of arginine vasopressin (AVP) and oxytocin from magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus (SON) is under the control of glutamate-dependent excitation and GABA-dependent inhibition. The possible role of the synaptic terminals attached to SON neurones has been investigated using whole-cell patch-clamp recording in in vitro rat brain slice preparations. Recent evidence has provided new insights into the repercussions of glial environment modifications on the physiology of MNCs at the synaptic level in the SON. In the present study, excitatory glutamatergic and inhibitory GABAergic synaptic inputs were recorded from an isolated single SON neurone cultured for 12 h, using the whole-cell patch clamp technique. Neurones expressed an AVP-enhanced green fluorescent protein (eGFP) fusion gene in MNCs. In addition, native synaptic terminals attached to a dissociated AVP-eGFP neurone were visualised with synaptic vesicle markers. These results suggest that the function of presynaptic nerve terminals may be evaluated directly in a single AVP-eGFP neurone. These preparations would be helpful in future studies aiming to electrophysiologically distinguish between the functions of synaptic terminals and glial modifications in the SON neurones.

  8. Modulation of presynaptic action potential kinetics underlies synaptic facilitation of type B photoreceptors after associative conditioning in Hermissenda.

    PubMed

    Gandhi, C C; Matzel, L D

    2000-03-01

    -cell action potential by a reduction of I(A) was sufficient to account for the observed synaptic facilitation. The occlusion of the effects of 4-AP by paired training was not attributable to a saturation of the capacity of the B-cell for transmitter exocytosis, because it was observed that tetraethylammonium (TEA)-induced inhibition of the delayed voltage-dependent K(+) current induced both spike broadening and synaptic facilitation regardless of training history. Collectively, these results demonstrate that training-induced facilitation at B-cell synapses is attributable to the effects of a reduction of a presynaptic K(+) conductance on action potential kinetics and suggest another critical similarity between the cellular basis for learning in Hermissenda and other invertebrate systems.

  9. Rate- and state-dependent seismicity during fluid injection in rocks

    NASA Astrophysics Data System (ADS)

    Wenzel, Friedemann

    2015-04-01

    Dieterich (1994) developed a theoretical frame of seismicity evolution due to stress changes in a medium based on rate- and state-theory of frictional fault motion. The theory assumes a volume density of seismic faults with a specific initial slip velocity distribution upon which the stress changes act. Each fault then follows the rate- and state-dependent frictional law where instabilities develop not as Coulomb failure. The evolution is expressed in the form of a differential equation, which can be used for aftershock generation after a shear stress change caused by a main shock but equally well for normal stress changes on faults caused by fluid pressure changes resulting from injection. For a constant injection rate the seismic activity increases at a given distance from the injection point once the pressure exceeds a threshold value. If the pressure rate is high enough the seismic activity becomes proportional to the local pressure rate in accordance with criticality theory of Shapiro (2002). Once the rate drops the seismicity reduced to lower levels. Shut off and variable injection rates must be evaluated numerically but lead to results comparable to the criticality theory. The presentation outlines the physical concept of the rate- and state-approach in comparison to the criticality approach and shows the main analytic and numerical results.

  10. Role of the pH in state-dependent blockade of hERG currents

    NASA Astrophysics Data System (ADS)

    Wang, Yibo; Guo, Jiqing; Perissinotti, Laura L.; Lees-Miller, James; Teng, Guoqi; Durdagi, Serdar; Duff, Henry J.; Noskov, Sergei Yu.

    2016-10-01

    Mutations that reduce inactivation of the voltage-gated Kv11.1 potassium channel (hERG) reduce binding for a number of blockers. State specific block of the inactivated state of hERG block may increase risks of drug-induced Torsade de pointes. In this study, molecular simulations of dofetilide binding to the previously developed and experimentally validated models of the hERG channel in open and open-inactivated states were combined with voltage-clamp experiments to unravel the mechanism(s) of state-dependent blockade. The computations of the free energy profiles associated with the drug block to its binding pocket in the intra-cavitary site display startling differences in the open and open-inactivated states of the channel. It was also found that drug ionization may play a crucial role in preferential targeting to the open-inactivated state of the pore domain. pH-dependent hERG blockade by dofetilie was studied with patch-clamp recordings. The results show that low pH increases the extent and speed of drug-induced block. Both experimental and computational findings indicate that binding to the open-inactivated state is of key importance to our understanding of the dofetilide’s mode of action.

  11. The effect of a musical mood induction procedure on mood state-dependent word retrieval.

    PubMed

    De L'Etoile, Shannon K

    2002-01-01

    The purpose of this experiment was to replicate and expand upon an earlier study by Thaut and de l'Etoile (1993) by examining the effect of a musical mood induction procedure on mood state-dependent word retrieval. Participants (N = 45) completed a 2-day testing procedure. On day one, participants read a list of adjectives and wrote down an antonym for each one. On day two, participants recalled as many of the antonyms as possible. During the testing procedure, participants were placed in 1 of 4 conditions: (a) mood induction at encoding, (b) mood induction at recall, (c) no mood induction, and (d) mood induction at both encoding and recall. The mood induction procedure included 3 steps. Participants first assessed their current mood state using a visual analog scale. They then listened to music for 5 minutes, determined the mood of the piece while listening, and tried to match their mood to the music. Finally, participants again used the visual analog scale to indicate their mood. Results indicated that participants who received mood induction prior to both encoding and recall were able to retrieve significantly more words than participants who did not undergo any mood induction. The results are discussed in light of the associative network theory of memory and emotions and the treatment of mood disorders.

  12. Cellular Mechanisms Underlying Behavioral State-Dependent Bidirectional Modulation of Motor Cortex Output

    PubMed Central

    Schiemann, Julia; Puggioni, Paolo; Dacre, Joshua; Pelko, Miha; Domanski, Aleksander; van Rossum, Mark C.W.; Duguid, Ian

    2015-01-01

    Summary Neuronal activity in primary motor cortex (M1) correlates with behavioral state, but the cellular mechanisms underpinning behavioral state-dependent modulation of M1 output remain largely unresolved. Here, we performed in vivo patch-clamp recordings from layer 5B (L5B) pyramidal neurons in awake mice during quiet wakefulness and self-paced, voluntary movement. We show that L5B output neurons display bidirectional (i.e., enhanced or suppressed) firing rate changes during movement, mediated via two opposing subthreshold mechanisms: (1) a global decrease in membrane potential variability that reduced L5B firing rates (L5Bsuppressed neurons), and (2) a coincident noradrenaline-mediated increase in excitatory drive to a subpopulation of L5B neurons (L5Benhanced neurons) that elevated firing rates. Blocking noradrenergic receptors in forelimb M1 abolished the bidirectional modulation of M1 output during movement and selectively impaired contralateral forelimb motor coordination. Together, our results provide a mechanism for how noradrenergic neuromodulation and network-driven input changes bidirectionally modulate M1 output during motor behavior. PMID:25981037

  13. State-dependent access of anions to the cystic fibrosis transmembrane conductance regulator chloride channel pore.

    PubMed

    Fatehi, Mohammad; Linsdell, Paul

    2008-03-07

    The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is gated by intracellular factors; however, conformational changes in the channel pore associated with channel activation have not been identified. We have used patch clamp recording to investigate the state-dependent accessibility of substituted cysteine residues in the CFTR channel pore to a range of cysteine-reactive reagents applied to the extracellular side of the membrane. Using functional modification of the channel current-voltage relationship as a marker of modification, we find that several positively charged reagents are able to penetrate deeply into the pore from the outside irrespective of whether or not the channels have been activated. In contrast, access of three anionic cysteine-reactive reagents, the methanesulfonate sodium (2-sulfonatoethyl)methanesulfonate, the organic mercurial p-chloromercuriphenylsulfonic acid, and the permeant anion Au(CN)(2)(-), to several different sites in the pore is strictly limited prior to channel activation. This suggests that in nonactivated channels some ion selectivity mechanism exists to exclude anions yet permit cations into the channel pore from the extracellular solution. We suggest that activation of CFTR channels involves a conformational change in the pore that removes a strong selectivity against anion entry from the extracellular solution. We propose further that this conformational change occurs in advance of channel opening, suggesting that multiple distinct closed pore conformations exist.

  14. Effect of rotational-state-dependent molecular alignment on the optical dipole force

    NASA Astrophysics Data System (ADS)

    Kim, Lee Yeong; Lee, Ju Hyeon; Kim, Hye Ah; Kwak, Sang Kyu; Friedrich, Bretislav; Zhao, Bum Suk

    2016-07-01

    The properties of molecule-optical elements such as lenses or prisms based on the interaction of molecules with optical fields depend in a crucial way on the molecular quantum state and its alignment created by the optical field. Herein, we consider the effects of state-dependent alignment in estimating the optical dipole force acting on the molecules and, to this end, introduce an effective polarizability which takes proper account of molecular alignment and is directly related to the alignment-dependent optical dipole force. We illustrate the significance of including molecular alignment in the optical dipole force by a trajectory study that compares previously used approximations with the present approach. The trajectory simulations were carried out for an ensemble of linear molecules subject to either propagating or standing-wave optical fields for a range of temperatures and laser intensities. The results demonstrate that the alignment-dependent effective polarizability can serve to provide correct estimates of the optical dipole force, on which a state-selection method applicable to nonpolar molecules could be based. We note that an analogous analysis of the forces acting on polar molecules subject to an inhomogeneous static electric field reveals a similarly strong dependence on molecular orientation.

  15. Singular Hopf bifurcation in a differential equation with large state-dependent delay.

    PubMed

    Kozyreff, G; Erneux, T

    2014-02-08

    We study the onset of sustained oscillations in a classical state-dependent delay (SDD) differential equation inspired by control theory. Owing to the large delays considered, the Hopf bifurcation is singular and the oscillations rapidly acquire a sawtooth profile past the instability threshold. Using asymptotic techniques, we explicitly capture the gradual change from nearly sinusoidal to sawtooth oscillations. The dependence of the delay on the solution can be either linear or nonlinear, with at least quadratic dependence. In the former case, an asymptotic connection is made with the Rayleigh oscillator. In the latter, van der Pol's equation is derived for the small-amplitude oscillations. SDD differential equations are currently the subject of intense research in order to establish or amend general theorems valid for constant-delay differential equation, but explicit analytical construction of solutions are rare. This paper illustrates the use of singular perturbation techniques and the unusual way in which solvability conditions can arise for SDD problems with large delays.

  16. Self-similar slip instability on interfaces with rate- and state-dependent friction

    NASA Astrophysics Data System (ADS)

    Viesca, Robert C.

    2016-08-01

    We examine the development of a frictional instability, with diverging sliding rate, at the interface of elastic bodies in contact. Evolution of friction is determined by a slip rate and state dependence. Following Viesca (2016 Phys. Rev. E 93, 060202(R). (doi:10.1103/PhysRevE.93.060202)), we show through an appropriate change of variable, the existence of blow-up solutions that are fixed points of a dynamical system. The solutions show self-similarity of the simple variety: separable dependence of time and space. For an interface with uniform frictional properties, there is a single-problem parameter. We examine the linear stability of these fixed points, as this problem parameter is varied. Specifically, we consider two archetypical elastic settings of the slip surface, in which interactions between points on the surface are either local or non-local. We show that, independent of the nature of elastic interactions, the fixed-points lose stability in the same matter as the parameter is increased towards a limit value: an apparently infinite sequence of Hopf bifurcations. However, for any value of the parameter, the nonlinear development of the instability is attraction, if not asymptotic convergence, towards these fixed points, owing to the existence of stable eigenmodes. For comparison, we perform numerical solutions of the original evolution equations and find precise agreement with the results of the analysis.

  17. Electromagnetic two-body problem: recurrent dynamics in the presence of state-dependent delay

    NASA Astrophysics Data System (ADS)

    De Luca, Jayme; Guglielmi, Nicola; Humphries, Tony; Politi, Antonio

    2010-05-01

    We study the electromagnetic two-body problem of classical electrodynamics as a prototype dynamical system with state-dependent delays. The equations of motion are analysed with reference to motion along a straight line in the presence of an electrostatic field. We consider the general electromagnetic equations of motion for point charges with advanced and retarded interactions and study two limits, (a) retarded-only interactions (Dirac electrodynamics) and (b) half-retarded plus half-advanced interactions (Wheeler-Feynman electrodynamics). A fixed point is created where the electrostatic field balances the Coulombian attraction, and we use local analysis near this fixed point to derive necessary conditions for a Hopf bifurcation. In case (a), we study a Hopf bifurcation about an unphysical fixed point and find that it is subcritical. In case (b), there is a Hopf bifurcation about a physical fixed point and we study several families of periodic orbits near this point. The bifurcating periodic orbits are illustrated and simulated numerically, by introducing a surrogate dynamical system into the numerical analysis which transforms future data into past data by exploiting the periodicity, thus obtaining systems with only delays.

  18. Effects of Electronic-State-Dependent Solute Polarizability: Application to Solute-Pump/Solvent-Probe Spectra.

    PubMed

    Sun, Xiang; Ladanyi, Branka M; Stratt, Richard M

    2015-07-23

    Experimental studies of solvation dynamics in liquids invariably ask how changing a solute from its electronic ground state to an electronically excited state affects a solution's dynamics. With traditional time-dependent-fluorescence experiments, that means looking for the dynamical consequences of the concomitant change in solute-solvent potential energy. But if one follows the shift in the dynamics through its effects on the macroscopic polarizability, as recent solute-pump/solvent-probe spectra do, there is another effect of the electronic excitation that should be considered: the jump in the solute's own polarizability. We examine the spectroscopic consequences of this solute polarizability change in the classic example of the solvation dye coumarin 153 dissolved in acetonitrile. After demonstrating that standard quantum chemical methods can be used to construct accurate multisite models for the polarizabilities of ground- and excited-state solvation dyes, we show via simulation that this polarizability change acts as a contrast agent, significantly enhancing the observable differences in optical-Kerr spectra between ground- and excited-state solutions. A comparison of our results with experimental solute-pump/solvent-probe spectra supports our interpretation and modeling of this spectroscopy. We predict, in particular, that solute-pump/solvent-probe spectra should be sensitive to changes in both the solvent dynamics near the solute and the electronic-state-dependence of the solute's own rotational dynamics.

  19. M/G/c/c state dependent travel time models and properties

    NASA Astrophysics Data System (ADS)

    MacGregor Smith, J.; Cruz, F. R. B.

    2014-02-01

    One of the most important problems in today’s modeling of transportation networks is an accurate estimate of travel time on arterial links, highway, and freeways. There are a number of deterministic formulas that have been developed over the years to achieve a simple and direct way to estimate travel times for this complex task. Realistically, however, travel time is a random variable. These deterministic formula are briefly reviewed and also a new way to compute travel time over arterial links, highway, and freeways, is presented based on an analytical state dependent queueing model. One of the features of the queueing model is that it is analyzed within the context of the theoretical three-phase traffic flow model. We show that the model provides a quantitative foundation alternative to qualitative three-phase traffic flow theory. An important property shown with the model is that the travel time function is not convex, but a sigmoid S-shaped (i.e. logistic curve). Extensive analytical and simulation experiments are shown to verify the S-shaped nature of the travel time function and the use of the model’s method of estimation of travel time over vehicular traffic links as compared with traditional approaches. Finally, it is shown that the point-of-inflection of the S-shaped curve represents the threshold point where the traffic flow volume switches from Free Flow to Congested Flow.

  20. Eyes wide shut: Transcranial alternating current stimulation drives alpha rhythm in a state dependent manner.

    PubMed

    Ruhnau, Philipp; Neuling, Toralf; Fuscá, Marco; Herrmann, Christoph S; Demarchi, Gianpaolo; Weisz, Nathan

    2016-06-02

    Transcranial alternating current stimulation (tACS) is used to modulate brain oscillations to measure changes in cognitive function. It is only since recently that brain activity in human subjects during tACS can be investigated. The present study aims to investigate the phase relationship between the external tACS signal and concurrent brain activity. Subjects were stimulated with tACS at individual alpha frequency during eyes open and eyes closed resting states. Electrodes were placed at Cz and Oz, which should affect parieto-occipital areas most strongly. Source space magnetoencephalography (MEG) data were used to estimate phase coherence between tACS and brain activity. Phase coherence was significantly increased in areas in the occipital pole in eyes open resting state only. The lag between tACS and brain responses showed considerable inter-individual variability. In conclusion, tACS at individual alpha frequency entrains brain activity in visual cortices. Interestingly, this effect is state dependent and is clearly observed with eyes open but only to a lesser extent with eyes closed.

  1. State-dependent decisions cause apparent violations of rationality in animal choice.

    PubMed

    Schuck-Paim, Cynthia; Pompilio, Lorena; Kacelnik, Alex

    2004-12-01

    Normative models of choice in economics and biology usually expect preferences to be consistent across contexts, or "rational" in economic language. Following a large body of literature reporting economically irrational behaviour in humans, breaches of rationality by animals have also been recently described. If proven systematic, these findings would challenge long-standing biological approaches to behavioural theorising, and suggest that cognitive processes similar to those claimed to cause irrationality in humans can also hinder optimality approaches to modelling animal preferences. Critical differences between human and animal experiments have not, however, been sufficiently acknowledged. While humans can be instructed conceptually about the choice problem, animals need to be trained by repeated exposure to all contingencies. This exposure often leads to differences in state between treatments, hence changing choices while preserving rationality. We report experiments with European starlings demonstrating that apparent breaches of rationality can result from state-dependence. We show that adding an inferior alternative to a choice set (a "decoy") affects choices, an effect previously interpreted as indicating irrationality. However, these effects appear and disappear depending on whether state differences between choice contexts are present or not. These results open the possibility that some expressions of maladaptive behaviour are due to oversights in the migration of ideas between economics and biology, and suggest that key differences between human and nonhuman research must be recognised if ideas are to safely travel between these fields.

  2. State-Dependent Decisions Cause Apparent Violations of Rationality in Animal Choice

    PubMed Central

    Schuck-Paim, Cynthia; Pompilio, Lorena

    2004-01-01

    Normative models of choice in economics and biology usually expect preferences to be consistent across contexts, or “rational” in economic language. Following a large body of literature reporting economically irrational behaviour in humans, breaches of rationality by animals have also been recently described. If proven systematic, these findings would challenge long-standing biological approaches to behavioural theorising, and suggest that cognitive processes similar to those claimed to cause irrationality in humans can also hinder optimality approaches to modelling animal preferences. Critical differences between human and animal experiments have not, however, been sufficiently acknowledged. While humans can be instructed conceptually about the choice problem, animals need to be trained by repeated exposure to all contingencies. This exposure often leads to differences in state between treatments, hence changing choices while preserving rationality. We report experiments with European starlings demonstrating that apparent breaches of rationality can result from state-dependence. We show that adding an inferior alternative to a choice set (a “decoy”) affects choices, an effect previously interpreted as indicating irrationality. However, these effects appear and disappear depending on whether state differences between choice contexts are present or not. These results open the possibility that some expressions of maladaptive behaviour are due to oversights in the migration of ideas between economics and biology, and suggest that key differences between human and nonhuman research must be recognised if ideas are to safely travel between these fields. PMID:15550984

  3. Thirst and the state-dependent representation of incentive stimulus value in human motive circuitry.

    PubMed

    Becker, Christoph A; Schmälzle, Ralf; Flaisch, Tobias; Renner, Britta; Schupp, Harald T

    2015-12-01

    Depletion imposes both need and desire to drink, and potentiates the response to need-relevant cues in the environment. The present fMRI study aimed to determine which neural structures selectively increase the incentive value of need-relevant stimuli in a thirst state. Towards this end, participants were scanned twice--either in a thirst or no-thirst state--while viewing pictures of beverages and chairs. As expected, thirst led to a selective increase in self-reported pleasantness and arousal by beverages. Increased responses to beverage when compared with chair stimuli were observed in the cingulate cortex, insular cortex and the amygdala in the thirst state, which were absent in the no-thirst condition. Enhancing the incentive value of need-relevant cues in a thirst state is a key mechanism for motivating drinking behavior. Overall, distributed regions of the motive circuitry, which are also implicated in salience processing, craving and interoception, provide a dynamic body-state dependent representation of stimulus value.

  4. State dependence, personality, and plants: light-foraging decisions in Mimosa pudica (L.).

    PubMed

    Simon, Franz W; Hodson, Christina N; Roitberg, Bernard D

    2016-09-01

    Plants make foraging decisions that are dependent on ecological conditions, such as resource availability and distribution. Despite the field of plant behavioral ecology gaining momentum, ecologists still know little about what factors impact plant behavior, especially light-foraging behavior. We made use of the behavioral reaction norm approach to investigate light foraging in a plant species that exhibits rapid movement: Mimosa pudica. We explored how herbivore avoidance behavior in M. pudica (which closes its leaflets temporarily when disturbed) is affected by an individual's energy state and the quality of the current environment and also repeatedly tested the behavior of individuals from two seed sources to determine whether individuals exhibit a "personality" (i.e., behavioral syndrome). We found that when individuals are in a low-energy state, they adopt a riskier light-foraging strategy, opening leaflets faster, and not closing leaflets as often in response to a disturbance. However, when plants are in a high-energy state, they exhibit a plastic light-foraging strategy dependent on environment quality. Although we found no evidence that individuals exhibit behavioral syndromes, we found that individuals from different seed sources consistently behave differently from each other. Our results suggest that plants are capable of making state-dependent decisions and that plant decision making is complex, depending on the interplay between internal and external factors.

  5. Role of the pH in state-dependent blockade of hERG currents

    PubMed Central

    Wang, Yibo; Guo, Jiqing; Perissinotti, Laura L.; Lees-Miller, James; Teng, Guoqi; Durdagi, Serdar; Duff, Henry J.; Noskov, Sergei Yu.

    2016-01-01

    Mutations that reduce inactivation of the voltage-gated Kv11.1 potassium channel (hERG) reduce binding for a number of blockers. State specific block of the inactivated state of hERG block may increase risks of drug-induced Torsade de pointes. In this study, molecular simulations of dofetilide binding to the previously developed and experimentally validated models of the hERG channel in open and open-inactivated states were combined with voltage-clamp experiments to unravel the mechanism(s) of state-dependent blockade. The computations of the free energy profiles associated with the drug block to its binding pocket in the intra-cavitary site display startling differences in the open and open-inactivated states of the channel. It was also found that drug ionization may play a crucial role in preferential targeting to the open-inactivated state of the pore domain. pH-dependent hERG blockade by dofetilie was studied with patch-clamp recordings. The results show that low pH increases the extent and speed of drug-induced block. Both experimental and computational findings indicate that binding to the open-inactivated state is of key importance to our understanding of the dofetilide’s mode of action. PMID:27731415

  6. State-dependent variation in the inhibitory effect of (D-Ala sup 2 , D-Leu sup 5 )-enkephalin on hippocampal serotonin release in ground squirrels

    SciTech Connect

    Kramarova, L.I.; Lee, T.F.; Cui, Y.; Wang, L.C.H. )

    1990-01-01

    Accumulated evidence has suggested that increased endogenous opioid activities may facilitate the onset of hibernation either directly or possibly through modulation of other neurotransmitter systems. The seasonal change of (D-Ala{sup 2}, D-Leu{sup 5})-enkephalin (DADLE), a {delta} receptor agonist, in modulating K{sup +}-induced ({sup 3}H)-5-hydroxytryptamine (5-HT) release from the hippocampal and hypothalamic slices of euthermic and hibernating Richardsons' ground squirrels was therefore investigated. DADLE had no effect on 5-HT release in the hypothalamic slices but elicited a dose-related inhibition on ({sup 3}H)-5-HT release from the hippocampal slices of the euthermic ground squirrel. The inhibitory effect of DADLE was completely reversed by naloxone, but not by tetrodotoxin. In contrast, DADLE failed to alter the K{sup +}-induced 5-HT release from the hippocampal slices of the hibernating ground squirrel. This state-dependent reduction in responsiveness to an opioid is consistent with the hypothesis that enhanced endogenous opioid activity in the hibernating phase could lead to down regulation of the opioid receptors and minimize its inhibition on hippocampal serotonergic activity. A high 5-HT activity would inhibit midbrain reticular activating system indirectly through non-serotonergic fibers, which in turn facilitate the onset or maintenance of hibernation.

  7. Modulation of dopamine and noradrenaline release and of intracellular Ca2+ concentration by presynaptic glutamate receptors in hippocampus.

    PubMed

    Malva, J O; Carvalho, A P; Carvalho, C M

    1994-12-01

    1. We studied the release of [3H]-dopamine and [3H]-noradrenaline (NA) from hippocampal synaptosomes induced by glutamate receptors and the associated Ca2+ influx through Ca2+ channels. The release of tritiated neurotransmitters was studied by use of superfusion system and the intracellular free Ca2+ concentration ([Ca2+]i) was determined by a fluorimetric assay with Indo-1 as a probe for Ca2+. 2. Presynaptic glutamate receptor activation induced Ca(2+)-dependent release of [3H]-dopamine and [3H]-NA from rat hippocampal synaptosomes. Thus, L-glutamate induced the release of both neurotransmitters in a dose-dependent manner (EC50 = 5.62 microM), and the effect of 100 microM L-glutamate was inhibited by 83.8% in the presence of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dioxine (CNQX), but was not affected by 1 microM (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine (MK-801). 3. Other glutamate receptor agonists also stimulated the Ca(2+)-dependent release of [3H]-dopamine and [3H]-NA as follows: N-methyl-D-aspartate (NMDA), at 200 microM, released 3.65 +/- 0.23% of the total 3H catecholamines, and this effect was inhibited by 81.2% in the presence of 1 microM MK-801; quisqualate (50 microM), S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid (AMPA) (100 microM) or kainate (100 microM) released 1.57 +/- 0.26%, 1.93 +/- 0.17% and 2.09 +/- 0.22%, of the total 3H catecholamines, respectively. 4. The ionotropic glutamate receptor agonist, AMPA, induced an increase in the [Ca2+]i which was inhibited by 58.6% in the presence of 10 microM CNQX. In contrast, the increase in [Ca2+]i due to stimulation by glutamate was not sensitive to CNQX or MK-801.5. Nitrendipine, at I JAM, did not inhibit the neurotransmitter release induced by AMPA, but, both 0.5 micro M -conotoxin GVIA (w-CgTx) and 100 nM w-Aga IVA reduced catecholamine release to 49.03 +/- 3.79% and 46.06 +/- 10.51% of the control, respectively. In the presence of both toxins the release was

  8. Hippocampal long-term potentiation is not accompanied by presynaptic spike broadening, unlike synaptic potentiation by K+ channel blockers.

    PubMed

    Laerum, H; Storm, J F

    1994-02-21

    The expression of hippocampal long-term potentiation (LTP) is thought to be at least partly due to increased transmitter release. To test whether this increase is due to a broadening of the presynaptic action potential, we have compared the presynaptic fibre volley before and after LTP induction, or application of K+ channel blockers, in CA1 of rat hippocampal slices. Tetraethylammonium (TEA; 1 mM) induced a parallel increase in the fibre volley duration of the slope of the field EPSP, indicating that a presynaptic spike broadening underlying synaptic potentiation can be detected. In contrast, induction of LTP did not produce any measurable change in the fibre volley, although the average increase in the EPSP slope was larger than with TEA. These results indicate that LTP expression is not primarily due to a presynaptic spike broadening.

  9. DGKθ Catalytic Activity is Required for Efficient Recycling of Presynaptic Vesicles at Excitatory Synapses

    PubMed Central

    Goldschmidt, Hana L.; Tu-Sekine, Becky; Volk, Lenora; Anggono, Victor; Huganir, Richard L.; Raben, Daniel M.

    2015-01-01

    Summary Synaptic transmission relies on coordinated coupling of synaptic vesicle (SV) exocytosis and endocytosis. While much attention has focused on characterizing proteins involved in SV recycling, the roles of membrane lipids and their metabolism remain poorly understood. Diacylglycerol, a major signaling lipid produced at synapses during synaptic transmission, is regulated by diacylglycerol kinase (DGK). Here we report a role for DGKθ in the mammalian central nervous system in facilitating recycling of presynaptic vesicles at excitatory synapses. Using synaptophysin- and vGlut1-pHluorin optical reporters, we found that acute and chronic deletion of DGKθ attenuated the recovery of SVs following neuronal stimulation. Rescue of recycling kinetics required DGKθ kinase activity. Our data establish a role for DGK catalytic activity and its byproduct, phosphatidic acid, at the presynaptic nerve terminal in SV recycling. Together these data suggest DGKθ supports synaptic transmission during periods of elevated neuronal activity. PMID:26748701

  10. Presynaptic spinophilin tunes neurexin signalling to control active zone architecture and function

    PubMed Central

    Muhammad, Karzan; Reddy-Alla, Suneel; Driller, Jan H; Schreiner, Dietmar; Rey, Ulises; Böhme, Mathias A.; Hollmann, Christina; Ramesh, Niraja; Depner, Harald; Lützkendorf, Janine; Matkovic, Tanja; Götz, Torsten; Bergeron, Dominique D.; Schmoranzer, Jan; Goettfert, Fabian; Holt, Mathew; Wahl, Markus C.; Hell, Stefan W.; Scheiffele, Peter; Walter, Alexander M.; Loll, Bernhard; Sigrist, Stephan J.

    2015-01-01

    Assembly and maturation of synapses at the Drosophila neuromuscular junction (NMJ) depend on trans-synaptic neurexin/neuroligin signalling, which is promoted by the scaffolding protein Syd-1 binding to neurexin. Here we report that the scaffold protein spinophilin binds to the C-terminal portion of neurexin and is needed to limit neurexin/neuroligin signalling by acting antagonistic to Syd-1. Loss of presynaptic spinophilin results in the formation of excess, but atypically small active zones. Neuroligin-1/neurexin-1/Syd-1 levels are increased at spinophilin mutant NMJs, and removal of single copies of the neurexin-1, Syd-1 or neuroligin-1 genes suppresses the spinophilin-active zone phenotype. Evoked transmission is strongly reduced at spinophilin terminals, owing to a severely reduced release probability at individual active zones. We conclude that presynaptic spinophilin fine-tunes neurexin/neuroligin signalling to control active zone number and functionality, thereby optimizing them for action potential-induced exocytosis. PMID:26471740

  11. Presynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity

    PubMed Central

    Corlew, Rebekah; Brasier, Daniel J.; Feldman, Daniel E.; Philpot, Benjamin D.

    2009-01-01

    Many aspects of synaptic development, plasticity, and neurotransmission are critically influenced by NMDA-type glutamate receptors (NMDARs). Moreover, dysfunction of NMDARs has been implicated in a broad array of neurological disorders, including schizophrenia, stroke, epilepsy, and neuropathic pain. Classically, NMDARs were thought to be exclusively postsynaptic. However, substantial evidence in the last 10 years demonstrates that NMDARs also exist presynaptically, and that presynaptic NMDA receptors (preNMDARs) modulate synapse function and have critical roles in plasticity at many synapses. Here we review current knowledge of the role of preNMDARs in synaptic transmission and plasticity, focusing on the neocortex. We discuss the prevalence, function, and development of these receptors, and their potential modification by experience and in brain pathology. PMID:19029059

  12. State dependent model predictive control for orbital rendezvous using pulse-width pulse-frequency modulated thrusters

    NASA Astrophysics Data System (ADS)

    Li, Peng; Zhu, Zheng H.; Meguid, S. A.

    2016-07-01

    This paper studies the pulse-width pulse-frequency modulation based trajectory planning for orbital rendezvous and proximity maneuvering near a non-cooperative spacecraft in an elliptical orbit. The problem is formulated by converting the continuous control input, output from the state dependent model predictive control, into a sequence of pulses of constant magnitude by controlling firing frequency and duration of constant-magnitude thrusters. The state dependent model predictive control is derived by minimizing the control error of states and control roughness of control input for a safe, smooth and fuel efficient approaching trajectory. The resulting nonlinear programming problem is converted into a series of quadratic programming problem and solved by numerical iteration using the receding horizon strategy. The numerical results show that the proposed state dependent model predictive control with the pulse-width pulse-frequency modulation is able to effectively generate optimized trajectories using equivalent control pulses for the proximity maneuvering with less energy consumption.

  13. A search for presynaptic inhibitory histamine receptors in guinea-pig tissues: Further H3 receptors but no evidence for H4 receptors.

    PubMed

    Petri, Doris; Schlicker, Eberhard

    2016-07-01

    The histamine H4 receptor is coupled to Gi/o proteins and expressed on inflammatory cells and lymphoid tissues; it was suggested that this receptor also occurs in the brain or on peripheral neurones. Since many Gi/o protein-coupled receptors, including the H3 receptor, serve as presynaptic inhibitory receptors, we studied whether the sympathetic neurones supplying four peripheral tissues and the cholinergic neurones in the hippocampus from the guinea-pig are equipped with release-modulating H4 and H3 receptors. For this purpose, we preincubated tissue pieces from the aorta, atrium, renal cortex and vas deferens with (3)H-noradrenaline and hippocampal slices with (3)H-choline and determined the electrically evoked tritium overflow. The stimulation-evoked overflow in the five superfused tissues was inhibited by the muscarinic receptor agonist oxotremorine, which served as a positive control, but not affected by the H4 receptor agonist 4-methylhistamine. The H3 receptor agonist R-α-methylhistamine inhibited noradrenaline release in the peripheral tissues without affecting acetylcholine release in the hippocampal slices. Thioperamide shifted the concentration-response curve of histamine in the aorta and the renal cortex to the right, yielding apparent pA2 values of 8.0 and 8.1, respectively, which are close to its affinity at other H3 receptors but higher by one log unit than its pKi at the H4 receptor of the guinea-pig. In conclusion, histamine H4 receptors could not be identified in five experimental models of the guinea-pig that are suited for the detection of presynaptic inhibitory receptors whereas H3 receptors could be shown in the peripheral tissues but not in the hippocampus. This article is part of the Special Issue entitled 'Histamine Receptors'.

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

    DTIC Science & Technology

    2015-07-01

    6658. [38] Pacheco Otalora LF, Skinner F , Oliveira MS, Farrell B , Arshadmansab MF, Pandari T et al. Chronic deficit in the expression of voltage-gated...respectively) (Figure 31, b and c). No statistically significant changes were detected for gene expression of Calb28 ( F =2.6, p=0.09) and VGlut1 ( F ...and presynaptic structure in the pilocarpine model of temporal lobe epilepsy.” Upreti C, Otero R, Partida C, Skinner F , Thakker R, Pacheco LF, Zhou

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

    DTIC Science & Technology

    2014-07-01

    genetically-encoded fusion protein of the vesicle protein Vesicular Associated Membrane Protein (VAMP2) and pH-sensitive Enhanced Green Fluorescent...new therapeutic target for treatment of unresponsive epilepsies. While LEV binds to both the synaptic vesicle protein SV2a and N-type Ca2+ channels... Protein (EGFP). Research Goals: Task 1. Assess the effect of chronic treatment with antiepileptic drugs acting on presynaptic glutamate release

  16. Presynaptic Release-Regulating mGlu1 Receptors in Central Nervous System

    PubMed Central

    Pittaluga, Anna

    2016-01-01

    Group I metabotropic glutamate (mGlu) receptors consists of mGlu1 and mGlu5 receptor subtypes. These receptors are widely distributed in the central nervous system (CNS), where they preferentially mediate facilitatory signaling in neurones and glial cells, mainly by favoring phospholipase (PLC) translocation. Based on the literature so far available, group I Metabotropic glutamate receptors (mGluRs) are preferentially expressed at the postsynaptic side of chemical synapsis, where they participate in the progression of the chemical stimulus. Studies, however, have shown the presence of these receptors also at the presynaptic level, where they exert several functions, including the modulation of transmitter exocytosis. Presynaptic Group I mGluRs can be both autoreceptors regulating release of glutamate and heteroreceptors regulating the release of various transmitters, including GABA, dopamine, noradrenaline, and acetylcholine. While the existence of presynaptic release-regulating mGlu5 receptors is largely recognized, the possibility that mGlu1 receptors also are present at this level has been a matter of discussion for a long time. A large body of evidence published in the last decade, however, supports this notion. This review aims at revisiting the data from in vitro studies concerning the existence and the role of release-regulating mGlu1 receptors presynaptically located in nerve terminals isolated from selected regions of the CNS. The functional interaction linking mGlu5 and mGlu1 receptor subtypes at nerve terminals and their relative contributions as modulators of central transmission will also be discussed. We apologize in advance for omission in our coverage of the existing literature. PMID:27630571

  17. Mechanism of Calcium Current Modulation Underlying Presynaptic Facilitation and Behavioral Sensitization in Aplysia

    NASA Astrophysics Data System (ADS)

    Klein, Marc; Kandel, Eric R.

    1980-11-01

    Behavioral sensitization of the gill-withdrawal reflex of Aplysia is caused by presynaptic facilitation at the synapses of the mechanoreceptor sensory neurons of the reflex onto the motor neurons and interneurons. The presynaptic facilitation has been shown to be simulated by serotonin (the putative presynaptic facilitatory transmitter) and by cyclic AMP and to be accompanied by an increase in the Ca2+ current of sensory neuron cell bodies exposed to tetraethylammonium. This increase in the Ca2+ current could result from either a direct action on the Ca2+ channel or an action on an opposing K+ current. Here we report voltage clamp experiments which indicate that the increase in Ca2+ current associated with presynaptic facilitation results from a decrease in a K+ current. Stimulation of the connective (the pathway that mediates sensitization) or application of serotonin causes a decrease in a voltage-sensitive, steady-state outward current measured under voltage clamp as well as an increase in the transient net inward and a decrease in the transient outward currents elicited by brief depolarizing command steps. The reversal potential of the steady-state synaptic current is sensitive to extracellular K+ concentration, and both the steady-state synaptic current and the changes in the transient currents are blocked by K+ current blocking agents and by washout of K+. These results suggest that serotonin and the natural transmitter released by connective stimulation act to decrease a voltage-sensitive K+ current. The decrease in K+ current prolongs the action potential, and this in turn increases the duration of the inward Ca2+ current and thereby enhances transmitter release.

  18. Outbreaks by canopy-feeding geometrid moth cause state-dependent shifts in understorey plant communities.

    PubMed

    Karlsen, Stein Rune; Jepsen, Jane Uhd; Odland, Arvid; Ims, Rolf Anker; Elvebakk, Arve

    2013-11-01

    The increased spread of insect outbreaks is among the most severe impacts of climate warming predicted for northern boreal forest ecosystems. Compound disturbances by insect herbivores can cause sharp transitions between vegetation states with implications for ecosystem productivity and climate feedbacks. By analysing vegetation plots prior to and immediately after a severe and widespread outbreak by geometrid moths in the birch forest-tundra ecotone, we document a shift in forest understorey community composition in response to the moth outbreak. Prior to the moth outbreak, the plots divided into two oligotrophic and one eutrophic plant community. The moth outbreak caused a vegetation state shift in the two oligotrophic communities, but only minor changes in the eutrophic community. In the spatially most widespread communities, oligotrophic dwarf shrub birch forest, dominance by the allelopathic dwarf shrub Empetrum nigrum ssp. hermaphroditum, was effectively broken and replaced by a community dominated by the graminoid Avenella flexuosa, in a manner qualitatively similar to the effect of wild fires in E. nigrum communities in coniferous boreal forest further south. As dominance by E. nigrum is associated with retrogressive succession the observed vegetation state shift has widespread implications for ecosystem productivity on a regional scale. Our findings reveal that the impact of moth outbreaks on the northern boreal birch forest system is highly initial-state dependent, and that the widespread oligotrophic communities have a low resistance to such disturbances. This provides a case for the notion that climate impacts on arctic and northern boreal vegetation may take place most abruptly when conveyed by changed dynamics of irruptive herbivores.

  19. Using Brain–Computer Interfaces and Brain-State Dependent Stimulation as Tools in Cognitive Neuroscience

    PubMed Central

    Jensen, Ole; Bahramisharif, Ali; Oostenveld, Robert; Klanke, Stefan; Hadjipapas, Avgis; Okazaki, Yuka O.; van Gerven, Marcel A. J.

    2011-01-01

    Large efforts are currently being made to develop and improve online analysis of brain activity which can be used, e.g., for brain–computer interfacing (BCI). A BCI allows a subject to control a device by willfully changing his/her own brain activity. BCI therefore holds the promise as a tool for aiding the disabled and for augmenting human performance. While technical developments obviously are important, we will here argue that new insight gained from cognitive neuroscience can be used to identify signatures of neural activation which reliably can be modulated by the subject at will. This review will focus mainly on oscillatory activity in the alpha band which is strongly modulated by changes in covert attention. Besides developing BCIs for their traditional purpose, they might also be used as a research tool for cognitive neuroscience. There is currently a strong interest in how brain-state fluctuations impact cognition. These state fluctuations are partly reflected by ongoing oscillatory activity. The functional role of the brain state can be investigated by introducing stimuli in real-time to subjects depending on the actual state of the brain. This principle of brain-state dependent stimulation may also be used as a practical tool for augmenting human behavior. In conclusion, new approaches based on online analysis of ongoing brain activity are currently in rapid development. These approaches are amongst others informed by new insight gained from electroencephalography/magnetoencephalography studies in cognitive neuroscience and hold the promise of providing new ways for investigating the brain at work. PMID:21687463

  20. Intracellular CHO Cell Metabolite Profiling Reveals Steady-State Dependent Metabolic Fingerprints in Perfusion Culture.

    PubMed

    Karst, Daniel J; Steinhoff, Robert F; Kopp, Marie R G; Serra, Elisa; Soos, Miroslav; Zenobi, Renato; Morbidelli, Massimo

    2016-12-20

    Perfusion cell culture processes allow the steady-state culture of mammalian cells at high viable cell density, which is beneficial for overall product yields and homogeneity of product quality in the manufacturing of therapeutic proteins. In this study, the extent of metabolic steady state and the change of the metabolite profile between different steady states of an industrial Chinese hamster ovary (CHO) cell line producing a monoclonal antibody (mAb) was investigated in stirred tank perfusion bioreactors. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) of daily cell extracts revealed more than a hundred peaks, among which 76 metabolites were identified by tandem MS (MS/MS) and high resolution Fourier transform ion cyclotron resonance (FT-ICR) MS. Nucleotide ratios (Uridine (U)-ratio, nucleotide triphosphate (NTP)-ratio and energy charge (EC)) and multivariate analysis of all features indicated a consistent metabolite profile for a stable culture performed at 40 × 10(6) cells/mL over 26 days of culture. Conversely, the reactor was operated continuously so as to reach three distinct steady states one after the other at 20, 60, and 40 × 10(6) cells/mL. In each case, a stable metabolite profile was achieved after an initial transient phase of approximately three days at constant cell density when varying between these set points. Clear clustering according to cell density was observed by principal component analysis, indicating steady-state dependent metabolite profiles. In particular, varying levels of nucleotides, nucleotide sugar, and lipid precursors explained most of the variance between the different cell density set points. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 2016.

  1. Differential behavioral state-dependence in the burst properties of CA3 and CA1 neurons.

    PubMed

    Tropp Sneider, J; Chrobak, J J; Quirk, M C; Oler, J A; Markus, E J

    2006-09-15

    Brief bursts of fast high-frequency action potentials are a signature characteristic of CA3 and CA1 pyramidal neurons. Understanding the factors determining burst and single spiking is potentially significant for sensory representation, synaptic plasticity and epileptogenesis. A variety of models suggest distinct functional roles for burst discharge, and for specific characteristics of the burst in neural coding. However, little in vivo data demonstrate how often and under what conditions CA3 and CA1 actually exhibit burst and single spike discharges. The present study examined burst discharge and single spiking of CA3 and CA1 neurons across distinct behavioral states (awake-immobility and maze-running) in rats. In both CA3 and CA1 spike bursts accounted for less than 20% of all spike events. CA3 neurons exhibited more spikes per burst, greater spike frequency, larger amplitude spikes and more spike amplitude attenuation than CA1 neurons. A major finding of the present study is that the propensity of CA1 neurons to burst was affected by behavioral state, while the propensity of CA3 to burst was not. CA1 neurons exhibited fewer bursts during maze running compared with awake-immobility. In contrast, there were no differences in burst discharge of CA3 neurons. Neurons in both subregions exhibited smaller spike amplitude, fewer spikes per burst, longer inter-spike intervals and greater spike amplitude attenuation within a burst during awake-immobility compared with maze running. These findings demonstrate that the CA1 network is under greater behavioral state-dependent regulation than CA3. The present findings should inform both theoretic and computational models of CA3 and CA1 function.

  2. Metrics for palaeo climate sensitivity in the presence state-dependent feedbacks

    NASA Astrophysics Data System (ADS)

    von der Heydt, A. S.; Ashwin, P.

    2015-12-01

    Equilibrium climate sensitivity is one measure that is frequently used to predict long-term climate change in GCMs. Despite much research over the last decades, little progress has been made in constraining the uncertainty on climate sensitivity. One reason for this is the fact that the climate has a strong internal variability on many time scales, is subject to a non-stationary forcing and mostly out of equilibrium with the changes in the radiative forcing. Palaeo records of past climate variations can give insight into how the climate system responds to various forcings although care must be taken of the slow feedback processes at comparing palaeo climate sensitivity estimates with estimates from (short time scale) model simulations. In addition, for the late Pleistocene ice age cycles it has been shown from both proxy data and a conceptual climate model that climate sensitivity varies considerably between the cold and warm phases because the fast feedback processes change their relative strength over one cycle. Records of past CO2 and temperature together with 3D ice sheet model results extending back into the Pliocene suggest yet another value for the climate sensitivity in the warmer Pliocene. Here we use a conceptual model with known dynamics modelling the late Pleistocene ice ages to explore how climate sensitivity can be estimated from the model time series. Extracting the climate sensitivity from the relation between radiative forcing and global mean temperature leads to strongly state dependent behaviour and even negative values for climate sensitivity at rapid transitions into the deep glacial states. The degree to which the system is out of equilibrium and its relation to the equilibrium assumption of climate sensitivity needs therefore to be taken into account. Furthermore, Milankovitch forcing is generally not considered in palaeo climate sensitivity estimates. In the model time series we show how the sensitivity to Milankovitch forcing can be

  3. State-dependent blocker interactions with the CFTR chloride channel: implications for gating the pore.

    PubMed

    Linsdell, Paul

    2014-12-01

    Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is subject to voltage-dependent open-channel block by a diverse range of cytoplasmic anions. However, in most cases the ability of these blocking substances to influence the pore opening and closing process has not been reported. In the present work, patch clamp recording was used to investigate the state-dependent block of CFTR by cytoplasmic Pt(NO2)4(2-) ions. Two major effects of Pt(NO2)4(2-) were identified. First, this anion caused fast, voltage-dependent block of open channels, leading to an apparent decrease in single-channel current amplitude. Secondly, Pt(NO2)4(2-) also decreased channel open probability due to an increase in interburst closed times. Interestingly, mutations in the pore that weakened (K95Q) or strengthened (I344K, V345K) interactions with Pt(NO2)4(2-) altered blocker effects both on Cl(-) permeation and on channel gating, suggesting that both these effects are a consequence of Pt(NO2)4(2-) interaction with a single site within the pore. Experiments at reduced extracellular Cl(-) concentration hinted that Pt(NO2)4(2-) may have a third effect, possibly increasing channel activity by interfering with channel closure. These results suggest that Pt(NO2)4(2-) can enter from the cytoplasm into the pore inner vestibule of both open and closed CFTR channels, and that Pt(NO2)4(2-) bound in the inner vestibule blocks Cl(-) permeation as well as interfering with channel opening and, perhaps, channel closure. Implications for the location of the channel gate in the pore, and the operation of this gate, are discussed.

  4. Mitochondrial support of persistent presynaptic vesicle mobilization with age-dependent synaptic growth after LTP

    PubMed Central

    Smith, Heather L; Bourne, Jennifer N; Cao, Guan; Chirillo, Michael A; Ostroff, Linnaea E; Watson, Deborah J; Harris, Kristen M

    2016-01-01

    Mitochondria support synaptic transmission through production of ATP, sequestration of calcium, synthesis of glutamate, and other vital functions. Surprisingly, less than 50% of hippocampal CA1 presynaptic boutons contain mitochondria, raising the question of whether synapses without mitochondria can sustain changes in efficacy. To address this question, we analyzed synapses from postnatal day 15 (P15) and adult rat hippocampus that had undergone theta-burst stimulation to produce long-term potentiation (TBS-LTP) and compared them to control or no stimulation. At 30 and 120 min after TBS-LTP, vesicles were decreased only in presynaptic boutons that contained mitochondria at P15, and vesicle decrement was greatest in adult boutons containing mitochondria. Presynaptic mitochondrial cristae were widened, suggesting a sustained energy demand. Thus, mitochondrial proximity reflected enhanced vesicle mobilization well after potentiation reached asymptote, in parallel with the apparently silent addition of new dendritic spines at P15 or the silent enlargement of synapses in adults. DOI: http://dx.doi.org/10.7554/eLife.15275.001 PMID:27991850

  5. Slit2 as a β-catenin/Ctnnb1-dependent retrograde signal for presynaptic differentiation

    PubMed Central

    Wu, Haitao; Barik, Arnab; Lu, Yisheng; Shen, Chengyong; Bowman, Andrew; Li, Lei; Sathyamurthy, Anupama; Lin, Thiri W; Xiong, Wen-Cheng; Mei, Lin

    2015-01-01

    Neuromuscular junction formation requires proper interaction between motoneurons and muscle cells. β-Catenin (Ctnnb1) in muscle is critical for motoneuron differentiation; however, little is known about the relevant retrograde signal. In this paper, we dissected which functions of muscle Ctnnb1 are critical by an in vivo transgenic approach. We show that Ctnnb1 mutant without the transactivation domain was unable to rescue presynaptic deficits of Ctnnb1 mutation, indicating the involvement of transcription regulation. On the other hand, the cell-adhesion function of Ctnnb1 is dispensable. We screened for proteins that may serve as a Ctnnb1-directed retrograde factor and identified Slit2. Transgenic expression of Slit2 specifically in the muscle was able to diminish presynaptic deficits by Ctnnb1 mutation in mice. Slit2 immobilized on beads was able to induce synaptophysin puncta in axons of spinal cord explants. Together, these observations suggest that Slit2 serves as a factor utilized by muscle Ctnnb1 to direct presynaptic differentiation. DOI: http://dx.doi.org/10.7554/eLife.07266.001 PMID:26159615

  6. Slit2 as a β-catenin/Ctnnb1-dependent retrograde signal for presynaptic differentiation.

    PubMed

    Wu, Haitao; Barik, Arnab; Lu, Yisheng; Shen, Chengyong; Bowman, Andrew; Li, Lei; Sathyamurthy, Anupama; Lin, Thiri W; Xiong, Wen-Cheng; Mei, Lin

    2015-07-10

    Neuromuscular junction formation requires proper interaction between motoneurons and muscle cells. β-Catenin (Ctnnb1) in muscle is critical for motoneuron differentiation; however, little is known about the relevant retrograde signal. In this paper, we dissected which functions of muscle Ctnnb1 are critical by an in vivo transgenic approach. We show that Ctnnb1 mutant without the transactivation domain was unable to rescue presynaptic deficits of Ctnnb1 mutation, indicating the involvement of transcription regulation. On the other hand, the cell-adhesion function of Ctnnb1 is dispensable. We screened for proteins that may serve as a Ctnnb1-directed retrograde factor and identified Slit2. Transgenic expression of Slit2 specifically in the muscle was able to diminish presynaptic deficits by Ctnnb1 mutation in mice. Slit2 immobilized on beads was able to induce synaptophysin puncta in axons of spinal cord explants. Together, these observations suggest that Slit2 serves as a factor utilized by muscle Ctnnb1 to direct presynaptic differentiation.

  7. Asymmetry of glia near central synapses favors presynaptically directed glutamate escape.

    PubMed Central

    Lehre, Knut Petter; Rusakov, Dmitri A

    2002-01-01

    Recent findings demonstrate that synaptically released excitatory neurotransmitter glutamate activates receptors outside the immediate synaptic cleft and that the extent of such extrasynaptic actions is regulated by the high affinity glutamate uptake. The bulk of glutamate transporter systems are evenly distributed in the synaptic neuropil, and it is generally assumed that glutamate escaping the cleft affects pre- and postsynaptic receptors to a similar degree. To test whether this is indeed the case, we use quantitative electron microscopy and establish the stochastic pattern of glial occurrence in the three-dimensional (3D) vicinity of two common types of excitatory central synapses, stratum radiatum synapses in hippocampus and parallel fiber synapses in cerebellum. We find that the occurrence of glia postsynaptically is strikingly higher (3-4-fold) than presynaptically, in both types of synapses. To address the functional consequences of this asymmetry, we simulate diffusion and transport of synaptically released glutamate in these two brain areas using a detailed 3D compartmental model of the extracellular space with glutamate transporters arranged unevenly, in accordance with the obtained experimental data. The results predict that glutamate escaping the synaptic cleft is 2-4 times more likely to activate presynaptic compared to postsynaptic receptors. Simulations also show that postsynaptic neuronal transporters (EAAT4 type) at dendritic spines of cerebellar Purkinje cells exaggerate this asymmetry further. Our data suggest that the perisynaptic environment of these common central synapses favors fast presynaptic feedback in the information flow while preserving the specificity of the postsynaptic input. PMID:12080105

  8. Dopamine synapse is a neuroligin-2-mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures.

    PubMed

    Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

    2016-04-12

    Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets.

  9. Mechanical tension contributes to clustering of neurotransmitter vesicles at presynaptic terminals

    PubMed Central

    Siechen, Scott; Yang, Shengyuan; Chiba, Akira; Saif, Taher

    2009-01-01

    Memory and learning in animals are mediated by neurotransmitters that are released from vesicles clustered at the synapse. As a synapse is used more frequently, its neurotransmission efficiency increases, partly because of increased vesicle clustering in the presynaptic neuron. Vesicle clustering has been believed to result primarily from biochemical signaling processes that require the connectivity of the presynaptic terminal with the cell body, the central nervous system, and the postsynaptic cell. Our in vivo experiments on the embryonic Drosophila nervous system show that vesicle clustering at the neuromuscular presynaptic terminal depends on mechanical tension within the axons. Vesicle clustering vanishes upon severing the axon from the cell body, but is restored when mechanical tension is applied to the severed end of the axon. Clustering increases when intact axons are stretched mechanically by pulling the postsynaptic muscle. Using micro mechanical force sensors, we find that embryonic axons that have formed neuromuscular junctions maintain a rest tension of ≈1 nanonewton. If the rest tension is perturbed mechanically, axons restore the rest tension either by relaxing or by contracting over a period of ≈15 min. Our results suggest that neuromuscular synapses employ mechanical tension as a signal to modulate vesicle accumulation and synaptic plasticity. PMID:19620718

  10. Presynaptic actions of 4-aminopyridine and gamma-aminobutyric acid on rat sympathetic ganglia in vitro.

    PubMed

    Galvan, M; Grafe, P; ten Bruggencate, G

    1980-11-01

    Responses to bath-applications of 4-aminopyridine(4-AP) and gamma-aminobutyric acid (GABA) were recorded intracellularly from neurones in the rat isolated superior cervical ganglion. 4-aminopyridine (0.1-1.0 mmol/l) usually induced spontaneous action potentials and excitatory postsynaptic potentials (EPSPs), which were blocked by hexamethonium. Membrane potential was unchanged; spike duration was slightly increased. Vagus nerve B- and C-fibre potentials were prolonged. In 4-AP solution (0.2-0.3 mmol/l), GABA (0.1 mmol/l), 3-aminopropanesulphonic acid or muscimol evoked "bursts" of spikes and EPSPs in addition to a neuronal depolarization. These "bursts", which were not elicited by glycine, glutamate, taurine or (+/-)-baclofen, were completely antagonised by hexamethonium, tetrodotoxin or bicuculline methochloride. It is concluded that: (a) 4-AP has a potent presynaptic action on sympathetic ganglia; (b) presynaptic actions of GABA can be recorded postsynaptically in the presence of 4-AP; and (c) the presynaptic GABA-receptors revealed in this condition are similar to those on the postsynaptic membrane.

  11. Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses

    PubMed Central

    Aoto, Jason; Földy, Csaba; Ilcus, Silviana Maria Ciurea; Tabuchi, Katsuhiko; Südhof, Thomas C.

    2015-01-01

    α- and β-neurexins are presynaptic cell-adhesion molecules whose general importance for synaptic transmission is well documented. The specific functions of neurexins, however, remain largely unknown because no conditional neurexin knockouts are available, and because targeting all α- and β-neurexins produced by a particular gene is challenging. Using newly-generated constitutive and conditional knockout mice that target all neurexin-3α and -3β isoforms, we here show that neurexin-3 is differentially required for distinct synaptic functions in different brain regions. Specifically, we find that in cultured neurons and acute slices of the hippocampus, presynaptic neurexin-3 mediates trans-synaptic regulation of postsynaptic AMPA-receptors via its extracellular sequences. In cultured neurons and acute slices of the olfactory bulb, however, presynaptic neurexin-3 is selectively required for GABA release by a mechanism involving its intracellular sequences. Thus, our data demonstrate that neurexin-3 performs distinct essential pre- or postsynaptic functions in different brain regions by distinct mechanisms. PMID:26030848

  12. A conotoxin from Conus textile with unusual posttranslational modifications reduces presynaptic Ca2+ influx

    PubMed Central

    Rigby, Alan C.; Lucas-Meunier, Estelle; Kalume, Dário E.; Czerwiec, Eva; Hambe, Björn; Dahlqvist, Ingrid; Fossier, Philippe; Baux, Gérard; Roepstorff, Peter; Baleja, James D.; Furie, Barbara C.; Furie, Bruce; Stenflo, Johan

    1999-01-01

    Cone snails are gastropod mollusks of the genus Conus that live in tropical marine habitats. They are predators that paralyze their prey by injection of venom containing a plethora of small, conformationally constrained peptides (conotoxins). We report the identification, characterization, and structure of a γ-carboxyglutamic acid-containing peptide, conotoxin ɛ-TxIX, isolated from the venom of the molluscivorous cone snail, Conus textile. The disulfide bonding pattern of the four cysteine residues, an unparalleled degree of posttranslational processing including bromination, hydroxylation, and glycosylation define a family of conotoxins that may target presynaptic Ca2+ channels or act on G protein-coupled presynaptic receptors via another mechanism. This conotoxin selectively reduces neurotransmitter release at an Aplysia cholinergic synapse by reducing the presynaptic influx of Ca2+ in a slow and reversible fashion. The three-dimensional structure, determined by two-dimensional 1H NMR spectroscopy, identifies an electronegative patch created by the side chains of two γ-carboxyglutamic acid residues that extend outward from a cavernous cleft. The glycosylated threonine and hydroxylated proline enclose a localized hydrophobic region centered on the brominated tryptophan residue within the constrained intercysteine region. PMID:10318957

  13. Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization.

    PubMed

    Vivekananda, Umesh; Novak, Pavel; Bello, Oscar D; Korchev, Yuri E; Krishnakumar, Shyam S; Volynski, Kirill E; Kullmann, Dimitri M

    2017-02-28

    Although action potentials propagate along axons in an all-or-none manner, subthreshold membrane potential fluctuations at the soma affect neurotransmitter release from synaptic boutons. An important mechanism underlying analog-digital modulation is depolarization-mediated inactivation of presynaptic Kv1-family potassium channels, leading to action potential broadening and increased calcium influx. Previous studies have relied heavily on recordings from blebs formed after axon transection, which may exaggerate the passive propagation of somatic depolarization. We recorded instead from small boutons supplied by intact axons identified with scanning ion conductance microscopy in primary hippocampal cultures and asked how distinct potassium channels interact in determining the basal spike width and its modulation by subthreshold somatic depolarization. Pharmacological or genetic deletion of Kv1.1 broadened presynaptic spikes without preventing further prolongation by brief depolarizing somatic prepulses. A heterozygous mouse model of episodic ataxia type 1 harboring a dominant Kv1.1 mutation had a similar broadening effect on basal spike shape as deletion of Kv1.1; however, spike modulation by somatic prepulses was abolished. These results argue that the Kv1.1 subunit is not necessary for subthreshold modulation of spike width. However, a disease-associated mutant subunit prevents the interplay of analog and digital transmission, possibly by disrupting the normal stoichiometry of presynaptic potassium channels.

  14. Membrane lipids tune synaptic transmission by direct modulation of presynaptic potassium channels.

    PubMed

    Carta, Mario; Lanore, Frederic; Rebola, Nelson; Szabo, Zsolt; Da Silva, Silvia Viana; Lourenço, Joana; Verraes, Agathe; Nadler, André; Schultz, Carsten; Blanchet, Christophe; Mulle, Christophe

    2014-02-19

    Voltage-gated potassium (Kv) channels are involved in action potential (AP) repolarization in excitable cells. Exogenous application of membrane-derived lipids, such as arachidonic acid (AA), regulates the gating of Kv channels. Whether membrane-derived lipids released under physiological conditions have an impact on neuronal coding through this mechanism is unknown. We show that AA released in an activity-dependent manner from postsynaptic hippocampal CA3 pyramidal cells acts as retrograde messenger, inducing a robust facilitation of mossy fiber (Mf) synaptic transmission over several minutes. AA acts by broadening presynaptic APs through the direct modulation of Kv channels. This form of short-term plasticity can be triggered when postsynaptic cell fires with physiologically relevant patterns and sets the threshold for the induction of the presynaptic form of long-term potentiation (LTP) at hippocampal Mf synapses. Hence, direct modulation of presynaptic Kv channels by activity-dependent release of lipids serves as a physiological mechanism for tuning synaptic transmission.

  15. Activity-dependent upregulation of presynaptic kainate receptors at immature CA3-CA1 synapses.

    PubMed

    Clarke, Vernon R J; Molchanova, Svetlana M; Hirvonen, Teemu; Taira, Tomi; Lauri, Sari E

    2014-12-10

    Presynaptic kainate-type glutamate receptors (KARs) regulate glutamate release probability and short-term plasticity in various areas of the brain. Here we show that long-term depression (LTD) in the area CA1 of neonatal rodent hippocampus is associated with an upregulation of tonic inhibitory KAR activity, which contributes to synaptic depression and causes a pronounced increase in short-term facilitation of transmission. This increased KAR function was mediated by high-affinity receptors and required activation of NMDA receptors, nitric oxide (NO) synthetase, and postsynaptic calcium signaling. In contrast, KAR activity was irreversibly downregulated in response to induction of long-term potentiation in a manner that depended on activation of the TrkB-receptor of BDNF. Both tonic KAR activity and its plasticity were restricted to early stages of synapse development and were lost in parallel with maturation of the network due to ongoing BDNF-TrkB signaling. These data show that presynaptic KARs are targets for activity-dependent modulation via diffusible messengers NO and BDNF, which enhance and depress tonic KAR activity at immature synapses, respectively. The plasticity of presynaptic KARs in the developing network allows nascent synapses to shape their response to incoming activity. In particular, upregulation of KAR function after LTD allows the synapse to preferentially pass high-frequency afferent activity. This can provide a potential rescue from synapse elimination by uncorrelated activity and also increase the computational dynamics of the developing CA3-CA1 circuitry.

  16. ATP hydrolysis Promotes Duplex DNA Release by the RecA Presynaptic Complex.

    PubMed

    Lee, Ja Yil; Qi, Zhi; Greene, Eric C

    2016-10-14

    Homologous recombination is an important DNA repair pathway that plays key roles in maintaining genome stability. Escherichia coli RecA is an ATP-dependent DNA-binding protein that catalyzes the DNA strand exchange reactions in homologous recombination. RecA assembles into long helical filaments on single-stranded DNA, and these presynaptic complexes are responsible for locating and pairing with a homologous duplex DNA. Recent single molecule studies have provided new insights into RecA behavior, but the potential influence of ATP in the reactions remains poorly understood. Here we examine how ATP influences the ability of the RecA presynaptic complex to interact with homologous dsDNA. We demonstrate that over short time regimes, RecA presynaptic complexes sample heterologous dsDNA similarly in the presence of either ATP or ATPγS, suggesting that initial interactions do not depend on ATP hydrolysis. In addition, RecA stabilizes pairing intermediates in three-base steps, and stepping energetics is seemingly unaltered in the presence of ATP. However, the overall dissociation rate of these paired intermediates with ATP is ∼4-fold higher than with ATPγS. These experiments suggest that ATP plays an unanticipated role in promoting the turnover of captured duplex DNA intermediates as RecA attempts to align homologous sequences during the early stages of recombination.

  17. Altered neurotransmitter release, vesicle recycling and presynaptic structure in the pilocarpine model of temporal lobe epilepsy

    PubMed Central

    Upreti, Chirag; Otero, Rafael; Partida, Carlos; Skinner, Frank; Thakker, Ravi; Pacheco, Luis F.; Zhou, Zhen-yu; Maglakelidze, Giorgi; Velíšková, Jana; Velíšek, Libor; Romanovicz, Dwight; Jones, Theresa; Stanton, Patric K.

    2012-01-01

    In searching for persistent seizure-induced alterations in brain function that might be causally related to epilepsy, presynaptic transmitter release has relatively been neglected. To measure directly the long-term effects of pilocarpine-induced status epilepticus on vesicular release and recycling in hippocampal mossy fibre presynaptic boutons, we used (i) two-photon imaging of FM1-43 vesicular release in rat hippocampal slices; and (ii) transgenic mice expressing the genetically encoded pH-sensitive fluorescent reporter synaptopHluorin preferentially at glutamatergic synapses. In this study we found that, 1–2 months after pilocarpine-induced status epilepticus, there were significant increases in mossy fibre bouton size, faster rates of action potential-driven vesicular release and endocytosis. We also analysed the ultrastructure of rat mossy fibre boutons using transmission electron microscopy. Pilocarpine-induced status epilepticus led to a significant increase in the number of release sites, active zone length, postsynaptic density area and number of vesicles in the readily releasable and recycling pools, all correlated with increased release probability. Our data show that presynaptic release machinery is persistently altered in structure and function by status epilepticus, which could contribute to the development of the chronic epileptic state and may represent a potential new target for antiepileptic therapies. PMID:22344585

  18. Somatic membrane potential and Kv1 channels control spike repolarization in cortical axon collaterals and presynaptic boutons.

    PubMed

    Foust, Amanda J; Yu, Yuguo; Popovic, Marko; Zecevic, Dejan; McCormick, David A

    2011-10-26

    The shape of action potentials invading presynaptic terminals, which can vary significantly from spike waveforms recorded at the soma, may critically influence the probability of synaptic neurotransmitter release. Revealing the conductances that determine spike shape in presynaptic boutons is important for understanding how changes in the electrochemical context in which a spike is generated, such as subthreshold depolarization spreading from the soma, can modulate synaptic strength. Utilizing recent improvements in the signal-to-noise ratio of voltage-sensitive dye imaging in mouse brain slices, we demonstrate that intracortical axon collaterals and en passant presynaptic terminals of layer 5 pyramidal cells exhibit a high density of Kv1 subunit-containing ion channels, which generate a slowly inactivating K(+) current critically important for spike repolarization in these compartments. Blockade of the current by low doses of 4-aminopyridine or α-dendrotoxin dramatically slows the falling phase of action potentials in axon collaterals and presynaptic boutons. Furthermore, subthreshold depolarization of the soma broadened action potentials in collaterals bearing presynaptic boutons, an effect abolished by blocking Kv1 channels with α-dendrotoxin. These results indicate that action potential-induced synaptic transmission may operate through a mix of analog-digital transmission owing to the properties of Kv1 channels in axon collaterals and presynaptic boutons.

  19. Identification of common interneurons mediating pre- and postsynaptic inhibition in the cat spinal cord.

    PubMed

    Solodkin, M; Jiménez, I; Rudomin, P

    1984-06-29

    The spike-triggered averaging of dorsal and ventral root potentials permits the identification of two populations of interneurons in the intermediate nucleus of the cat spinal cord. One produced negative dorsal root potentials and inhibitory ventral root potentials, in some cases with monosynaptic latencies, suggesting that they mediate presynaptic inhibition of group I afferent fibers from muscles and postsynaptic inhibition of motoneurons. The other population mediated only nonreciprocal postsynaptic inhibition of motoneurons.

  20. Prolonged nicotine exposure down-regulates presynaptic NMDA receptors in dopaminergic terminals of the rat nucleus accumbens.

    PubMed

    Salamone, Alessia; Zappettini, Stefania; Grilli, Massimo; Olivero, Guendalina; Agostinho, Paula; Tomé, Angelo R; Chen, Jiayang; Pittaluga, Anna; Cunha, Rodrigo A; Marchi, Mario

    2014-04-01

    The presynaptic control of dopamine release in the nucleus accumbens (NAc) by glutamate and acetylcholine has a profound impact on reward signaling. Here we provide immunocytochemical and neurochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartic acid (NMDA) receptors in dopaminergic terminals of the NAc. Most NAc dopaminergic terminals possessed the nAChR α4 subunit and the pre-exposure of synaptosomes to nicotine (30 μM) or to the α4β2-containing nAChR agonist 5IA85380 (10 nM) selectively inhibited the NMDA (100 μM)-evoked, but not the 4-aminopyridine (10 μM)-evoked, [(3)H] dopamine outflow; this inhibition was blunted by mecamylamine (10 μM). Nicotine and 5IA85380 pretreatment also inhibited the NMDA (100 μM)-evoked increase of calcium levels in single nerve terminals, an effect prevented by dihydro-β-erythroidine (1 μM). This supports a functional interaction between α4β2-containing nAChR and NMDA receptors within the same terminal, as supported by the immunocytochemical co-localization of α4 and GluN1 subunits in individual NAc dopaminergic terminals. The NMDA-evoked [(3)H]dopamine outflow was blocked by MK801 (1 μM) and inhibited by the selective GluN2B-selective antagonists ifenprodil (1 μM) and RO 25-6981 (1 μM), but not by the GluN2A-preferring antagonists CPP-19755 (1 μM) and ZnCl2 (1 nM). Notably, nicotine pretreatment significantly decreased the density of biotin-tagged GluN2B proteins in NAc synaptosomes. These results show that nAChRs dynamically and negatively regulate NMDA receptors in NAc dopaminergic terminals through the internalization of GluN2B receptors.

  1. Mood State-Dependent Retention Using Identical or Non-Identical Mood Inductions at Learning and Recall.

    ERIC Educational Resources Information Center

    Haaga, David A.

    State-dependent retention (SDR) refers to the tendency to recall something more easily when in the same state as when one first learned it. The most directly relevant evidence in favor of mood SDR has confounded matching of mood at learning and recall with matching of mood induction procedure. A study was conducted to test directly whether the use…

  2. State Dependency of Chemosensory Coding in the Gustatory Thalamus (VPMpc) of Alert Rats

    PubMed Central

    Liu, Haixin

    2015-01-01

    The parvicellular portion of the ventroposteromedial nucleus (VPMpc) is the part of the thalamus that processes gustatory information. Anatomical evidence shows that the VPMpc receives ascending gustatory inputs from the parabrachial nucleus (PbN) in the brainstem and sends projections to the gustatory cortex (GC). Although taste processing in PbN and GC has been the subject of intense investigation in behaving rodents, much less is known on how VPMpc neurons encode gustatory information. Here we present results from single-unit recordings in the VPMpc of alert rats receiving multiple tastants. Thalamic neurons respond to taste with time-varying modulations of firing rates, consistent with those observed in GC and PbN. These responses encode taste quality as well as palatability. Comparing responses to tastants either passively delivered, or self-administered after a cue, unveiled the effects of general expectation on taste processing in VPMpc. General expectation led to an improvement of taste coding by modulating response dynamics, and single neuron ability to encode multiple tastants. Our results demonstrate that the time course of taste coding as well as single neurons' ability to encode for multiple qualities are not fixed but rather can be altered by the state of the animal. Together, the data presented here provide the first description that taste coding in VPMpc is dynamic and state-dependent. SIGNIFICANCE STATEMENT Over the past years, a great deal of attention has been devoted to understanding taste coding in the brainstem and cortex of alert rodents. Thanks to this research, we now know that taste coding is dynamic, distributed, and context-dependent. Alas, virtually nothing is known on how the gustatory thalamus (VPMpc) processes gustatory information in behaving rats. This manuscript investigates taste processing in the VPMpc of behaving rats. Our results show that thalamic neurons encode taste and palatability with time-varying patterns of activity

  3. Oxidation-state dependence of rheology in peralkaline glasses of phonolitic composition

    NASA Astrophysics Data System (ADS)

    Scherrer, M. C.; Hess, K.-U.; Fehr, K. T.; Dingwell, D. B.

    2012-04-01

    The precise description of magmatic melts rheology at the glass transition is crucial in understanding dynamic processes in volcanology. The glass transition has been described to scale with the viscosity of the material according to Maxwell's relaxation theory for viscoelastic liquids (Dingwell and Webb, 1989). The temperature dependence of the viscosity of multi-component systems can adequately be calculated using empirical models such as Hess et al. (1996), Giordano et al. (2008) and Hui and Zhang (2008); yet, within these calculations, the influence of oxidation state has been so far considered minor and was consequently neglected. The rheological behavior of some iron-rich silicate melts has shown noteworthy oxidation state-dependent variations (Cukierman and Uhlmann 1974, Dingwell and Virgo 1987). The focus of our study is to improve the viscosity models by investigating the necessity of an additional redox-parameter. Thirteen re-melted glass samples of natural phonolitic composition (peralkaline lavas with 8.5 wt. % FeOtot) were produced under different oxygen fugacity (fO2) conditions in a CO/CO2 gas-mixing furnace. Their oxidation-state (Fe3+/Fetot) ranges from 0.44 to 0.93 (±0.05). The viscosity above the liquidus was recorded via the concentric cylinder technique at a constant temperature of 1186 ° C. Additionally, viscosities were measured in the interval of 107to 1011Pa swith temperatures up to 900 ° C at ambient pressure via a BAEHR micro-penetration viscometer. Glass transition temperatures (Tg) have been determined with a constant heating/cooling rate of 10K/min on a SETARAM Sensys evo DSC using the peak of the specific heat capacity curve. Under a constant temperature in the super-liquidus state, the viscosity increases strongly with increasing fO2. In the sub-liquidus state, the measured calorimetric Tgis shifted to lower temperatures as the ratio of ferrous/total iron decreases from 638 ° C to 610 ° C. However, there is no equivalent

  4. Pair supersolid with atom-pair hopping on the state-dependent triangular lattice

    NASA Astrophysics Data System (ADS)

    Zhang, Wanzhou; Yin, Ruoxi; Wang, Yancheng

    2013-11-01

    degeneracy of pair solids in classical limits. We describe the experimental realization of pair tunneling on state dependent lattice.

  5. Hippocampal CA1 lacunosum-moleculare interneurons: modulation of monosynaptic GABAergic IPSCs by presynaptic GABAB receptors.

    PubMed

    Khazipov, R; Congar, P; Ben-Ari, Y

    1995-11-01

    1. Whole cell patch-clamp recordings were employed to characterize monosynaptic inhibitory postsynaptic currents (IPSCs) in morphologically and electrophysiologically identified interneurons located in the stratum lacunosum moleculare, or near the border of the stratum radiatum (LM interneurons), in the CA1 region of hippocampal slices taken from 3- to 4-wk-old rats. Monosynaptic IPSCs, evoked in the presence of glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20 microM) and D-2-amino-5-phosphopentanoate (APV; 50 microM) were biphasic. The gamma-aminobutyric acid-A (GABAA) receptor antagonist, bicuculline (20 microM), blocked the fast IPSC, and the slow IPSC was blocked by the GABAB receptor antagonist CGP35348 (500 microM). 2. Monosynaptic IPSCs were evoked by electrical stimulation in several distant regions including the stratum radiatum, the stratum oriens, the stratum lacunosum-moleculare, and the molecular layer of dentate gyrus, suggesting an extensive network of inhibitory interneurons in the hippocampus. In paired recordings of CA1 interneurons and pyramidal cells, IPSCs were evoked by electrical stimulation of most of these distal regions with the exception of the molecular layer of dentate gyrus, which evoked an IPSC only in LM interneurons. 3. Frequent (> 0.1 Hz) stimulation depressed the evoked IPSCs. With a paired-pulse protocol, the second IPSC was depressed and the maximal depression (40-50%) was observed with an interstimulus interval of 100-200 ms. 4. The GABAB receptor agonist baclofen (1 microM) reduced the amplitude of evoked IPSCs and the paired-pulse depression of the second IPSC. The GABAB receptor antagonist CGP35348 (0.5-1 mM) had no significant effect on the amplitude of isolated IPSCs. However, CGP35348 reduced but did not fully block paired-pulse depression, suggesting that this depression is partly due to the activation of presynaptic GABAB receptors. 5. The paired-pulse depression depended on the level of

  6. 7-(3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy)-2 (1H)-quinolinone (OPC-4392), a presynaptic dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist

    SciTech Connect

    Yasuda, Y.; Kikuchi, T.; Suzuki, S.; Tsutsui, M.; Yamada, K.; Hiyama, T.

    1988-01-01

    The assertion that OPC-4392 acts as an agonist at presynaptic dopamine autoreceptors is supported by the following behavioral and biochemical observations: OPC-4392, 3-PPP and apomorphine inhibited the reserpine-induced increase in DOPA accumulation in the forebrain of mice and in the frontal cortex, limbic forebrain and striatum of rats. In addition, the gamma-butyrolactone (GBL)-induced increase in DOPA accumulation in the mouse forebrain was also inhibited by OPC-4392, 3-PPP and apomorphine. The inhibitory effect of OPC-4392 on GBL-induced DOPA accumulation lasted for at least 8 hours after oral administration to mice, while that of 3-PPP and apomorphine disappeared in 4 hours after subcutaneous injection. OPC-4392 failed to increase spontaneous motor activity in reserpinized mice, enhance spontaneous ipsilateral rotation in rats with unilateral striatal kainic acid (KA) lesions, induce contralateral rotation in rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesions and inhibit /sup 14/C-acetylcholine (Ach) release stimulated by 20 mM KCl in rat striatal slices.

  7. Presynaptic modulation by L-glutamate and GABA of sympathetic co-transmission in rat isolated vas deferens.

    PubMed

    Kwan, Y W; Ngan, M P; Tsang, K Y; Lee, H M; Chu, L A

    1996-06-01

    , whilst kainate (Kain, 1 microM-1 mM) caused an inhibition of the EFS-induced contractions. Effects of Kain could be abolished by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dioxine (CNQX, 10 microM). NMDA, Quis and Kain had no effect on the exogenous ATP- or noradrenaline-induced contractions. 7. It is concluded that the excitatory amino acid L-glutamate modulates the electrically evoked vas deferens contraction through conversion to the inhibitory amino acid GABA by a specific GABA transaminase. The GABA formed may then act on GABAB receptors and cause inhibition of the contraction through a presynaptic mechanism.

  8. Presynaptic localization of GluK5 in rod photoreceptors suggests a novel function of high affinity glutamate receptors in the mammalian retina

    PubMed Central

    Frotscher, Michael

    2017-01-01

    Kainate receptors mediate glutamatergic signaling through both pre- and presynaptic receptors. Here, we studied the expression of the high affinity kainate receptor GluK5 in the mouse retina. Double-immunofluoresence labeling and electron microscopic analysis revealed a presynaptic localization of GluK5 in the outer plexiform layer. Unexpectedly, we found GluK5 almost exclusively localized to the presynaptic ribbon of photoreceptor terminals. Moreover, in GluK5-deficient mutant mice the structural integrity of synaptic ribbons was severely altered pointing to a novel function of GluK5 in organizing synaptic ribbons in the presynaptic terminals of rod photoreceptors. PMID:28235022

  9. A subnanomolar concentration of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) pre-synaptically modulates glutamatergic transmission in the rat hippocampus acting through acetylcholine.

    PubMed

    Pecoraro, Valeria; Sardone, Lara Maria; Chisari, Mariangela; Licata, Flora; Li Volsi, Guido; Perciavalle, Vincenzo; Ciranna, Lucia; Costa, Lara

    2017-01-06

    The neuropeptide PACAP modulates synaptic transmission in the hippocampus exerting multiple effects through different receptor subtypes: the underlying mechanisms have not yet been completely elucidated. The neurotransmitter acetylcholine (ACh) also exerts a well-documented modulation of hippocampal synaptic transmission and plasticity. Since PACAP was shown to stimulate ACh release in the hippocampus, we tested whether PACAP acting through ACh might indirectly modulate glutamate-mediated synaptic transmission at a pre- and/or at a post-synaptic level. Using patch clamp on rat hippocampal slices, we tested PACAP effects on stimulation-evoked AMPA receptor-mediated excitatory post-synaptic currents (EPSCsAMPA) in the CA3-CA1 synapse and on spontaneous miniature EPSCs (mEPSCs) in CA1 pyramidal neurons. A subnanomolar dose of PACAP (0.5nM) decreased EPSCsAMPA amplitude, enhanced EPSC paired-pulse facilitation (PPF) and reduced mEPSC frequency, indicating a pre-synaptic decrease of glutamate release probability: these effects were abolished by simultaneous blockade of muscarinic and nicotinic ACh receptors, indicating the involvement of endogenous ACh. The effect of subnanomolar PACAP was abolished by a PAC1 receptor antagonist but not by a VPAC receptor blocker. At a higher concentration (10nM), PACAP inhibited EPSCsAMPA: this effect persisted in the presence of ACh receptor antagonists and did not involve any change in PPF or in mEPSC frequency, thus was not mediated by ACh and was exerted post- synaptically on CA1 pyramidal neurons. We suggest that a high-affinity PAC1 receptor pre-synaptically modulates hippocampal glutamatergic transmission acting through ACh. Therefore, administration of PACAP at very low doses might be envisaged in cognitive diseases with reduced cholinergic transmission.

  10. Presynaptic CaV2.1 calcium channels carrying familial hemiplegic migraine mutation R192Q allow faster recovery from synaptic depression in mouse calyx of Held

    PubMed Central

    Inchauspe, Carlota González; Urbano, Francisco J.; Di Guilmi, Mariano N.; Ferrari, Michel D.; van den Maagdenberg, Arn M. J. M.; Forsythe, Ian D.

    2012-01-01

    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 α1A 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. PMID:22956801

  11. Presynaptic functional trkB receptors mediate the release of excitatory neurotransmitters from primary afferent terminals in lamina II (substantia gelatinosa) of postnatal rat spinal cord.

    PubMed

    Merighi, Adalberto; Bardoni, Rita; Salio, Chiara; Lossi, Laura; Ferrini, Francesco; Prandini, Massimiliano; Zonta, Micaela; Gustincich, Stefano; Carmignoto, Giorgio

    2008-03-01

    A subset of primary sensory neurons produces BDNF, which is implicated in control of nociceptive neurotransmission. We previously localized full-length trkB receptors on their terminals within lamina II. To functionally study these receptors, we here employed patch-clamp recordings, calcium imaging and immunocytochemistry on slices from 8-12 days post-natal rats. In this preparation, BDNF (100-500 ng/mL) enhances the release of sensory neurotransmitters (glutamate, substance P, CGRP) in lamina II by acting on trkB receptors expressed by primary afferent fibers of the peptidergic nociceptive type (PN-PAFs). Effect was blocked by trk antagonist K252a or anti-trkB antibody clone 47. A pre-synaptic mechanism was demonstrated after (i) patch-clamp recordings where the neurotrophin induced a significant increase in frequency, but not amplitude, of AMPA-mediated mEPSCs, (ii) real time calcium imaging, where sustained application of BDNF evoked an intense response in up to 57% lamina II neurons with a significant frequency rise. Antagonists of ionotropic glutamate receptors and NK(1) receptors completely inhibited the calcium response to BDNF. Reduction of CGRP (a specific marker of PN-PAFs) and substance P content in dorsal horn following BDNF preincubation, and analysis of the calcium response after depletion with capsaicin, confirmed that the neurotrophin presynaptically enhanced neurotransmitter release from PN-PAFs. This is the first demonstration that trkB receptors expressed by PN-PAF terminals in lamina II are functional during postnatal development. Implications of this finding are discussed considering that BDNF can be released by these same terminals and microglia, a fraction of which (as shown here) contains BDNF also in unactivated state.

  12. Interaction between neuronal uptake inhibitors and presynaptic serotonin autoreceptors in rat hypothalamic slices: comparison of K+ and electrical depolarization.

    PubMed

    Passarelli, F; Galzin, A M; Langer, S Z

    1987-09-01

    In rat hypothalamic slices prelabeled with [3H]-5-hydroxytryptamine ([3H]-5-HT), exposure to the 5-HT receptor agonist lysergic acid diethylamide (0.1-1 microM) or 5-methoxytryptamine (0.1-10 microM) decreased in a concentration-dependent manner the release of 3H-transmitter elicited by high K+ or electrical stimulation. Exposure to the 5-HT autoreceptor antagonist methiothepin (0.1-1 microM) increased in a concentration-dependent manner the K+ stimulation-evoked overflow of [3H]-5-HT and a similar increase was observed under conditions of electrical stimulation. In contrast, exposure to the nontricyclic 5-HT uptake inhibitor citalopram (0.1-1 microM) did not modify by itself the electrically evoked overflow of [3H]-5-HT, but increased in a concentration-dependent manner the release of 3H-transmitter elicited by K+ stimulation. This effect of citalopram on transmitter release was potentiated when the endogenous stores of 5-HT were depleted by pretreatment with para-chlorophenylalanine methyl ester (300 mg/kg i.p.). Citalopram was shown previously to antagonize the inhibition by lysergic acid diethylamide of the electrically evoked release of [3H]-5-HT in rat hypothalamic slices. Yet, this inhibitor of neuronal uptake of 5-HT did not antagonize the effects of lysergic acid diethylamide when the release of [3H]-5-HT was evoked by K+ depolarization. Electrical stimulation represents a more physiological experimental model for transmitter release than exposure to high K+, and therefore the interaction between 5-HT uptake blockade and presynaptic inhibitory 5-HT autoreceptors, observed in the hypothalamus with electrical stimulation but not with K+ depolarization, remains of biological relevance.

  13. Acute and sustained effects of methylphenidate on cognition and presynaptic dopamine metabolism: an [18F]FDOPA PET study.

    PubMed

    Schabram, Ina; Henkel, Karsten; Mohammadkhani Shali, Siamak; Dietrich, Claudia; Schmaljohann, Jörn; Winz, Oliver; Prinz, Susanne; Rademacher, Lena; Neumaier, Bernd; Felzen, Marc; Kumakura, Yoshitaka; Cumming, Paul; Mottaghy, Felix M; Gründer, Gerhard; Vernaleken, Ingo

    2014-10-29

    Methylphenidate (MPH) inhibits the reuptake of dopamine and noradrenaline. PET studies with MPH challenge show increased competition at postsynaptic D2/3-receptors, thus indirectly revealing presynaptic dopamine release. We used [(18)F]fluorodopamine ([(18)F]FDOPA)-PET in conjunction with the inlet-outlet model (IOM) of Kumakura et al. (2007) to investigate acute and long-term changes in dopamine synthesis capacity and turnover in nigrostriatal fibers of healthy subjects with MPH challenge. Twenty healthy human females underwent two dynamic [(18)F]FDOPA PET scans (124 min; slow bolus-injection; arterial blood sampling), with one scan in untreated baseline condition and the other after MPH administration (0.5 mg/kg, p.o.), in randomized order. Subjects underwent cognitive testing at each PET session. Time activity curves were obtained for ventral putamen and caudate and were analyzed according to the IOM to obtain the regional net-uptake of [(18)F]FDOPA (K; dopamine synthesis capacity) as well as the [(18)F]fluorodopamine washout rate (kloss, index of dopamine turnover). MPH substantially decreased kloss in putamen (-22%; p = 0.003). In the reversed treatment order group (MPH/no drug), K was increased by 18% at no drug follow-up. The magnitude of K at the no drug baseline correlated with cognitive parameters. Furthermore, individual kloss changes correlated with altered cognitive performance under MPH. [(18)F]FDOPA PET in combination with the IOM detects an MPH-evoked decrease in striatal dopamine turnover, in accordance with the known acute pharmacodynamics of MPH. Furthermore, the scan-ordering effect on K suggested that a single MPH challenge persistently increased striatal dopamine synthesis capacity. Attenuation of dopamine turnover by MPH is linked to enhanced cognitive performance in healthy females.

  14. Selective presynaptic insectotoxin (alpha-latroinsectotoxin) isolated from black widow spider venom.

    PubMed

    Magazanik, L G; Fedorova, I M; Kovalevskaya, G I; Pashkov, V N; Bulgakov, O V; Grishin, E V

    1992-01-01

    A homogenous protein of 120,000 mol. wt isolated from black widow spider (Lactrodectus mactans tredecimguttatus) venom and referred to as alpha-latroinsectotoxin was highly potent (4 nM) in the induction of an increase of the frequency of miniature excitatory postsynaptic potentials in blowfly (Calliphora vicina) larvae neuromuscular preparations. In the frog nerve ending, however, even 50 nM alpha-latroinsectotoxin failed to affect transmitter release. Pretreatment of insect preparations with alpha-latrotoxin or frog preparations with alpha-latroinsectotoxin did not prevent the specific effect of consequent applications of alpha-latroinsectotoxin (insect) and alpha-latrotoxin (frog), respectively. The binding of labelled [125I]alpha-latroinsectotoxin to insect and [125I]alpha-latrotoxin to bovine membrane preparations was saturable and highly specific. The presynaptic effect, but not the binding of alpha-latroinsectotoxin, was dependent on the presence of divalent cations in the external medium. Mg2+ could readily substitute for Ca2+ and increase of transmitter release induced by alpha-latroinsectotoxin also occurred in Ca(2+)-free solutions. Pretreatment of preparations with 300 micrograms/ml concanavalin A completely abolished both the presynaptic effect of alpha-latroinsectotoxin and its binding to insect membrane preparations. Thus, the phenomenology of alpha-latroinsectotoxin action on insects resembles in general that described for the action of alpha-latrotoxin on vertebrates. The selectivity of alpha-latrotoxin and alpha-latroinsectotoxin seems to be due to differences in the structure of neurotoxin receptors in nerve endings of vertebrates and insects, although the mode of presynaptic action has a great deal in common.

  15. A Kinetic Model Unifying Presynaptic Short-Term Facilitation and Depression

    PubMed Central

    Lee, Chuang-Chung J.; Anton, Mihai; Poon, Chi-Sang; McRae, Gregory J.

    2009-01-01

    Short-term facilitation and depression refer to the increase and decrease of synaptic strength under repetitive stimuli within a timescale of milliseconds to seconds. This phenomenon has been attributed to primarily presynaptic mechanisms such as calcium-dependent transmitter release and presynaptic vesicle depletion. Previous modeling studies that aimed to integrate the complex short-term facilitation and short-term depression data derived from varying synapses have relied on computer simulation or abstract mathematical approaches. Here, we propose a unified theory of synaptic short-term plasticity based on realistic yet tractable and testable model descriptions of the underlying intracellular biochemical processes. Analysis of the model equations leads to a closed-form solution of the resonance frequency, a function of several critical biophysical parameters, as the single key indicator of the propensity for synaptic facilitation or depression under repetitive stimuli. This integrative model is supported by a broad range of transient and frequency response experimental data including those from facilitating, depressing or mixed-mode synapses. Specifically, the theory predicts that high calcium initial concentration and large gain of calcium action result in low resonance frequency and hence depressing behavior. In contrast, for synapses that are less sensitive to calcium or have higher recovery rate, resonance frequency becomes higher and thus facilitation prevails. The notion of resonance frequency therefore allows valuable quantitative parametric assessment of the contributions of various presynaptic mechanisms to the directionality of synaptic short-term plasticity. Thus, the model provides the reasons behind the switching behavior between facilitation and depression observed in experiments. New experiments are also suggested to control the short-term synaptic signal processing through adjusting the resonance frequency and bandwidth. PMID:19093195

  16. Interactions between Aβ oligomers and presynaptic cholinergic signaling: age-dependent effects on attentional capacities

    PubMed Central

    Parikh, Vinay; Bernard, Carcha S.; Naughton, Sean X.; Yegla, Brittney

    2014-01-01

    Substantial evidence suggests that cerebral deposition of the neurotoxic fibrillar form of amyloid precursor protein, β-amyloid (Aβ), plays a critical role in the pathogenesis of Alzheimer's disease (AD). Yet, many aspects of AD pathology including the cognitive symptoms and selective vulnerability of cortically-projecting basal forebrain (BF) cholinergic neurons are not well explained by this hypothesis. Specifically, it is not clear why cognitive decline appears early when the loss of BF cholinergic neurons and plaque deposition are manifested late in AD. Soluble oligomeric forms of Aβ are proposed to appear early in the pathology and to be better predictors of synaptic loss and cognitive deficits. The present study was designed to examine the impact of Aβ oligomers on attentional functions and presynaptic cholinergic transmission in young and aged rats. Chronic intracranial infusions of Aβ oligomers produced subtle decrements in the ability of rats to sustain attentional performance with time on task, irrespective of the age of the animals. However, Aβ oligomers produced robust detrimental effects on performance under conditions of enhanced attentional load in aged animals. In vivo electrochemical recordings show reduced depolarization-evoked cholinergic signals in Aβ-infused aged rats. Moreover, soluble Aβ disrupted the capacity of cholinergic synapses to clear exogenous choline from the extracellular space in both young and aged rats, reflecting impairments in the choline transport process that is critical for acetylcholine (ACh) synthesis and release. Although aging per se reduced the cross-sectional area of BF cholinergic neurons and presynaptic cholinergic proteins in the cortex, attentional performance and ACh release remained unaffected in aged rats infused with the control peptide. Taken together, these data suggest that soluble Aβ may marginally influence attentional functions at young ages primarily by interfering with the choline uptake

  17. Cortical Synaptic Transmission and Plasticity in Acute Liver Failure Are Decreased by Presynaptic Events.

    PubMed

    Popek, Mariusz; Bobula, Bartosz; Sowa, Joanna; Hess, Grzegorz; Polowy, Rafał; Filipkowski, Robert Kuba; Frontczak-Baniewicz, Małgorzata; Zabłocka, Barbara; Albrecht, Jan; Zielińska, Magdalena

    2017-01-23

    Neurological symptoms of acute liver failure (ALF) reflect decreased excitatory transmission, but the status of ALF-affected excitatory synapse has not been characterized in detail. We studied the effects of ALF in mouse on synaptic transmission and plasticity ex vivo and its relation to distribution of (i) synaptic vesicles (sv) and (ii) functional synaptic proteins within the synapse. ALF-competent neurological and biochemical changes were induced in mice with azoxymethane (AOM). Electrophysiological characteristics (long-term potentiation, whole-cell recording) as well as synapse ultrastructure were evaluated in the cerebral cortex. Also, sv were quantified in the presynaptic zone by electron microscopy. Finally, presynaptic proteins in the membrane-enriched (P2) and cytosolic (S2) fractions of cortical homogenates were quantitated by Western blot. Slices derived from symptomatic AOM mice presented a set of electrophysiological correlates of impaired transmitter release including decreased field potentials (FPs), increased paired-pulse facilitation (PPF), and decreased frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs/mEPSCs) accompanied by reduction of the spontaneous transmitter release-driving protein, vti1A. Additionally, an increased number of sv per synapse and a decrease of P2 content and/or P2/S2 ratio for sv-associated proteins, i.e. synaptophysin, synaptotagmin, and Munc18-1, were found, in spite of decreased content of the sv-docking protein, syntaxin-1. Slices from AOM-treated asymptomatic mice showed impaired long-term potentiation (LTP) and increased PPF but no changes in transmitter release or presynaptic protein composition. Our findings demonstrate that a decrease of synaptic transmission in symptomatic ALF is associated with inefficient recruitment of sv proteins and/or impaired sv trafficking to transmitter release sites.

  18. Distribution of muscarinic acetylcholine receptors and presynaptic nerve terminals in amphibian heart

    PubMed Central

    1980-01-01

    At many synapses, neurotransmitter receptor molecules in the postsynaptic membrane are selectively concentrated at a site directly opposite the presynaptic nerve terminal. In this paper, I examine acetylcholine (ACh) receptor distribution in cardiac muscle in relatin to the distribution of presynaptic axonal varicosities. The density of varicosities, stained with zinc iodide and osmium, ranges from 0.7/100 micrometer 2 in ventricle to 1.9/100 micrometer 2 in sinus venosus. It is estimated that < 3% of the muscle surface is apposed to presynaptic varicosities. ACh receptors, however, are randomly distributed on the muscle surface and not concentrated in patche. ACh receptor distribution was determined by iontophoretic application of ACh and mapping of ACh sensitivity and by [3H]QNB (quinuclidinyl benzilate) binding and autoradiography [3H]QNB binds with > 90% specificity to a single, saturable, high-affinity (Kd = 11.1 pM at 21 degrees C) class of binding sites. QNB binding sites are thought to correspond to ACh receptors, because muscarinic agonists compete for [3H]QNB binding and produce a hyperpolarization in the sinus venosus with the same order of potency. The concentrations of QNB binding sites in the sinus and atria are about twice those found in ventricle. The receptor density corresponds to the density of innervation measured by zinc iodide and osmium staining. Autoradiographic experiments show that [3H]QNB binding sites are distributed randomly over the entire surface of the muscle. This distribution of ACh receptors in cardiac muscle has important implications for the function of the cardiac neuroeffector junction. PMID:6968315

  19. LKB1 Regulates Mitochondria-Dependent Presynaptic Calcium Clearance and Neurotransmitter Release Properties at Excitatory Synapses along Cortical Axons

    PubMed Central

    Kwon, Seok-Kyu; Sando, Richard; Maximov, Anton; Polleux, Franck

    2016-01-01

    Individual synapses vary significantly in their neurotransmitter release properties, which underlie complex information processing in neural circuits. Presynaptic Ca2+ homeostasis plays a critical role in specifying neurotransmitter release properties, but the mechanisms regulating synapse-specific Ca2+ homeostasis in the mammalian brain are still poorly understood. Using electrophysiology and genetically encoded Ca2+ sensors targeted to the mitochondrial matrix or to presynaptic boutons of cortical pyramidal neurons, we demonstrate that the presence or absence of mitochondria at presynaptic boutons dictates neurotransmitter release properties through Mitochondrial Calcium Uniporter (MCU)-dependent Ca2+ clearance. We demonstrate that the serine/threonine kinase LKB1 regulates MCU expression, mitochondria-dependent Ca2+ clearance, and thereby, presynaptic release properties. Re-establishment of MCU-dependent mitochondrial Ca2+ uptake at glutamatergic synapses rescues the altered neurotransmitter release properties characterizing LKB1-null cortical axons. Our results provide novel insights into the cellular and molecular mechanisms whereby mitochondria control neurotransmitter release properties in a bouton-specific way through presynaptic Ca2+ clearance. PMID:27429220

  20. Regulation of N-type voltage-gated calcium channels and presynaptic function by cyclin-dependent kinase 5

    PubMed Central

    Su, Susan C.; Seo, Jinsoo; Pan, Jen Q.; Samuels, Benjamin Adam; Rudenko, Andrii; Ericsson, Maria; Neve, Rachael L.; Yue, David T.; Tsai, Li-Huei

    2012-01-01

    SUMMARY N-type voltage-gated calcium channels (CaV2.2) localize to presynaptic nerve terminals and mediate key events including synaptogenesis and neurotransmission. While several kinases have been implicated in the modulation of calcium channels, their impact on presynaptic functions remains unclear. Here we report that the N-type calcium channel is a substrate for cyclin-dependent kinase 5 (Cdk5). The pore-forming α1 subunit of the N-type calcium channel is phosphorylated in the C-terminal domain, and phosphorylation results in enhanced calcium influx due to increased channel open probability. Phosphorylation of the N-type calcium channel by Cdk5 facilitates neurotransmitter release and alters presynaptic plasticity by increasing the number of docked vesicles at the synaptic cleft. These effects are mediated by an altered interaction between N-type calcium channels and RIM1, which tethers presynaptic calcium channels to the active zone. Collectively, our results highlight a molecular mechanism by which N-type calcium channels are regulated by Cdk5 to affect presynaptic functions. PMID:22920258

  1. Early Exposure to General Anesthesia Disrupts Spatial Organization of Presynaptic Vesicles in Nerve Terminals of the Developing Rat Subiculum.

    PubMed

    Lunardi, N; Oklopcic, A; Prillaman, M; Erisir, A; Jevtovic-Todorovic, V

    2015-10-01

    Exposure to general anesthesia (GA) during critical stages of brain development induces widespread neuronal apoptosis and causes long-lasting behavioral deficits in numerous animal species. Although several studies have focused on the morphological fate of neurons dying acutely by GA-induced developmental neuroapoptosis, the effects of an early exposure to GA on the surviving synapses remain unclear. The aim of this study is to study whether exposure to GA disrupts the fine regulation of the dynamic spatial organization and trafficking of synaptic vesicles in presynaptic terminals. We exposed postnatal day 7 (PND7) rat pups to a clinically relevant anesthetic combination of midazolam, nitrous oxide, and isoflurane and performed a detailed ultrastructural analysis of the synaptic vesicle architecture at presynaptic terminals in the subiculum of rats at PND 12. In addition to a significant decrease in the density of presynaptic vesicles, we observed a reduction of docked vesicles, as well as a reduction of vesicles located within 100 nm from the active zone, in animals 5 days after an initial exposure to GA. We also found that the synaptic vesicles of animals exposed to GA are located more distally with respect to the plasma membrane than those of sham control animals and that the distance between presynaptic vesicles is increased in GA-exposed animals compared to sham controls. We report that exposure of immature rats to GA during critical stages of brain development causes significant disruption of the strategic topography of presynaptic vesicles within the nerve terminals of the subiculum.

  2. Presynaptic Spike Timing-Dependent Long-Term Depression in the Mouse Hippocampus

    PubMed Central

    Andrade-Talavera, Yuniesky; Duque-Feria, Paloma; Paulsen, Ole; Rodríguez-Moreno, Antonio

    2016-01-01

    Spike timing-dependent plasticity (STDP) is a Hebbian learning rule important for synaptic refinement during development and for learning and memory in the adult. Given the importance of the hippocampus in memory, surprisingly little is known about the mechanisms and functions of hippocampal STDP. In the present work, we investigated the requirements for induction of hippocampal spike timing-dependent long-term potentiation (t-LTP) and spike timing-dependent long-term depression (t-LTD) and the mechanisms of these 2 forms of plasticity at CA3-CA1 synapses in young (P12–P18) mouse hippocampus. We found that both t-LTP and t-LTD can be induced at hippocampal CA3-CA1 synapses by pairing presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz). Both t-LTP and t-LTD require NMDA-type glutamate receptors for their induction, but the location and properties of these receptors are different: While t-LTP requires postsynaptic ionotropic NMDA receptor function, t-LTD does not, and whereas t-LTP is blocked by antagonists at GluN2A and GluN2B subunit-containing NMDA receptors, t-LTD is blocked by GluN2C or GluN2D subunit-preferring NMDA receptor antagonists. Both t-LTP and t-LTD require postsynaptic Ca2+ for their induction. Induction of t-LTD also requires metabotropic glutamate receptor activation, phospholipase C activation, postsynaptic IP3 receptor-mediated Ca2+ release from internal stores, postsynaptic endocannabinoid (eCB) synthesis, activation of CB1 receptors and astrocytic signaling, possibly via release of the gliotransmitter d-serine. We furthermore found that presynaptic calcineurin is required for t-LTD induction. t-LTD is expressed presynaptically as indicated by fluctuation analysis, paired-pulse ratio, and rate of use-dependent depression of postsynaptic NMDA receptor currents by MK801. The results show that CA3-CA1 synapses display both NMDA receptor-dependent t-LTP and t-LTD during development and identify a

  3. Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer's disease.

    PubMed Central

    Masliah, E.; Iwai, A.; Mallory, M.; Uéda, K.; Saitoh, T.

    1996-01-01

    We have recently identified, in the brain tissue of patients afflicted with Alzheimer's disease (AD), the non-A beta component of AD amyloid (NAC) as a new constituent of amyloid. NAC is derived from a larger precursor, NACP, a presynaptic protein. To better understand the role of NACP/NAC in the pathogenesis of AD, we used semiquantitative immunoblotting and combined double-immunocytochemistry/laser scanning confocal microscopy to study the concentration and distribution of NACP/NAC in human brain, and compared them to the concentration and distribution of the presynaptic marker synaptophysin and the amyloid marker A beta. The semiquantitative immunoblotting demonstrated that the NACP concentration is slightly increased in the AD frontal cortex without statistical significance, whereas synaptophysin was reduced in its levels in AD. Consequently the proportion of NACP/synaptophysin was more than double in the AD frontal cortex as compared with controls. In the AD neocortex, NACP was colocalized with approximately 80% of the synaptophysin-immunoreactive structures (presumably the presynaptic terminals) and with the dystrophic neuritic component of the plaques. Computer-aided analysis showed that numbers of NACP-immunoreactive structures along synaptophysin-immunoreactive structures were significantly diminished (30 to 40%) in AD. Although the overall numbers of NACP-positive structures were decreased, there was a significant increase in the intensity of NACP-immunoreactivity per structure in AD. This increased intensity of NACP immunoreactivity per structure in AD was not observed with anti-synaptophysin, consistent with immunoblotting-based quantification. Antibodies against NAC immunoreacted with amyloid in 35% of the diffuse plaques and 55% of the mature plaques. Normal aged control brains containing small groups of diffuse plaques were negative with anti-NAC. Double-immunolabeling studies with A beta antibodies showed that NAC immunoreactivity is more abundant

  4. Myasthenia gravis with presynaptic neurophysiological signs: Two case reports and literature review.

    PubMed

    Alboini, Paolo Emilio; Damato, Valentina; Iorio, Raffaele; Luigetti, Marco; Evoli, Amelia

    2015-08-01

    The distinction between myasthenia gravis and Lambert-Eaton myasthenic syndrome is based on clinical, neurophysiological and immunological features. We hereby report two cases with a clinical diagnosis of myasthenia gravis and neurophysiological features consistent with a pre-synaptic neuromuscular transmission defect. Both patients had increased anti-acetylcholine receptor antibody titres and showed a good response to cholinesterase inhibitors, along with a >100% facilitation of the compound muscle action potential on electrophysiological studies. We provide a review of English literature studies on co-existing features of myasthenia gravis and Lambert-Eaton myasthenic syndrome, and discuss diagnostic controversies.

  5. Presynaptic effects of L-DOPA and their possible role in dyskinesia

    PubMed Central

    Mosharov, Eugene V.; Borgkvist, Anders; Sulzer, David

    2014-01-01

    L-DOPA replacement therapy has long provided the most effective treatment for Parkinson’s disease. We review how this dopamine precursor enhances dopaminergic transmission by providing a greater sphere of neurotransmitter influence, due to the confluence of increased quantal size and decreased dopamine reuptake, as well as loading dopamine as a false transmitter into surviving serotonin neuron synaptic vesicles. We further review literature on how presynaptic dysregulation of DA release following L-DOPA might trigger dyskinesias in Parkinson patients. PMID:25450307

  6. The Block of Shaker K+ Channels by κ-Conotoxin Pviia Is State Dependent

    PubMed Central

    Terlau, Heinrich; Boccaccio, Anna; Olivera, Baldomero M.; Conti, Franco

    1999-01-01

    κ-conotoxin PVIIA is the first conotoxin known to interact with voltage-gated potassium channels by inhibiting Shaker-mediated currents. We studied the mechanism of inhibition and concluded that PVIIA blocks the ion pore with a 1:1 stoichiometry and that binding to open or closed channels is very different. Open-channel properties are revealed by relaxations of partial block during step depolarizations, whereas double-pulse protocols characterize the slower reequilibration of closed-channel binding. In 2.5 mM-[K+]o, the IC50 rises from a tonic value of ∼50 to ∼200 nM during openings at 0 mV, and it increases e-fold for about every 40-mV increase in voltage. The change involves mainly the voltage dependence and a 20-fold increase at 0 mV of the rate of PVIIA dissociation, but also a fivefold increase of the association rate. PVIIA binding to Shaker Δ6-46 channels lacking N-type inactivation or to wild phenotypes appears similar, but inactivation partially protects the latter from open-channel unblock. Raising [K+]o to 115 mM has little effect on open-channel binding, but increases almost 10-fold the tonic IC50 of PVIIA due to a decrease by the same factor of the toxin rate of association to closed channels. In analogy with charybdotoxin block, we attribute the acceleration of PVIIA dissociation from open channels to the voltage-dependent occupancy by K+ ions of a site at the outer end of the conducting pore. We also argue that the occupancy of this site by external cations antagonizes on binding to closed channels, whereas the apparent competition disappears in open channels if the competing cation can move along the pore. It is concluded that PVIIA can also be a valuable tool for probing the state of ion permeation inside the pore. PMID:10398696

  7. An M/M/c/K State-Dependent Model for Pedestrian Flow Control and Design of Facilities.

    PubMed

    Rahman, Khalidur; Abdul Ghani, Noraida; Kamil, Anton Abdulbasah; Mustafa, Adli; Chowdhury, Md Ahmed Kabir

    2015-01-01

    Pedestrian overflow causes queuing delay and in turn, is controlled by the capacity of a facility. Flow control or blocking control takes action to avoid queues from building up to extreme values. Thus, in this paper, the problem of pedestrian flow control in open outdoor walking facilities in equilibrium condition is investigated using M/M/c/K queuing models. State dependent service rate based on speed and density relationship is utilized. The effective rate of the Poisson arrival process to the facility is determined so as there is no overflow of pedestrians. In addition, the use of the state dependent queuing models to the design of the facilities and the effect of pedestrian personal capacity on the design and the traffic congestion are discussed. The study does not validate the sustainability of adaptation of Western design codes for the pedestrian facilities in the countries like Bangladesh.

  8. An M/M/c/K State-Dependent Model for Pedestrian Flow Control and Design of Facilities

    PubMed Central

    Rahman, Khalidur; Abdul Ghani, Noraida; Kamil, Anton Abdulbasah; Mustafa, Adli; Chowdhury, Md. Ahmed Kabir

    2015-01-01

    Pedestrian overflow causes queuing delay and in turn, is controlled by the capacity of a facility. Flow control or blocking control takes action to avoid queues from building up to extreme values. Thus, in this paper, the problem of pedestrian flow control in open outdoor walking facilities in equilibrium condition is investigated using M/M/c/K queuing models. State dependent service rate based on speed and density relationship is utilized. The effective rate of the Poisson arrival process to the facility is determined so as there is no overflow of pedestrians. In addition, the use of the state dependent queuing models to the design of the facilities and the effect of pedestrian personal capacity on the design and the traffic congestion are discussed. The study does not validate the sustainability of adaptation of Western design codes for the pedestrian facilities in the countries like Bangladesh. PMID:26196124

  9. H∞ control of a class of 2-D continuous switched delayed systems via state-dependent switching

    NASA Astrophysics Data System (ADS)

    Ghous, Imran; Xiang, Zhengrong

    2016-01-01

    This paper addresses the problem of state feedback H∞ stabilisation of 2-D (two-dimensional) continuous switched state delayed systems represented by the Roesser model using the multiple Lyapunov functional approach. First, an asymptotical stability condition of 2-D continuous switched systems with state-dependent switching is derived. Second, a sufficient condition for H∞ performance of the underlying system is established. Third, a state feedback controller is proposed to ensure that the resulting closed-loop system has a prescribed H∞ performance level under a state-dependent switching signal. All the results are developed in terms of linear matrix inequalities. Finally, three examples are provided to demonstrate the validity and effectiveness of the proposed method.

  10. Novel conditions on exponential stability of a class of delayed neural networks with state-dependent switching.

    PubMed

    Zhang, Guodong; Shen, Yi

    2015-11-01

    This paper is concerned with the global exponential stability on a class of delayed neural networks with state-dependent switching. Under the novel conditions, some sufficient criteria ensuring exponential stability of the proposed system are obtained. In particular, the obtained conditions complement and improve earlier publications on conventional neural networks with continuous or discontinuous right-hand side. Numerical simulations are also presented to illustrate the effectiveness of the obtained results.

  11. Finite-time state-dependent Riccati equation for time-varying nonaffine systems: rigid and flexible joint manipulator control.

    PubMed

    Korayem, M H; Nekoo, S R

    2015-01-01

    This article investigates finite-time optimal and suboptimal controls for time-varying systems with state and control nonlinearities. The state-dependent Riccati equation (SDRE) controller was the main framework. A finite-time constraint imposed on the equation changes it to a differential equation, known as the state-dependent differential Riccati equation (SDDRE) and this equation was applied to the problem reported in this study that provides general formulation and stability analysis. The following four solution methods were developed for solving the SDDRE; backward integration, state transition matrix (STM) and the Lyapunov based method. In the Lyapunov approach, both positive and negative definite solutions to related SDRE were used to provide suboptimal gain for the SDDRE. Finite-time suboptimal control is applied for robotic manipulator, as finite-time constraint strongly decreases state error and operation time. General state-dependent coefficient (SDC) parameterizations for rigid and flexible joint arms (prismatic or revolute joints) are introduced. By including nonlinear control inputs in the formulation, the actuator׳s limits can be inserted directly to the state-space equation of a manipulator. A finite-time SDRE was implemented on a 6R manipulator both in theory and experimentally. And a reduced 3R arm was modeled and tested as a flexible joint robot (FJR). Evaluations of load carrying capacity and operation time were investigated to assess the capability of this approach, both of which showed significant improvement.

  12. Key modulatory role of presynaptic adenosine A2A receptors in cortical neurotransmission to the striatal direct pathway.

    PubMed

    Quiroz, César; Luján, Rafael; Uchigashima, Motokazu; Simoes, Ana Patrícia; Lerner, Talia N; Borycz, Janusz; Kachroo, Anil; Canas, Paula M; Orru, Marco; Schwarzschild, Michael A; Rosin, Diane L; Kreitzer, Anatol C; Cunha, Rodrigo A; Watanabe, Masahiko; Ferré, Sergi

    2009-11-18

    Basal ganglia processing results from a balanced activation of direct and indirect striatal efferent pathways, which are controlled by dopamine D1 and D2 receptors, respectively. Adenosine A2A receptors are considered novel antiparkinsonian targets, based on their selective postsynaptic localization in the indirect pathway, where they modulate D2 receptor function. The present study provides evidence for the existence of an additional, functionally significant, segregation of A2A receptors at the presynaptic level. Using integrated anatomical, electrophysiological, and biochemical approaches, we demonstrate that presynaptic A2A receptors are preferentially localized in cortical glutamatergic terminals that contact striatal neurons of the direct pathway, where they exert a selective modulation of corticostriatal neurotransmission. Presynaptic striatal A2A receptors could provide a new target for the treatment of neuropsychiatric disorders.

  13. A diversity of synaptic filters are created by temporal summation of excitation and inhibition

    PubMed Central

    George, Andrew A.; Lyons-Warren, Ariel M.; Ma, Xiaofeng; Carlson, Bruce A.

    2011-01-01

    Temporal filtering is a fundamental operation of nervous systems. In peripheral sensory systems, the temporal pattern of spiking activity can encode various stimulus qualities, and temporal filtering allows postsynaptic neurons to detect behaviorally-relevant stimulus features from these spike trains. Intrinsic excitability, short-term synaptic plasticity, and voltage-dependent dendritic conductances have all been identified as mechanisms that can establish temporal filtering behavior in single neurons. Here we show that synaptic integration of temporally-summating excitation and inhibition can establish diverse temporal filters of presynaptic input. Mormyrid electric fish communicate by varying the intervals between electric organ discharges. The timing of each discharge is coded by peripheral receptors into precisely-timed spikes. Within the midbrain posterior exterolateral nucleus, temporal filtering by individual neurons results in selective responses to a particular range of presynaptic interspike intervals. These neurons are diverse in their temporal filtering properties, reflecting the wide range of intervals that must be detected during natural communication behavior. By manipulating presynaptic spike timing with high temporal resolution, we demonstrate that tuning to behaviorally-relevant patterns of presynaptic input is similar in vivo and in vitro. We reveal that GABAergic inhibition plays a critical role in establishing different temporal filtering properties. Further, our results demonstrate that temporal summation of excitation and inhibition establishes selective responses to high and low rates of synaptic input, respectively. Simple models of synaptic integration reveal that variation in these two competing influences provides a basic mechanism for generating diverse temporal filters of synaptic input. PMID:21994388

  14. Action potential broadening induced by lithium may cause a presynaptic enhancement of excitatory synaptic transmission in neonatal rat hippocampus.

    PubMed

    Colino, A; García-Seoane, J J; Valentín, A

    1998-07-01

    Lithium enhances excitatory synaptic transmission in CA1 pyramidal cells, but the mechanisms remain unclear. The present study demonstrates that lithium enhances the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) receptor-mediated components of the excitatory postsynaptic current (EPSC). Lithium decreased the magnitude of paired-pulse facilitation and presented an inverse correlation between the lithium-induced enhancement of synaptic transmission and initial paired-pulse facilitation, which is consistent with a presynaptic mode of action. The enhancement of synaptic strength is likely to act, at least in part, by increasing the amplitude of the presynaptic Ca2+ transient. One mechanism which could account for this change of the presynaptic Ca2+ transient is an increase in the duration of the action potential. We investigated action potential in hippocampal pyramidal neurons and found that lithium (0.5-6 mM) increased the half-amplitude duration and reduced the rate of repolarization, whereas the rate of depolarization remained similar. To find out whether the lithium synaptic effects might be explained by spike broadening, we investigated the field recording of the excitatory postsynaptic potential (EPSP) in hippocampal slices and found three lines of evidence. First, the prolongation of the presynaptic action potential with 4-aminopyridine and tetraethylammonium blocked or reduced the synaptic effects of lithium. Second, the lithium-induced synaptic enhancement was modulated when presynaptic Ca2+ influx was varied by changing the external Ca2+ concentration. Finally, both effects, the synaptic transmission increment and the action potential broadening, were independent of inositol depletion. These results suggest that lithium enhances synaptic transmission in the hippocampus via a presynaptic site of action: the mechanism underlying the potentiating effect may be attributable to an increased Ca2+ influx consequent

  15. Activity-dependent modulation of the presynaptic potassium current in the frog neuromuscular junction.

    PubMed Central

    Miralles, F; Solsona, C

    1996-01-01

    1. Changes in the electrical properties of frog motor nerve endings caused by the invasion of an action potential were studied by the perineural recording technique. Two equal supramaximal stimuli separated by a variable time interval were applied to the nerve trunk. The latency and amplitude of the deflections associated with the nodal Na+ current and presynaptic K+ current elicited by the second pulse were compared with control currents. 2. The deflection associated with the presynaptic K+ current elicited in response to the second stimulus was absent at the shortest interstimulus interval and showed a progressive increase in its amplitude as the interstimulus interval was lengthened, reaching values greater than control in most terminals. During the same period the nodal Na+ current did not change. 3. The experimental results were compared with a computer model of the distal axonal segment and its terminal. Response of the model to twin-pulse stimulation was in marked disagreement with the experimental results unless an inactivating K+ channel, with properties derived ad hoc, was incorporated into the simulation. 4. These results suggest that in the first 6-7 ms after a nerve impulse has invaded a frog motor nerve ending, maximal K+ conductance remains below the value at rest due to the fast inactivation of a K+ conductance. Following this, there is a period in which K+ conductance is greater than control values although the basis for this is unknown. PMID:8887778

  16. Presynaptic GABAB Receptors Regulate Hippocampal Synapses during Associative Learning in Behaving Mice

    PubMed Central

    Jurado-Parras, M. Teresa; Delgado-García, José M.; Sánchez-Campusano, Raudel; Gassmann, Martin; Bettler, Bernhard; Gruart, Agnès

    2016-01-01

    GABAB receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the central nervous system. Pharmacological activation of GABAB receptors regulates neurotransmission and neuronal excitability at pre- and postsynaptic sites. Electrophysiological activation of GABAB receptors in brain slices generally requires strong stimulus intensities. This raises the question as to whether behavioral stimuli are strong enough to activate GABAB receptors. Here we show that GABAB1a-/- mice, which constitutively lack presynaptic GABAB receptors at glutamatergic synapses, are impaired in their ability to acquire an operant learning task. In vivo recordings during the operant conditioning reveal a deficit in learning-dependent increases in synaptic strength at CA3-CA1 synapses. Moreover, GABAB1a-/- mice fail to synchronize neuronal activity in the CA1 area during the acquisition process. Our results support that activation of presynaptic hippocampal GABAB receptors is important for acquisition of a learning task and for learning-associated synaptic changes and network dynamics. PMID:26848590

  17. Trio, a Rho Family GEF, Interacts with the Presynaptic Active Zone Proteins Piccolo and Bassoon

    PubMed Central

    Terry-Lorenzo, Ryan T.; Torres, Viviana I.; Wagh, Dhananjay; Galaz, Jose; Swanson, Selene K.; Florens, Laurence; Washburn, Michael P.; Waites, Clarissa L.; Gundelfinger, Eckart D.; Reimer, Richard J.; Garner, Craig C.

    2016-01-01

    Synaptic vesicles (SVs) fuse with the plasma membrane at a precise location called the presynaptic active zone (AZ). This fusion is coordinated by proteins embedded within a cytoskeletal matrix assembled at the AZ (CAZ). In the present study, we have identified a novel binding partner for the CAZ proteins Piccolo and Bassoon. This interacting protein, Trio, is a member of the Dbl family of guanine nucleotide exchange factors (GEFs) known to regulate the dynamic assembly of actin and growth factor dependent axon guidance and synaptic growth. Trio was found to interact with the C-terminal PBH 9/10 domains of Piccolo and Bassoon via its own N-terminal Spectrin repeats, a domain that is also critical for its localization to the CAZ. Moreover, our data suggest that regions within the C-terminus of Trio negatively regulate its interactions with Piccolo/Bassoon. These findings provide a mechanism for the presynaptic targeting of Trio and support a model in which Piccolo and Bassoon play a role in regulating neurotransmission through interactions with proteins, including Trio, that modulate the dynamic assembly of F-actin during cycles of synaptic vesicle exo- and endocytosis. PMID:27907191

  18. Phosphorylation of FEZ1 by Microtubule Affinity Regulating Kinases regulates its function in presynaptic protein trafficking

    PubMed Central

    Butkevich, Eugenia; Härtig, Wolfgang; Nikolov, Miroslav; Erck, Christian; Grosche, Jens; Urlaub, Henning; Schmidt, Christoph F.; Klopfenstein, Dieter R.; Chua, John Jia En

    2016-01-01

    Adapters bind motor proteins to cargoes and therefore play essential roles in Kinesin-1 mediated intracellular transport. The regulatory mechanisms governing adapter functions and the spectrum of cargoes recognized by individual adapters remain poorly defined. Here, we show that cargoes transported by the Kinesin-1 adapter FEZ1 are enriched for presynaptic components and identify that specific phosphorylation of FEZ1 at its serine 58 regulatory site is mediated by microtubule affinity-regulating kinases (MARK/PAR-1). Loss of MARK/PAR-1 impairs axonal transport, with adapter and cargo abnormally co-aggregating in neuronal cell bodies and axons. Presynaptic specializations are markedly reduced and distorted in FEZ1 and MARK/PAR-1 mutants. Strikingly, abnormal co-aggregates of unphosphorylated FEZ1, Kinesin-1 and its putative cargoes are present in brains of transgenic mice modelling aspects of Alzheimer’s disease, a neurodegenerative disorder exhibiting impaired axonal transport and altered MARK activity. Our findings suggest that perturbed FEZ1-mediated synaptic delivery of proteins arising from abnormal signalling potentially contributes to the process of neurodegeneration. PMID:27247180

  19. Zebrafish orthologue of mental retardation protein IL1RAPL1 regulates presynaptic differentiation.

    PubMed

    Yoshida, Tomoyuki; Mishina, Masayoshi

    2008-10-01

    IL1-receptor accessory protein-like 1 (IL1RAPL1), a member of interleukin-1/toll receptor (TIR) family, is responsible for a nonsyndromic form of mental retardation (MR). The zebrafish orthologue of mammalian IL1RAPL1, designated as Il1rapl1b, was expressed widely in the brain and in the olfactory placode. We employed an olfactory sensory neuron-specific gene manipulation system in combination with in vivo imaging of transparent zebrafish embryos to examine the functional role of Il1rapl1b in synaptic vesicle accumulation and subsequent morphological remodeling of axon terminals, the characteristic features of presynaptic differentiation of zebrafish olfactory sensory neurons during synapse formation. Antisense morpholino oligonucleotide against il1rapl1b suppressed both the synaptic vesicle accumulation and axon terminal remodeling. Consistently, the overexpression of Il1rapl1b stimulated synaptic vesicle accumulation. Swapping the carboxyl-terminal domain of Il1rapl1b with that of mouse IL-1 receptor accessory protein abolished the stimulatory effect. On the other hand, a substitution mutation in the TIR domain suppressed the morphological remodeling of axon terminals. Thus, the regulation of synaptic vesicle accumulation and subsequent morphological remodeling by Il1rapl1b appeared to be mediated by distinct domains. These results suggest that Il1rapl1b plays an important role in presynaptic differentiation during synapse formation.

  20. Mouse δ opioid receptors are located on presynaptic afferents to hippocampal pyramidal cells.

    PubMed

    Rezaï, Xavier; Faget, Lauren; Bednarek, Ewa; Schwab, Yannick; Kieffer, Brigitte L; Massotte, Dominique

    2012-05-01

    Delta opioid receptors participate in the control of chronic pain and emotional responses. Recent data have also identified their implication in drug-context associations pointing to a modulatory role on hippocampal activity. We used fluorescent knock-in mice that express a functional delta opioid receptor fused at its carboxy terminus with the green fluorescent protein in place of the native receptor to investigate the receptor neuroanatomical distribution in this structure. Fine mapping of the pyramidal layer was performed in hippocampal acute brain slices and organotypic cultures using fluorescence confocal imaging, co-localization with pre- and postsynaptic markers and correlative light-electron microscopy. The different approaches concurred to identify delta opioid receptors on presynaptic afferents to glutamatergic principal cells. In the latter, only scarce receptors were detected that were confined within the Golgi or vesicular intracellular compartments with no receptor present at the cell surface. In the mouse hippocampus, expression of functional delta opioid receptors is therefore mostly associated with interneurons emphasizing a presynaptic modulatory effect on the pyramidal cell firing rate.

  1. Visualizing Presynaptic Calcium Dynamics and Vesicle Fusion with a Single Genetically Encoded Reporter at Individual Synapses.

    PubMed

    Jackson, Rachel E; Burrone, Juan

    2016-01-01

    Synaptic transmission depends on the influx of calcium into the presynaptic compartment, which drives neurotransmitter release. Genetically encoded reporters are widely used tools to understand these processes, particularly pHluorin-based reporters that report vesicle exocytosis and endocytosis through pH dependent changes in fluorescence, and genetically encoded calcium indicators (GECIs) that exhibit changes in fluorescence upon binding to calcium. The recent expansion of the color palette of available indicators has made it possible to image multiple probes simultaneously within a cell. We have constructed a single molecule reporter capable of concurrent imaging of both presynaptic calcium influx and exocytosis, by fusion of sypHy, the vesicle associated protein synaptophysin containing a GFP-based pHluorin sensor, with the red-shifted GECI R-GECO1. Due to the fixed stoichiometry of the two probes, the ratio of the two responses can also be measured, providing an all optical correlate of the calcium dependence of release. Here, we have characterized stimulus-evoked sypHy-RGECO responses of hippocampal synapses in vitro, exploring the effects of different stimulus strengths and frequencies as well as variations in external calcium concentrations. By combining live sypHy-RGECO imaging with post hoc fixation and immunofluorescence, we have also investigated correlations between structural and functional properties of synapses.

  2. Visualizing Presynaptic Calcium Dynamics and Vesicle Fusion with a Single Genetically Encoded Reporter at Individual Synapses

    PubMed Central

    Jackson, Rachel E.; Burrone, Juan

    2016-01-01

    Synaptic transmission depends on the influx of calcium into the presynaptic compartment, which drives neurotransmitter release. Genetically encoded reporters are widely used tools to understand these processes, particularly pHluorin-based reporters that report vesicle exocytosis and endocytosis through pH dependent changes in fluorescence, and genetically encoded calcium indicators (GECIs) that exhibit changes in fluorescence upon binding to calcium. The recent expansion of the color palette of available indicators has made it possible to image multiple probes simultaneously within a cell. We have constructed a single molecule reporter capable of concurrent imaging of both presynaptic calcium influx and exocytosis, by fusion of sypHy, the vesicle associated protein synaptophysin containing a GFP-based pHluorin sensor, with the red-shifted GECI R-GECO1. Due to the fixed stoichiometry of the two probes, the ratio of the two responses can also be measured, providing an all optical correlate of the calcium dependence of release. Here, we have characterized stimulus-evoked sypHy-RGECO responses of hippocampal synapses in vitro, exploring the effects of different stimulus strengths and frequencies as well as variations in external calcium concentrations. By combining live sypHy-RGECO imaging with post hoc fixation and immunofluorescence, we have also investigated correlations between structural and functional properties of synapses. PMID:27507942

  3. Trio, a Rho Family GEF, Interacts with the Presynaptic Active Zone Proteins Piccolo and Bassoon.

    PubMed

    Terry-Lorenzo, Ryan T; Torres, Viviana I; Wagh, Dhananjay; Galaz, Jose; Swanson, Selene K; Florens, Laurence; Washburn, Michael P; Waites, Clarissa L; Gundelfinger, Eckart D; Reimer, Richard J; Garner, Craig C

    2016-01-01

    Synaptic vesicles (SVs) fuse with the plasma membrane at a precise location called the presynaptic active zone (AZ). This fusion is coordinated by proteins embedded within a cytoskeletal matrix assembled at the AZ (CAZ). In the present study, we have identified a novel binding partner for the CAZ proteins Piccolo and Bassoon. This interacting protein, Trio, is a member of the Dbl family of guanine nucleotide exchange factors (GEFs) known to regulate the dynamic assembly of actin and growth factor dependent axon guidance and synaptic growth. Trio was found to interact with the C-terminal PBH 9/10 domains of Piccolo and Bassoon via its own N-terminal Spectrin repeats, a domain that is also critical for its localization to the CAZ. Moreover, our data suggest that regions within the C-terminus of Trio negatively regulate its interactions with Piccolo/Bassoon. These findings provide a mechanism for the presynaptic targeting of Trio and support a model in which Piccolo and Bassoon play a role in regulating neurotransmission through interactions with proteins, including Trio, that modulate the dynamic assembly of F-actin during cycles of synaptic vesicle exo- and endocytosis.

  4. Presynaptic calcium measurements at physiological temperatures using a new class of dextran-conjugated indicators.

    PubMed

    Beierlein, Michael; Gee, Kyle R; Martin, Vladimir V; Regehr, Wade G

    2004-07-01

    Presynaptic calcium (Ca(pre)) has been studied extensively because of its role in triggering and modulating neurotransmitter release. Although calcium regulation and calcium-driven processes can be strongly temperature dependent, technical difficulties have limited most studies of Ca(pre) to temperatures well below the physiological range. Here we assessed the use of membrane-permeant acetoxymethyl (AM) indicators and dextran-conjugated indicators for measuring Ca(pre) at physiological temperatures. A comparison of these two types of indicators loaded into parallel fibers of rat cerebellar slices revealed striking differences. AM indicators were rapidly extruded from axons and presynaptic terminals and therefore cannot be used for long-term measurements at high temperatures. In contrast, dextran-conjugated indicators were retained within parallel fibers and are therefore well suited to measuring Ca(pre) at physiological temperatures. The limited number of dextran indicators available prompted us to synthesize three new indicators that show peak emission in the red (575-600 nm). These indicators allow for simultaneous use of multiple calcium indicators that can be readily distinguished on the basis of excitation and emission wavelengths, use of excitation and emission wavelengths that are relatively insensitive to tissue autofluorescence, and measurements in systems with expression of green fluorescent protein (GFP). Thus we find that dextran-conjugated indicators are well suited to long-term recordings of Ca(pre) at physiological temperatures and that the development of new red indicators greatly extends their utility.

  5. Presynaptic (Type III) cells in mouse taste buds sense sour (acid) taste.

    PubMed

    Huang, Yijen A; Maruyama, Yutaka; Stimac, Robert; Roper, Stephen D

    2008-06-15

    Taste buds contain two types of cells that directly participate in taste transduction - receptor (Type II) cells and presynaptic (Type III) cells. Receptor cells respond to sweet, bitter and umami taste stimulation but until recently the identity of cells that respond directly to sour (acid) tastants has only been inferred from recordings in situ, from behavioural studies, and from immunostaining for putative sour transduction molecules. Using calcium imaging on single isolated taste cells and with biosensor cells to identify neurotransmitter release, we show that presynaptic (Type III) cells specifically respond to acid taste stimulation and release serotonin. By recording responses in cells isolated from taste buds and in taste cells in lingual slices to acetic acid titrated to different acid levels (pH), we also show that the active stimulus for acid taste is the membrane-permeant, uncharged acetic acid moiety (CH(3)COOH), not free protons (H(+)). That observation is consistent with the proximate stimulus for acid taste being intracellular acidification, not extracellular protons per se. These findings may also have implications for other sensory receptors that respond to acids, such as nociceptors.

  6. Contributions of SERCA pump and ryanodine-sensitive stores to presynaptic residual Ca2+

    PubMed Central

    Scullin, Chessa S.; Partridge, L. Donald

    2010-01-01

    The presynaptic Ca2+ signal, which triggers vesicle release, disperses to a broadly distributed residual [Ca2+] ([Ca2+]res) that plays an important role in synaptic plasticity. We have previously reported a slowing in the decay timecourse of [Ca2+]res during the second of paired pulses. In this study, we investigated the contributions of organelle and plasma membrane Ca2+ flux pathways to the reduction of effectiveness of [Ca2+]res clearance during short-term plasticity in Schaffer collateral terminals in the CA1 field of the hippocampus. We show that the slowed decay timecourse is mainly the result of a transport-dependent Ca2+ clearance process; that presynaptic caffeine-sensitive Ca2+ stores are not functionally loaded in the unstimulated terminal, but that these stores can effectively take up Ca2+ even during high frequency trains of stimuli; and that a rate limiting step of sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) kinetics following the first pulse is responsible for a large portion of the observed slowing of [Ca2+]res clearance during the second pulse. We were able to accurately fit our [Ca2+]res data with a kinetic model based on these observations and this model predicted a reduction in availability of unbound SERCA during paired pulses, but no saturation of Ca2+ buffer in the endoplasmic reticulum. PMID:20153896

  7. Presynaptic structure of Aplysia single live neuron by atomic force and confocal laser scanning microscope.

    PubMed

    Park, Aee-Young; Chae, Yeon-Su; Lee, Seung-Hee; Kaang, Bong-Kiun; Lee, Seonghoon

    2013-05-02

    The structural and functional plasticity of Aplysia mechanosensory presynaptic neurons has been studied in relation with the mechanism underlying learning and memory. Long-term facilitation (LTF), which is a well-known cellular model for long-term memory in Aplysia, is accompanied by new synaptic structural growth or change. We developed a combined atomic force microscope and confocal laser scanning microscope (AFM-CLSM) system integrated with a MATLAB routine for image processing to concurrently obtain high-resolution 3-dimensional (3D) outer-surface morphological images and 3D interior fluorescence images. With our combined AFM-CLSM system, volumetric changes in the presynaptic structures (varicosities) of Aplysia live sensory-motor neuron cocultures were observed. The spatial distribution of synaptic vesicle molecules in the preexisting varicosities was monitored together with a volumetric change in the varicosities. Our combined AFM-CLSM system is successfully adapted for measuring learning-related structural changes and the movement of synaptic molecules in the single live neuron through interaction force and fluorescence imaging.

  8. Presynaptic C-terminal truncated tau is released from cortical synapses in Alzheimer's disease

    PubMed Central

    Sokolow, Sophie; Henkins, Kristen M.; Bilousova, Tina; Gonzalez, Bianca; Vinters, Harry V.; Miller, Carol A.; Cornwell, Lindsey; Poon, Wayne W.; Gylys, Karen H.

    2015-01-01

    The microtubule-associated protein tau has primarily been associated with axonal location and function; however, recent work shows tau release from neurons and suggests an important role for tau in synaptic plasticity. In our study, we measured synaptic levels of total tau using synaptosomes prepared from cryopreserved human postmortem Alzheimer's disease (AD) and control samples. Flow cytometry data show that a majority of synaptic terminals are highly immunolabeled with the total tau antibody (HT7) in both AD and control samples. Immunoblots of synaptosomal fractions reveal increases in a 20 kDa tau fragment and in tau dimers in AD synapses, and terminal-specific antibodies show that in many synaptosome samples tau lacks a C-terminus. Flow cytometry experiments to quantify the extent of C-terminal truncation reveal that only 15-25% of synaptosomes are positive for intact C-terminal tau. Potassium-induced depolarization demonstrates release of tau and tau fragments from presynaptic terminals, with increased release from AD compared to control samples. This study indicates that tau is normally highly localized to synaptic terminals in cortex where it is well-positioned to affect synaptic plasticity. Tau cleavage may facilitate tau aggregation as well as tau secretion and propagation of tau pathology from the presynaptic compartment in AD. PMID:25393609

  9. Impaired synaptic vesicle recycling contributes to presynaptic dysfunction in lipoprotein lipase-deficient mice.

    PubMed

    Liu, X; Zhang, B; Yang, H; Wang, H; Liu, Y; Huang, A; Liu, T; Tian, X; Tong, Y; Zhou, T; Zhang, T; Xing, G; Xiao, W; Guo, X; Fan, D; Han, X; Liu, G; Zhou, Z; Chui, D

    2014-11-07

    Lipoprotein lipase (LPL) is expressed at high levels in hippocampal neurons, although its function is unclear. We previously reported that LPL-deficient mice have learning and memory impairment and fewer synaptic vesicles in hippocampal neurons, but properties of synaptic activity in LPL-deficient neurons remain unexplored. In this study, we found reduced frequency of miniature excitatory postsynaptic currents (mEPSCs) and readily releasable pool (RRP) size in LPL-deficient neurons, which led to presynaptic dysfunction and plasticity impairment without altering postsynaptic activity. We demonstrated that synaptic vesicle recycling, which is known to play an important role in maintaining the RRP size in active synapses, is impaired in LPL-deficient neurons. Moreover, lipid assay revealed deficient docosahexaenoic acid (DHA) and arachidonic acid (AA) in the hippocampus of LPL-deficient mice; exogenous DHA or AA supplement partially restored synaptic vesicle recycling capability. These results suggest that impaired synaptic vesicle recycling results from deficient DHA and AA and contributes to the presynaptic dysfunction and plasticity impairment in LPL-deficient neurons.

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

    PubMed Central

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

    2016-01-01

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

  11. Translating neuronal activity at the synapse: presynaptic calcium sensors in short-term plasticity

    PubMed Central

    de Jong, Arthur P. H.; Fioravante, Diasynou

    2014-01-01

    The complex manner in which patterns of presynaptic neural activity are translated into short-term plasticity (STP) suggests the existence of multiple presynaptic calcium (Ca2+) sensors, which regulate the amplitude and time-course of STP and are the focus of this review. We describe two canonical Ca2+-binding protein domains (C2 domains and EF-hands) and define criteria that need to be met for a protein to qualify as a Ca2+ sensor mediating STP. With these criteria in mind, we discuss various forms of STP and identify established and putative Ca2+ sensors. We find that despite the multitude of proposed sensors, only three are well established in STP: Munc13, protein kinase C (PKC) and synaptotagmin-7. For putative sensors, we pinpoint open questions and potential pitfalls. Finally, we discuss how the molecular properties and modes of action of Ca2+ sensors can explain their differential involvement in STP and shape net synaptic output. PMID:25400547

  12. Is state-dependent alternation of slow dynamics in central single neurons during sleep present in the rat ventroposterior thalamic nucleus?

    PubMed

    Takahashi, Kazumi; Koyama, Yoshimasa; Kayama, Yukihiko; Nakamura, Kazuhiro; Yamamoto, Mitsuaki

    2004-02-01

    Based upon our previous results in cats, we hypothesized that neurons in the central processor systems of the brain generally exhibit state-dependent dynamics alternation of slow fluctuations in spontaneous activity during sleep. To test the validity of this hypothesis across species, we recorded single neuronal activity during sleep from the ventroposterior (VP) thalamic nucleus in unanesthetized, head-restrained rats. Spectral analysis was performed on successive spike-counts of neuronal activity recorded during three stages of the sleep-wakefulness cycle: wakefulness (W, n=6), slow-wave sleep (SWS, n=20), and paradoxical sleep (PS, n=32). We found that firing of VP neurons displayed white-noise-like dynamics over the range of 0.04-1.0 Hz during SWS and 1/f-noise-like dynamics over the same range during PS. We also demonstrated for the first time that the slow dynamics of neuronal activity during quiet wakefulness (but not drowsiness) are white-noise-like. These results suggest that our hypothesis is true across species. During W and SWS, the brain may be considered as under global inhibition. Conversely, PS may represent a state of global disinhibition in the brain, where neuronal activity exhibits 1/f-noise-like dynamics. Fluctuations observed in living organisms may be involved in essential processes in generation and function of sleep states.

  13. Mutual interactions of the presynaptic histamine H3 and prostaglandin EP3 receptors on the noradrenergic terminals in the mouse brain.

    PubMed

    Schlicker, E; Marr, I

    1997-07-01

    We studied whether interactions between the presynaptic histamine H3 and prostaglandin EP3 receptors on the noradrenergic neurons of the mouse brain cortex occur. Cerebral cortex slices from the mouse (and, in few experiments, from the rat) were preincubated with [3H]noradrenaline and then superfused with a physiological salt solution. Tritium overflow was evoked electrically, either at 0.3 or 3 Hz (2 min) (standard stimulation protocol) or at 100 Hz (eight pulses) (stimulation protocol under which almost no activation of the presynaptic alpha2-adrenoceptors by endogenous noradrenaline occurs). In another set of experiments, Ca2+ ions were introduced into Ca2+-free K+-rich medium containing tetrodotoxin to evoke tritium overflow. The electrically-evoked tritium overflow (0.3 Hz) was inhibited by histamine or the H3 receptor agonist imetit, acting via H3 receptors. and by prostaglandin E2 or the EP3 receptor agonist sulprostone, acting via EP3 receptors. When histamine or imetit was given first (at concentrations causing the maximum effect at H3 receptors), the effect of prostaglandin E2 on the evoked tritium overflow was attenuated by 5-10%. When prostaglandin E2 or sulprostone was given first (at concentrations causing the maximum effect at EP3 receptors), the effect of histamine or imetit on the evoked overflow was attenuated by almost 50%. The previous administration of prostaglandin E2 also blunted the effect of histamine on the evoked tritium overflow evoked at 3 Hz; the degree of attenuation was identical when the current strength was 25 mA or was increased to 100 or 200 mA in order to partially compensate for the inhibitory effect of prostaglandin E2 on the evoked overflow. In addition, prostaglandin E2 attenuated the effect of histamine when tritium overflow was evoked (i) by 100 Hz, eight pulses or (ii) by Ca2+ ions or (iii) when rat (instead of mouse) brain cortex slices were used. An interaction of prostaglandin E2 or sulprostone with the H3 receptor

  14. cGMP-Dependent Protein Kinase Inhibition Extends the Upper Temperature Limit of Stimulus-Evoked Calcium Responses in Motoneuronal Boutons of Drosophila melanogaster Larvae

    PubMed Central

    Dawson-Scully, Ken

    2016-01-01

    While the mammalian brain functions within a very narrow range of oxygen concentrations and temperatures, the fruit fly, Drosophila melanogaster, has employed strategies to deal with a much wider range of acute environmental stressors. The foraging (for) gene encodes the cGMP-dependent protein kinase (PKG), has been shown to regulate thermotolerance in many stress-adapted species, including Drosophila, and could be a potential therapeutic target in the treatment of hyperthermia in mammals. Whereas previous thermotolerance studies have looked at the effects of PKG variation on Drosophila behavior or excitatory postsynaptic potentials at the neuromuscular junction (NMJ), little is known about PKG effects on presynaptic mechanisms. In this study, we characterize presynaptic calcium ([Ca2+]i) dynamics at the Drosophila larval NMJ to determine the effects of high temperature stress on synaptic transmission. We investigated the neuroprotective role of PKG modulation both genetically using RNA interference (RNAi), and pharmacologically, to determine if and how PKG affects presynaptic [Ca2+]i dynamics during hyperthermia. We found that PKG activity modulates presynaptic neuronal Ca2+ responses during acute hyperthermia, where PKG activation makes neurons more sensitive to temperature-induced failure of Ca2+ flux and PKG inhibition confers thermotolerance and maintains normal Ca2+ dynamics under the same conditions. Targeted motoneuronal knockdown of PKG using RNAi demonstrated that decreased PKG expression was sufficient to confer thermoprotection. These results demonstrate that the PKG pathway regulates presynaptic motoneuronal Ca2+ signaling to influence thermotolerance of presynaptic function during acute hyperthermia. PMID:27711243

  15. Fear extinction can be made state-dependent on peripheral epinephrine: role of norepinephrine in the nucleus tractus solitarius.

    PubMed

    Rosa, Jessica; Myskiw, Jociane C; Furini, Cristiane R G; Sapiras, Gerson G; Izquierdo, Ivan

    2014-09-01

    We investigate whether the extinction of inhibitory avoidance (IA) learning can be subjected to endogenous state-dependence with systemic injections of epinephrine (E), and whether endogenous norepinephrine (NE) and the nucleus tractus solitarius (NTS)→locus coeruleus→hippocampus/amygdala (HIPP/BLA) pathway participate in this. Rats trained in IA were submitted to two sessions of extinction 24 h apart: In the first, the animals were submitted to a training session of extinction, and in the second they were tested for the retention of extinction. Saline or E were given i.p. immediately after the extinction training (post-extinction training injections) and/or 6 min before the extinction test (pre-extinction test). Post-extinction training E (50 or 100 μg/kg) induced a poor retrieval of extinction in the test session of this task unless an additional E injection (50 μg/kg) was given prior to the extinction test. This suggested state-dependence. Muscimol (0.01 μg/side) microinfused into the NTS prior to the extinction test session blocked E-induced state-dependence. Norepinephrine (NE, 1 μg/side) infused bilaterally into NTS restores the extinction impairment caused by post-extinction training i.p. E. In animals with bilateral NTS blockade induced by muscimol, NE (1 μg/side) given prior to the extinction test into the CA1 region of the dorsal hippocampus or into the basolateral amygdala restored the normal extinction levels that had been impaired by muscimol. These results suggest a role for the NTS→locus coeruleus→HIPP/BLA pathway in the retrieval of extinction, as it has been shown to have in the consolidation of inhibitory avoidance and of object recognition learning.

  16. Selective presynaptic terminal remodeling induced by spatial, but not cued, learning: a quantitative confocal study.

    PubMed

    McGonigal, R; Tabatadze, N; Routtenberg, A

    2012-06-01

    The hippocampal mossy fibers (MFs) are capable of behaviorally selective, use-dependent structural remodeling. Indeed, we previously observed a new layer of Timm's staining induced in the stratum oriens (SO) in CA3 after spatial but not cued water maze learning (Rekart et al., (2007) Learn Mem 14:416-421). This led to the prediction that there is a learning-specific induction of presynaptic terminal plasticity of MF axons. This study confirms this prediction demonstrating, at the confocal level of analysis, terminal-specific, and behavior-selective presynaptic structural plasticity linked to long-term memory. Male adult Wistar rats were trained for 5 days to locate a hidden or visible platform in a water maze and a retention test was performed 7 days later. MF terminal subtypes, specifically identified by an antibody to zinc transporter 3 (ZnT3), were counted from confocal z-stacks in the stratum lucidum (SL) and the SO. In hidden platform trained rats, there was a significant increase in the number of large MF terminals (LMTs, 2.5-10 μm diameter, >2 μm(2) area) compared to controls both in the proximal SL (P < 0.05) and in the SO (P < 0.01). Surprisingly, there was no detectable increase in small MF terminals (SMTs, 0.5-2 μm diameter, <2 μm(2) area) in either SL or SO as a consequence of training. This distinction of the two MF terminal types is functionally important as LMTs synapse on CA3 pyramidal neurons, while SMTs are known to target inhibitory interneurons. The present findings highlight the pivotal role in memory of presynaptic structural plasticity. Because the "sprouting" observed is specific to the LMT, with no detectable change in the number of the SMT, learning may enhance net excitatory input to CA3 pyramidal neurons. Given the sparse coding of the MF-CA3 connection, and the role that granule cells play in pattern separation, the remodeling observed here may be expected to have a major impact on the long-term integration of spatial context into

  17. Localization of Kv1.3 channels in presynaptic terminals of brainstem auditory neurons

    PubMed Central

    Gazula, Valeswara-Rao; Strumbos, John G.; Mei, Xiaofeng; Chen, Haijun; Rahner, Christoph; Kaczmarek, Leonard K.

    2010-01-01

    Elimination of the Kv1.3 voltage-dependent potassium channel gene produces striking changes in the function of the olfactory bulb, raising the possibility that this channel also influences other sensory systems. We have examined the cellular and subcellular localization of Kv1.3 in the Medial Nucleus of the Trapezoid Body (MNTB) in the auditory brainstem, a nucleus in which neurons fire at high rates with high temporal precision. A clear gradient of Kv1.3 immunostaining along the lateral to medial tonotopic axis of the MNTB was detected. Highest levels were found in the lateral region of the MNTB, which corresponds to neurons that respond selectively to low frequency auditory stimuli. Previous studies have demonstrated that MNTB neurons and their afferent inputs from the cochlear nucleus express three other members of the Kv1 family, Kv1.1, Kv1.2 and Kv1.6. Nevertheless, confocal microscopy of MNTB sections co-immunostained for Kv1.3 with these subunits revealed that the distribution of Kv1.3 differed significantly from other Kv1 family subunits. In particular, no axonal staining of Kv1.3 was detected and most prominent labeling was in structures surrounding the somata of the principal neurons, suggesting specific localization to the large calyx of Held presynaptic endings that envelop the principal cells. The presence of Kv1.3 in presynaptic terminals was confirmed by co-immunolocalization with the synaptic markers synaptophysin, syntaxin, and synaptotagmin and by immunogold electron microscopy. Kv1.3 immunogold particles in the terminals were arrayed along the plasma membrane and on internal vesicular structures. To confirm these patterns of staining, we carried out immunolabeling on sections from Kv1.3−/− mice. No immunoreactivity could be detected in Kv1.3−/− mice either at the light level or in immunogold experiments. The finding of a tonotopic gradient in presynaptic terminals suggests that Kv1.3 may regulate neurotransmitter release differentially in

  18. Calcium-Dependent and Synapsin-Dependent Pathways for the Presynaptic Actions of BDNF

    PubMed Central

    Cheng, Qing; Song, Sang-Ho; Augustine, George J.

    2017-01-01

    We used cultured hippocampal neurons to determine the signaling pathways mediating brain-derived neurotrophic factor (BDNF) regulation of spontaneous glutamate and GABA release. BDNF treatment elevated calcium concentration in presynaptic terminals; this calcium signal reached a peak within 1 min and declined in the sustained presence of BDNF. This BDNF-induced transient rise in presynaptic calcium was reduced by SKF96365, indicating that BDNF causes presynaptic calcium influx via TRPC channels. BDNF treatment increased the frequency of miniature excitatory postsynaptic currents (mEPSCs). This response consisted of two components: a transient component that peaked within 1 min of initiating BDNF application and a second component that was sustained, at a lower mEPSC frequency, for the duration of BDNF application. The initial transient component was greatly reduced by removing external calcium or by treatment with SKF96365, as well as by Pyr3, a selective blocker of TRPC3 channels. In contrast, the sustained component was unaffected in these conditions but was eliminated by U0126, an inhibitor of the MAP kinase (MAPK) pathway, as well as by genetic deletion of synapsins in neurons from a synapsin triple knock-out (TKO) mouse. Thus, two pathways mediate the ability of BDNF to enhance spontaneous glutamate release: the transient component arises from calcium influx through TRPC3 channels, while the sustained component is mediated by MAPK phosphorylation of synapsins. We also examined the ability of these two BDNF-dependent pathways to regulate spontaneous release of the inhibitory neurotransmitter, GABA. BDNF had no effect on the frequency of spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in neurons from wild-type (WT) mice, but surprisingly did increase mIPSC frequency in synapsin TKO mice. This covert BDNF response was blocked by removal of external calcium or by treatment with SKF96365 or Pyr3, indicating that it results from calcium influx

  19. Selective presynaptic terminal remodeling induced by spatial, but not cued, learning: a quantitative confocal study

    PubMed Central

    McGonigal, R.; Tabatadze, N.; Routtenberg, A.

    2011-01-01

    The hippocampal mossy fibers (MFs) are capable of behaviorally-selective, use-dependent structural remodeling. Indeed, we previously observed a new layer of Timm’s staining induced in the stratum oriens (SO) in CA3 after spatial but not cued water maze learning (Rekart et al., Learn. Mem. 2007; 14:416–421). This led to the prediction that there is a learning-specific induction of presynaptic terminal plasticity of MF axons. The present study confirms this prediction demonstrating, at the confocal level of analysis, terminal-specific and behavior-selective presynaptic structural plasticity linked to long-term memory. Male adult Wistar rats were trained for 5d to locate a hidden or visible platform in a water maze and a retention test was performed 7d later. MF terminal subtypes, specifically identified by an antibody to zinc transporter 3 (ZnT3), were counted from confocal z-stacks in the stratum lucidum (SL) and the SO. In hidden platform trained rats there was a significant increase in the number of large MF terminals (LMTs, 2.5–10µm diameter, >2µm2 area) compared to controls both in the proximal SL (p <0.05) and in the SO (p < 0.01). Surprisingly, there was no detectable increase in small MF terminals (SMTs, 0.5–2µm diameter, <2µm2 area) in either SL or SO as a consequence of training. This distinction of the two MF terminal types is functionally important as LMTs synapse on CA3 pyramidal neurons, while SMTs are known to target inhibitory interneurons. The present findings highlight the pivotal role in memory of presynaptic structural plasticity. Because the ‘sprouting’ observed is specific to the LMT, with no detectable change in the number of the SMT, learning may enhance net excitatory input to CA3 pyramidal neurons. Given the sparse coding of the MF-CA3 connection, and the role that granule cells play in pattern separation, the remodeling observed here may be expected to have a major impact on the long-term integration of spatial context into

  20. Imaging and analysis of evoked excitatory-postsynaptic-calcium-transients by individual presynaptic-boutons of cultured Aplysia sensorimotor synapse.

    PubMed

    Malkinson, Guy; Spira, Micha E

    2010-04-01

    The use of the sensory-motor (SN-MN) synapse of the Aplysia gill withdrawal reflex has contributed immensely to the understanding of synaptic transmission, learning and memory acquisition processes. Whereas the majority of the studies focused on analysis of the presynaptic mechanisms, recent studies indicated that as in mammalian synapses, long term potentiation (LTP) formed by Aplysia SN-MN synapse depends on elevation of the postsynaptic free intracellular calcium concentration ([Ca2+](i)). Consistently, injection of the fast calcium chelator BAPTA to the MN prevents the formation of serotonin-induced LTP. Nevertheless, currently there are no published reports that directly examine and document whether evoked synaptic transmission is associated with transient increase in the postsynaptic [Ca2+](i). In the present study we imaged, for the first time, alterations in the postsynaptic [Ca2+](i) in response to presynaptic stimulation and analyzed the underlying mechanisms. Using live imaging of the postsynaptic [Ca2+](i) while monitoring the EPSP, we found that evoked transmitter release generates excitatory postsynaptic calcium concentration transients (EPSCaTs) by two mechanisms: (a) activation of DNQX-sensitive postsynaptic receptors-gated calcium influx and (b) calcium influx through nitrendipine-sensitive voltage-gated calcium channels (VGCCs). Concomitant confocal imaging of presynaptic boutons and EPSCaTs revealed that approximately 86% of the presynaptic boutons are associated with functional synapses.

  1. Presynaptic TRPV1 vanilloid receptor function is age- but not CB1 cannabinoid receptor-dependent in the rodent forebrain.

    PubMed

    Köles, László; Garção, Pedro; Zádori, Zoltán S; Ferreira, Samira G; Pinheiro, Bárbara S; da Silva-Santos, Carla S; Ledent, Catherine; Köfalvi, Attila

    2013-08-01

    Neocortical and striatal TRPV1 (vanilloid or capsaicin) receptors (TRPV1Rs) are excitatory ligand-gated ion channels, and are implicated in psychiatric disorders. However, the purported presynaptic neuromodulator role of TRPV1Rs in glutamatergic, serotonergic or dopaminergic terminals of the rodent forebrain remains little understood. With the help of patch-clamp electrophysiology and neurochemical approaches, we mapped the age-dependence of presynaptic TRPV1R function, and furthermore, we aimed at exploring whether the presence of CB1 cannabinoid receptors (CB1Rs) influences the function of the TRPV1Rs, as both receptor types share endogenous ligands. We found that the major factor which affects presynaptic TRPV1R function is age: by post-natal day 13, the amplitude of capsaicin-induced release of dopamine and glutamate is halved in the rat striatum, and two weeks later, capsaicin already loses its effect. However, TRPV1R receptor function is not enhanced by chemical or genetic ablation of the CB1Rs in dopaminergic, glutamatergic and serotonergic terminals of the mouse brain. Altogether, our data indicate a possible neurodevelopmental role for presynaptic TRPV1Rs in the rodent brain, but we found no cross-talk between TRPV1Rs and CB1Rs in the same nerve terminal.

  2. Liprin-α2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission.

    PubMed

    Spangler, Samantha A; Schmitz, Sabine K; Kevenaar, Josta T; de Graaff, Esther; de Wit, Heidi; Demmers, Jeroen; Toonen, Ruud F; Hoogenraad, Casper C

    2013-06-10

    The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-α2 as a key organizer in this process. We show that liprin-α2 levels were regulated by synaptic activity and the ubiquitin-proteasome system. Furthermore, liprin-α2 organized presynaptic ultrastructure and controlled synaptic output by regulating synaptic vesicle pool size. The presence of liprin-α2 at presynaptic sites did not depend on other active zone scaffolding proteins but was critical for recruitment of several components of the release machinery, including RIM1 and CASK. Fluorescence recovery after photobleaching showed that depletion of liprin-α2 resulted in reduced turnover of RIM1 and CASK at presynaptic terminals, suggesting that liprin-α2 promotes dynamic scaffolding for molecular complexes that facilitate synaptic vesicle release. Therefore, liprin-α2 plays an important role in maintaining active zone dynamics to modulate synaptic efficacy in response to changes in network activity.

  3. Liprin-α2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission

    PubMed Central

    Spangler, Samantha A.; Schmitz, Sabine K.; Kevenaar, Josta T.; de Graaff, Esther; de Wit, Heidi; Demmers, Jeroen

    2013-01-01

    The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-α2 as a key organizer in this process. We show that liprin-α2 levels were regulated by synaptic activity and the ubiquitin–proteasome system. Furthermore, liprin-α2 organized presynaptic ultrastructure and controlled synaptic output by regulating synaptic vesicle pool size. The presence of liprin-α2 at presynaptic sites did not depend on other active zone scaffolding proteins but was critical for recruitment of several components of the release machinery, including RIM1 and CASK. Fluorescence recovery after photobleaching showed that depletion of liprin-α2 resulted in reduced turnover of RIM1 and CASK at presynaptic terminals, suggesting that liprin-α2 promotes dynamic scaffolding for molecular complexes that facilitate synaptic vesicle release. Therefore, liprin-α2 plays an important role in maintaining active zone dynamics to modulate synaptic efficacy in response to changes in network activity. PMID:23751498

  4. Localization of the presynaptic cytomatrix protein Piccolo at ribbon and conventional synapses in the rat retina: comparison with Bassoon.

    PubMed

    Dick, O; Hack, I; Altrock, W D; Garner, C C; Gundelfinger, E D; Brandstätter, J H

    2001-10-15

    In recent years significant progress has been made in the elucidation of the molecular assembly of the postsynaptic density at synapses, whereas little is known as yet about the components of the presynaptic active zone. Piccolo and Bassoon, two structurally related presynaptic cytomatrix proteins, are highly concentrated at the active zones of both excitatory and inhibitory synapses in rat brain. In this study we used immunocytochemistry to examine the cellular and ultrastructural localization of Piccolo at synapses in the rat retina and compared it with that of Bassoon. Both proteins showed strong punctate immunofluorescence in the outer and the inner plexiform layers of the retina. They were found presynaptically at glutamatergic ribbon synapses and at conventional GABAergic and glycinergic synapses. Although the two proteins were coexpressed at all photoreceptor ribbon synapses and at some conventional amacrine cell synapses, at bipolar cell ribbon synapses only Piccolo was present. Our data demonstrate similarities but also differences in the molecular composition of the presynaptic apparatuses of the synapses in the retina, differences that may account for the functional differences observed between the ribbon and the conventional amacrine cell synapses and between the photoreceptor and the bipolar cell ribbon synapses in the retina.

  5. Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures.

    PubMed

    Myrick, Leila K; Deng, Pan-Yue; Hashimoto, Hideharu; Oh, Young Mi; Cho, Yongcheol; Poidevin, Mickael J; Suhl, Joshua A; Visootsak, Jeannie; Cavalli, Valeria; Jin, Peng; Cheng, Xiaodong; Warren, Stephen T; Klyachko, Vitaly A

    2015-01-27

    Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.

  6. Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

    PubMed Central

    Myrick, Leila K.; Deng, Pan-Yue; Hashimoto, Hideharu; Oh, Young Mi; Cho, Yongcheol; Poidevin, Mickael J.; Suhl, Joshua A.; Visootsak, Jeannie; Cavalli, Valeria; Jin, Peng; Cheng, Xiaodong; Warren, Stephen T.; Klyachko, Vitaly A.

    2015-01-01

    Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP’s canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP’s interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes. PMID:25561520

  7. Targeted gene transfer of different genes to presynaptic and postsynaptic neocortical neurons connected by a glutamatergic synapse.

    PubMed

    Zhang, Guo-rong; Zhao, Hua; Cao, Haiyan; Li, Xu; Geller, Alfred I

    2012-09-14

    Genetic approaches to analyzing neuronal circuits and learning would benefit from a technology to first deliver a specific gene into presynaptic neurons, and then deliver a different gene into an identified subset of their postsynaptic neurons, connected by a specific synapse type. Here, we describe targeted gene transfer across a neocortical glutamatergic synapse, using as the model the projection from rat postrhinal to perirhinal cortex. The first gene transfer, into the presynaptic neurons in postrhinal cortex, used a virus vector and standard gene transfer procedures. The vector expresses an artificial peptide neurotransmitter containing a dense core vesicle targeting domain, a NMDA NR1 subunit binding domain (from a monoclonal antibody), and the His tag. Upon release, this peptide neurotransmitter binds to NMDA receptors on the postsynaptic neurons. Antibody-mediated targeted gene transfer to these postsynaptic neurons in perirhinal cortex used a His tag antibody, as the peptide neurotransmitter contains the His tag. Confocal microscopy showed that with untargeted gene transfer, ~3% of the transduced presynaptic axons were proximal to a transduced postsynaptic dendrite. In contrast, with targeted gene transfer, ≥ 20% of the presynaptic axons were proximal to a transduced postsynaptic dendrite. Targeting across other types of synapses might be obtained by modifying the artificial peptide neurotransmitter to contain a binding domain for a different neurotransmitter receptor. This technology may benefit elucidating how specific neurons and subcircuits contribute to circuit physiology, behavior, and learning.

  8. Rapid State-Dependent Alteration in Kv3 Channel Availability Drives Flexible Synaptic Signaling Dependent on Somatic Subthreshold Depolarization.

    PubMed

    Rowan, Matthew J M; Christie, Jason M

    2017-02-21

    In many neurons, subthreshold depolarization in the soma can transiently increase action-potential (AP)-evoked neurotransmission via analog-to-digital facilitation. The mechanisms underlying this form of short-term synaptic plasticity are unclear, in part, due to the relative inaccessibility of the axon to direct physiological interrogation. Using voltage imaging and patch-clamp recording from presynaptic boutons of cerebellar stellate interneurons, we observed that depolarizing somatic potentials readily spread into the axon, resulting in AP broadening, increased spike-evoked Ca(2+) entry, and enhanced neurotransmission strength. Kv3 channels, which drive AP repolarization, rapidly inactivated upon incorporation of Kv3.4 subunits. This leads to fast susceptibility to depolarization-induced spike broadening and analog facilitation independent of Ca(2+)-dependent protein kinase C signaling. The spread of depolarization into the axon was attenuated by hyperpolarization-activated currents (Ih currents) in the maturing cerebellum, precluding analog facilitation. These results suggest that analog-to-digital facilitation is tempered by development or experience in stellate cells.

  9. Neurosteroid-induced enhancement of short-term facilitation involves a component downstream from presynaptic calcium in hippocampal slices

    PubMed Central

    Schiess, Adrian R B; Scullin, Chessa S; Partridge, L Donald

    2006-01-01

    We used Magnesium Green AM to measure Ca2+ transients in Schaffer collateral presynaptic terminals simultaneously with postsynaptic field potentials (fEPSPs) to investigate the mechanism of neurosteroid enhancement of short-term synaptic facilitation. Measurement of [Ca2+]i, isolated to presynaptic events, using the fluorescence ratio (ΔF/F0) demonstrated that at a constant stimulus intensity there was no change in the excitability of presynaptic fibres between paired stimuli or between ACSF and 1 μm pregnenolone sulphate (PREGS). Paired-pulse facilitation (PPF) was correlated with residual Ca2+ ([Ca2+]res), and there was an additional increase in the ∫ΔF/F0 for the [Ca2+]res-subtracted response to the second of paired stimuli, resulting primarily from a slowing of the decay time constant. In addition to the role of presynaptic [Ca2+]res in PPF, we observed a decrease in EC50 and a greater maximum for Hill function fits to fEPSP versus ΔF/F0 during the second of paired responses. The enhancement of fEPSP PPF by PREGS did not result from an increase of ΔF/F0. The data presented here support a PREGS-induced increase in presynaptic glutamate release from the second, but not the first, of a pair of stimuli for a given presynaptic [Ca2+] because: (a) there is actually a decrease in the ∫ΔF/F0 of the [Ca2+]res-subtracted second response over that seen in ACSF; (b) PREGS causes no change in presynaptic Ca2+ buffering; and (c) there is a decrease in EC50 and an increase of ymax in the Hill function fits to ΔF/F0versus fEPSP data. We hypothesize that PREGS enhances short-term facilitation by acting on the Ca2+-dependent vesicle release machinery and that this mechanism plays a role in the cognitive effects of this sulphated neurosteroid. PMID:16931546

  10. Adaptations of Presynaptic Dopamine Terminals Induced by Psychostimulant Self-Administration

    PubMed Central

    2015-01-01

    A great deal of research has focused on investigating neurobiological alterations induced by chronic psychostimulant use in an effort to describe, understand, and treat the pathology of psychostimulant addiction. It has been known for several decades that dopamine neurotransmission in the nucleus accumbens is integrally involved in the selection and execution of motivated and goal-directed behaviors, and that psychostimulants act on this system to exert many of their effects. As such, a large body of work has focused on defining the consequences of psychostimulant use on dopamine signaling in the striatum as it relates to addictive behaviors. Here, we review presynaptic dopamine terminal alterations observed following self-administration of cocaine and amphetamine, as well as possible mechanisms by which these alterations occur and their impact on the progression of addiction. PMID:25491345

  11. The Sodium-Driven Chloride/Bicarbonate Exchanger in Presynaptic Terminals

    PubMed Central

    Burette, Alain C.; Weinberg, Richard J.; Sassani, Patrick; Abuladze, Natalia; Kao, Liyo; Kurtz, Ira

    2013-01-01

    The sodium-driven chloride/bicarbonate exchanger (NDCBE), a member of the SLC4 family of bicarbonate transporters, was recently found to modulate excitatory neurotransmission in hippocampus. By using light and electron microscopic immunohistochemistry, we demonstrate here that NDCBE is expressed throughout the adult rat brain, and selectively concentrates in presynaptic terminals, where it is closely associated with synaptic vesicles. NDCBE is in most glutamatergic axon terminals, and is also present in the terminals of parvalbumin-positive γ-aminobutyric acid (GABA)ergic cells. These findings suggest that NDCBE can regulate glutamatergic transmission throughout the brain, and point to a role for NDCBE as a possible regulator of GABAergic neurotransmission. PMID:22102085

  12. Stereotyped initiation of retinal waves by bipolar cells via presynaptic NMDA autoreceptors

    PubMed Central

    Zhang, Rong-wei; Li, Xiao-quan; Kawakami, Koichi; Du, Jiu-lin

    2016-01-01

    Glutamatergic retinal waves, the spontaneous patterned neural activities propagating among developing retinal ganglion cells (RGCs), instruct the activity-dependent refinement of visuotopic maps. However, its initiation and underlying mechanism remain largely elusive. Here using larval zebrafish and multiple in vivo approaches, we discover that bipolar cells (BCs) are responsible for the generation of glutamatergic retinal waves. The wave originates from BC axon terminals (ATs) and propagates laterally to nearby BCs and vertically to downstream RGCs and the optic tectum. Its initiation is triggered by the activation of and consequent glutamate release from BC ATs, and is mediated by the N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) expressed at these ATs. Intercellular asymmetry of NMDAR expression at BC ATs enables the preferential initiation of waves at the temporal retina, where BC ATs express more NMDARs. Thus, our findings indicate that glutamatergic retinal waves are initiated by BCs through a presynaptic NMDA autoreceptor-dependent process. PMID:27586999

  13. Changes in presynaptic release, but not reuptake, of bioamines induced by long-term antidepressant treatment

    SciTech Connect

    Dolzhenko, A.T.; Komissarov, I.V.

    1986-10-01

    This paper describes an investigation into the effect of long-term administration of antidepressants on neuronal uptake of NA and 5-HT and on their release, induced by electrical stimulation, in rat brain slices. The effects of the test substances on neuronal uptake of /sup 14/C-NA and /sup 3/H-5-HT by the slices was investigated. Values of IC/sub 50/ and EC/sub 2/ were found and compared in the experiments and control. The inhibitory effect of clonidine (10/sup -4/ M) and of 5-HT (10/sup -5/ M) on presynaptic release of /sup 14/C-NA and /sup 3/H-5-HT also was studied in brain slices from intact rats and rats treated for two weeks with antidepressants.

  14. Two-photon fluorescence lifetime imaging of primed SNARE complexes in presynaptic terminals and β cells

    PubMed Central

    Takahashi, Noriko; Sawada, Wakako; Noguchi, Jun; Watanabe, Satoshi; Ucar, Hasan; Hayashi-Takagi, Akiko; Yagishita, Sho; Ohno, Mitsuyo; Tokumaru, Hiroshi; Kasai, Haruo

    2015-01-01

    It remains unclear how readiness for Ca2+-dependent exocytosis depends on varying degrees of SNARE complex assembly. Here we directly investigate the SNARE assembly using two-photon fluorescence lifetime imaging (FLIM) of Förster resonance energy transfer (FRET) between three pairs of neuronal SNAREs in presynaptic boutons and pancreatic β cells in the islets of Langerhans. These FRET probes functionally rescue their endogenous counterparts, supporting ultrafast exocytosis. We show that trans-SNARE complexes accumulated in the active zone, and estimate the number of complexes associated with each docked vesicle. In contrast, SNAREs were unassembled in resting state, and assembled only shortly prior to insulin exocytosis, which proceeds slowly. We thus demonstrate that distinct states of fusion readiness are associated with SNARE complex formation. Our FRET/FLIM approaches enable optical imaging of fusion readiness in both live and chemically fixed tissues. PMID:26439845

  15. Na+ current in presynaptic terminals of the crayfish opener cannot initiate action potentials

    PubMed Central

    2015-01-01

    Action potential (AP) propagation in presynaptic axons of the crayfish opener neuromuscular junction (NMJ) was investigated by simultaneously recording from a terminal varicosity and a proximal branch. Although orthodromically conducting APs could be recorded in terminals with amplitudes up to 70 mV, depolarizing steps in terminals to −20 mV or higher failed to fire APs. Patch-clamp recordings did detect Na+ current (INa) in most terminals. The INa exhibited a high threshold and fast activation rate. Local perfusion of Na+-free saline showed that terminal INa contributed to AP waveform by slightly accelerating the rising phase and increasing the peak amplitude. These findings suggest that terminal INa functions to “touch up” but not to generate APs. PMID:26561611

  16. Two-photon fluorescence lifetime imaging of primed SNARE complexes in presynaptic terminals and β cells

    NASA Astrophysics Data System (ADS)

    Takahashi, Noriko; Sawada, Wakako; Noguchi, Jun; Watanabe, Satoshi; Ucar, Hasan; Hayashi-Takagi, Akiko; Yagishita, Sho; Ohno, Mitsuyo; Tokumaru, Hiroshi; Kasai, Haruo

    2015-10-01

    It remains unclear how readiness for Ca2+-dependent exocytosis depends on varying degrees of SNARE complex assembly. Here we directly investigate the SNARE assembly using two-photon fluorescence lifetime imaging (FLIM) of Förster resonance energy transfer (FRET) between three pairs of neuronal SNAREs in presynaptic boutons and pancreatic β cells in the islets of Langerhans. These FRET probes functionally rescue their endogenous counterparts, supporting ultrafast exocytosis. We show that trans-SNARE complexes accumulated in the active zone, and estimate the number of complexes associated with each docked vesicle. In contrast, SNAREs were unassembled in resting state, and assembled only shortly prior to insulin exocytosis, which proceeds slowly. We thus demonstrate that distinct states of fusion readiness are associated with SNARE complex formation. Our FRET/FLIM approaches enable optical imaging of fusion readiness in both live and chemically fixed tissues.

  17. BDNF and its pro-peptide are stored in presynaptic dense core vesicles in brain neurons

    PubMed Central

    Dieni, Sandra; Matsumoto, Tomoya; Dekkers, Martijn; Rauskolb, Stefanie; Ionescu, Mihai S.; Deogracias, Ruben; Gundelfinger, Eckart D.; Kojima, Masami; Nestel, Sigrun; Frotscher, Michael

    2012-01-01

    Although brain-derived neurotrophic factor (BDNF) regulates numerous and complex biological processes including memory retention, its extremely low levels in the mature central nervous system have greatly complicated attempts to reliably localize it. Using rigorous specificity controls, we found that antibodies reacting either with BDNF or its pro-peptide both stained large dense core vesicles in excitatory presynaptic terminals of the adult mouse hippocampus. Both moieties were ∼10-fold more abundant than pro-BDNF. The lack of postsynaptic localization was confirmed in Bassoon mutants, a seizure-prone mouse line exhibiting markedly elevated levels of BDNF. These findings challenge previous conclusions based on work with cultured neurons, which suggested activity-dependent dendritic synthesis and release of BDNF. They instead provide an ultrastructural basis for an anterograde mode of action of BDNF, contrasting with the long-established retrograde model derived from experiments with nerve growth factor in the peripheral nervous system. PMID:22412021

  18. State-dependent variability of dynamic functional connectivity between frontoparietal and default networks relates to cognitive flexibility.

    PubMed

    Douw, Linda; Wakeman, Daniel G; Tanaka, Naoaki; Liu, Hesheng; Stufflebeam, Steven M

    2016-12-17

    The brain is a dynamic, flexible network that continuously reconfigures. However, the neural underpinnings of how state-dependent variability of dynamic functional connectivity (vdFC) relates to cognitive flexibility are unclear. We therefore investigated flexible functional connectivity during resting-state and task-state functional magnetic resonance imaging (rs-fMRI and t-fMRI, resp.) and performed separate, out-of-scanner neuropsychological testing. We hypothesize that state-dependent vdFC between the frontoparietal network (FPN) and the default mode network (DMN) relates to cognitive flexibility. Seventeen healthy subjects performed the Stroop color word test and underwent t-fMRI (Stroop computerized version) and rs-fMRI. Time series were extracted from a cortical atlas, and a sliding window approach was used to obtain a number of correlation matrices per subject. vdFC was defined as the standard deviation of connectivity strengths over these windows. Higher task-state FPN-DMN vdFC was associated with greater out-of-scanner cognitive flexibility, while the opposite relationship was present for resting-state FPN-DMN vdFC. Moreover, greater contrast between task-state and resting-state vdFC related to better cognitive performance. In conclusion, our results suggest that not only the dynamics of connectivity between these networks is seminal for optimal functioning, but also that the contrast between dynamics across states reflects cognitive performance.

  19. Hardware-In-the-Loop Simulations of spacecraft attitude synchronization using the State-Dependent Riccati Equation technique

    NASA Astrophysics Data System (ADS)

    Jung, Junoh; Park, Sang-Young; Kim, Sung-Woo; Eun, Young Ho; Chang, Young-Keun

    2013-02-01

    A nonlinear control technique pertaining to attitude synchronization problems is presented for formation flying spacecraft by utilizing the State-Dependent Riccati Equation (SDRE) technique. An attitude controller consisting of relative control and absolute control is designed using a reaction wheel assembly for regulator and tracking problems. To achieve effective relative control, the selective state-dependent connectivity is also adopted. The global asymptotic stability of the controller is confirmed using the Lyapunov theorem and is verified by Monte-Carlo simulations. An air-bearing-based Hardware-In-the-Loop Simulator (HILS) is also developed to validate the proposed control laws in real-time environments. The SDRE controller is discretized for implementation of a real-time processor in the HILS. The pointing errors are about 0.2° in the numerical simulations and about 1° in the HILS simulations, and experimental simulations confirm the effectiveness of the control algorithm for attitude synchronization in a spacecraft formation flying mission. Consequently, experiments using the HILS in a real-time environment can appropriately perform spacecraft attitude synchronization algorithms for formation flying spacecraft.

  20. State-dependent anisotrophy--Comparison of quasi-analytical solutions with stochastic results for steady gravity drainage

    USGS Publications Warehouse

    Green, Timothy R.; Freyberg, David L.

    1995-01-01

    Anisotropy in large-scale unsaturated hydraulic conductivity of layered soils changes with the moisture state. Here, state-dependent anisotropy is computed under conditions of large-scale gravity drainage. Soils represented by Gardner's exponential function are perfectly stratified, periodic, and inclined. Analytical integration of Darcy’s law across each layer results in a system of nonlinear equations that is solved iteratively for capillary suction at layer interfaces and for the Darcy flux normal to layering. Computed fluxes and suction profiles are used to determine both upscaled hydraulic conductivity in the principal directions and the corresponding “state-dependent” anisotropy ratio as functions of the mean suction. Three groups of layered soils are analyzed and compared with independent predictions from the stochastic results of Yeh et al. (1985b). The small-perturbation approach predicts appropriate behaviors for anisotropy under nonarid conditions. However, the stochastic results are limited to moderate values of mean suction; this limitation is linked to a Taylor series approximation in terms of a group of statistical and geometric parameters. Two alternative forms of the Taylor series provide upper and lower bounds for the state-dependent anisotropy of relatively dry soils.

  1. State-dependent differential Riccati equation to track control of time-varying systems with state and control nonlinearities.

    PubMed

    Korayem, M H; Nekoo, S R

    2015-07-01

    This work studies an optimal control problem using the state-dependent Riccati equation (SDRE) in differential form to track for time-varying systems with state and control nonlinearities. The trajectory tracking structure provides two nonlinear differential equations: the state-dependent differential Riccati equation (SDDRE) and the feed-forward differential equation. The independence of the governing equations and stability of the controller are proven along the trajectory using the Lyapunov approach. Backward integration (BI) is capable of solving the equations as a numerical solution; however, the forward solution methods require the closed-form solution to fulfill the task. A closed-form solution is introduced for SDDRE, but the feed-forward differential equation has not yet been obtained. Different ways of solving the problem are expressed and analyzed. These include BI, closed-form solution with corrective assumption, approximate solution, and forward integration. Application of the tracking problem is investigated to control robotic manipulators possessing rigid or flexible joints. The intention is to release a general program for automatic implementation of an SDDRE controller for any manipulator that obeys the Denavit-Hartenberg (D-H) principle when only D-H parameters are received as input data.

  2. The Amyloid Precursor Protein—A Novel Player within the Molecular Array of Presynaptic Nanomachines

    PubMed Central

    Laßek, Melanie; Weingarten, Jens; Wegner, Martin; Volknandt, Walter

    2016-01-01

    More than 20 years ago the amyloid precursor protein (APP) was identified as the precursor protein of the Aβ peptide, the main component of senile plaques in brains affected by Alzheimer’s disease (AD). The pathophysiology of AD, characterized by a massive loss of synapses, cognitive decline, and behavioral changes was in principle attributed to the accumulation of Aβ. Within the last decades, much effort has gone into understanding the molecular basis of the progression of AD. However, little is known about the actual physiological function of APPs. Allocating APP to the proteome of the structurally and functionally dynamic presynaptic active zone (PAZ) highlights APP as a hitherto unknown player within the setting of the presynapse. The molecular array of presynaptic nanomachines comprising the life cycle of synaptic vesicles, exo- and endocytosis, cytoskeletal rearrangements, and mitochondrial activity provides a balance between structural and functional maintenance and diversity. The generation of genetically designed mouse models further deciphered APP as an essential player in synapse formation and plasticity. Deletion of APP causes an age-dependent phenotype: while younger mice revealed almost no physiological impairments, this condition was changed in the elderly mice. Interestingly, the proteomic composition of neurotransmitter release sites already revealed substantial changes at young age. These changes point to a network that incorporates APP into a cluster of nanomachines. Currently, the underlying mechanism of how APP acts within these machines is still elusive. Within the scope of this review, we shall construct a network of APP interaction partners within the PAZ. Furthermore, we intend to outline how deletion of APP affects this network during space and time leading to impairments in learning and memory. These alterations may provide a molecular link to the pathogenesis of AD and the physiological function of APP in the central nervous system

  3. Prophylactic versus Therapeutic Fingolimod: Restoration of Presynaptic Defects in Mice Suffering from Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Merega, Elisa; Di Prisco, Silvia; Padolecchia, Cristina; Grilli, Massimo; Milanese, Marco; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Bonanno, Giambattista; Marchi, Mario

    2017-01-01

    Fingolimod, the first oral, disease-modifying therapy for MS, has been recently proposed to modulate glutamate transmission in the central nervous system (CNS) of mice suffering from Experimental Autoimmune Encephalomyelitis (EAE) and in MS patients. Our study aims at investigating whether oral fingolimod recovers presynaptic defects that occur at different stages of disease in the CNS of EAE mice. In vivo prophylactic (0.3 mg/kg for 14 days, from the 7th day post immunization, d.p.i, the drug dissolved in the drinking water) fingolimod significantly reduced the clinical symptoms and the anxiety-related behaviour in EAE mice. Spinal cord inflammation, demyelination and glial cell activation are markers of EAE progression. These signs were ameliorated following oral fingolimod administration. Glutamate exocytosis was shown to be impaired in cortical and spinal cord terminals isolated from EAE mice at 21 ± 1 d.p.i., while GABA alteration emerged only at the spinal cord level. Prophylactic fingolimod recovered these presynaptic defects, restoring altered glutamate and GABA release efficiency. The beneficial effect occurred in a dose-dependent, region-specific manner, since lower (0.1–0.03 mg/kg) doses restored, although to a different extent, synaptic defects in cortical but not spinal cord terminals. A delayed reduction of glutamate, but not of GABA, exocytosis was observed in hippocampal terminals of EAE mice at 35 d.p.i. Therapeutic (0.3 mg/kg, from 21 d.p.i. for 14 days) fingolimod restored glutamate exocytosis in the cortex and in the hippocampus of EAE mice at 35 ± 1 d.p.i. but not in the spinal cord, where also GABAergic defects remained unmodified. These results improve our knowledge of the molecular events accounting for the beneficial effects elicited by fingolimod in demyelinating disorders. PMID:28125677

  4. Genetic Variation Within Adrenergic Pathways Determines In Vivo Effects of Presynaptic Stimulation in Humans

    PubMed Central

    Fung, Maple M.; Nguyen, Carie; Mehtani, Parag; Salem, Rany M.; Perez, Brandon; Thomas, Brenda; Das, Madhusudan; Schork, Nicholas J.; Mahata, Sushil K.; Ziegler, Michael G.; O’Connor, Daniel T.

    2009-01-01

    Background Catecholamines govern stress blood pressure responses. Catecholaminergic responses may be partially genetic and contribute to the complex heritability of hypertension. Methods and Results To evaluate catecholaminergic responses without systemic counterregulation, we infused graded concentrations of tyramine, an indirect presynaptic norepinephrine releaser, into dorsal hand veins of 49 normotensive men and women of 5 ethnicities. Vascular responses were coupled to common (minor allele frequency >10%) single-nucleotide polymorphisms at adrenergic target loci within presynaptic pathways. Significance was set at P<0.003 after Bonferroni correction. Generalized analysis of molecular variance (GAMOVA) was performed to determine whether genetic admixture contributed to results. Venoconstriction progressed to 47% with increasing concentrations of tyramine (0.129 to 25.8 mmol/L; P<0.001). Family history of hypertension (P<0.001) and female sex (P=0.02) predicted blunted tyramine responses. Two genetic loci significantly predicted vascular response: chromogranin B, which encodes a protein that catalyzes catecholamine vesicle formation (CHGB, exon 4, Glu348Glu; P=0.002), and cytochrome b-561 (CYB561, intron 1, C719G; P<0.001), an electron shuttle for catecholamine synthesis. Stepwise regression suggested important effects for the CHGB locus, with polymorphisms for the vacuolar-ATPase β-subunit (ATP6V1B1, exon 1, Ile30Thr) and flavin-containing monooxygenase-3 (FMO3, exon 3, Lys158Glu, P=0.002). GAMOVA did not show a significant relationship between overall genetic profile and hand-vein constriction (P=0.29), which indicates that population stratification did not contribute to this phenotype. Conclusions Locally infused tyramine produced dose-dependent pressor responses, predicted by family history of hypertension, sex, and genetic variants at loci, particularly CHGB, that encode the biosynthesis, storage, and metabolism of catecholamines. Such variants may

  5. Phosphorylation of synaptotagmin-1 controls a post-priming step in PKC-dependent presynaptic plasticity

    PubMed Central

    de Jong, Arthur P. H.; Meijer, Marieke; Saarloos, Ingrid; Cornelisse, Lennart Niels; Toonen, Ruud F. G.; Sørensen, Jakob B.; Verhage, Matthijs

    2016-01-01

    Presynaptic activation of the diacylglycerol (DAG)/protein kinase C (PKC) pathway is a central event in short-term synaptic plasticity. Two substrates, Munc13-1 and Munc18-1, are essential for DAG-induced potentiation of vesicle priming, but the role of most presynaptic PKC substrates is not understood. Here, we show that a mutation in synaptotagmin-1 (Syt1T112A), which prevents its PKC-dependent phosphorylation, abolishes DAG-induced potentiation of synaptic transmission in hippocampal neurons. This mutant also reduces potentiation of spontaneous release, but only if alternative Ca2+ sensors, Doc2A/B proteins, are absent. However, unlike mutations in Munc13-1 or Munc18-1 that prevent DAG-induced potentiation, the synaptotagmin-1 mutation does not affect paired-pulse facilitation. Furthermore, experiments to probe vesicle priming (recovery after train stimulation and dual application of hypertonic solutions) also reveal no abnormalities. Expression of synaptotagmin-2, which lacks a seven amino acid sequence that contains the phosphorylation site in synaptotagmin-1, or a synaptotagmin-1 variant with these seven residues removed (Syt1Δ109–116), supports normal DAG-induced potentiation. These data suggest that this seven residue sequence in synaptotagmin-1 situated in the linker between the transmembrane and C2A domains is inhibitory in the unphosphorylated state and becomes permissive of potentiation upon phosphorylation. We conclude that synaptotagmin-1 phosphorylation is an essential step in PKC-dependent potentiation of synaptic transmission, acting downstream of the two other essential DAG/PKC substrates, Munc13-1 and Munc18-1. PMID:27091977

  6. Phosphorylation of synaptotagmin-1 controls a post-priming step in PKC-dependent presynaptic plasticity.

    PubMed

    de Jong, Arthur P H; Meijer, Marieke; Saarloos, Ingrid; Cornelisse, Lennart Niels; Toonen, Ruud F G; Sørensen, Jakob B; Verhage, Matthijs

    2016-05-03

    Presynaptic activation of the diacylglycerol (DAG)/protein kinase C (PKC) pathway is a central event in short-term synaptic plasticity. Two substrates, Munc13-1 and Munc18-1, are essential for DAG-induced potentiation of vesicle priming, but the role of most presynaptic PKC substrates is not understood. Here, we show that a mutation in synaptotagmin-1 (Syt1(T112A)), which prevents its PKC-dependent phosphorylation, abolishes DAG-induced potentiation of synaptic transmission in hippocampal neurons. This mutant also reduces potentiation of spontaneous release, but only if alternative Ca(2+) sensors, Doc2A/B proteins, are absent. However, unlike mutations in Munc13-1 or Munc18-1 that prevent DAG-induced potentiation, the synaptotagmin-1 mutation does not affect paired-pulse facilitation. Furthermore, experiments to probe vesicle priming (recovery after train stimulation and dual application of hypertonic solutions) also reveal no abnormalities. Expression of synaptotagmin-2, which lacks a seven amino acid sequence that contains the phosphorylation site in synaptotagmin-1, or a synaptotagmin-1 variant with these seven residues removed (Syt1(Δ109-116)), supports normal DAG-induced potentiation. These data suggest that this seven residue sequence in synaptotagmin-1 situated in the linker between the transmembrane and C2A domains is inhibitory in the unphosphorylated state and becomes permissive of potentiation upon phosphorylation. We conclude that synaptotagmin-1 phosphorylation is an essential step in PKC-dependent potentiation of synaptic transmission, acting downstream of the two other essential DAG/PKC substrates, Munc13-1 and Munc18-1.

  7. Presynaptic depolarization of unmyelinated primary afferent fibers in the spinal cord of the cat.

    PubMed

    Calvillo, O; Madrid, J; Rudomín, P

    1982-06-01

    Low intensity (1-20 micro A) intraspinal stimulation produces in the sural nerve of the anesthetized cat short latency responses (3-4 ms) due to antidromic activation of fibers conducting in the A range (43-65 m/s). With higher stimulus intensities (up to 400 micro A) late responses (120-250 ms latency) may also be recorded. Simultaneous recording from two sites in the sural nerve shows that the peripheral processes of the fibers generating the late responses have a conduction velocity between 0.8-1.3 m/s. Collision between antidromic and orthodromic responses further indicates that these fibers have a peripheral threshold 20-25 times that of the A fibers. The late responses were largest when the intraspinal stimulating electrode was located in the dorsal horn, in the region corresponding to Laminae II and III of Rexed. The above observations suggest that the late responses are due to population responses of C fibers which are antidromically activated in the dorsal horn. The excitability of the C fiber terminals is increased by conditioning stimuli applied to other cutaneous afferents with a time course resembling that of the excitability increase of the A fibers on the same nerve. It is suggested that the effectiveness of synaptic transmission from C fibers to second order cells may be modulated presynaptically. In the decerebrate cat the antidromic responses of C fibers are reduced, but not abolished, by reversible spinalization produced by cooling or by sectioning the thoracic spinal cord. This suggests in addition that in the decerebrate preparation the presynaptic effectiveness of the C fiber (presumably nociceptive) input may be tonically decreased by supraspinal influences.

  8. Prophylactic versus Therapeutic Fingolimod: Restoration of Presynaptic Defects in Mice Suffering from Experimental Autoimmune Encephalomyelitis.

    PubMed

    Bonfiglio, Tommaso; Olivero, Guendalina; Merega, Elisa; Di Prisco, Silvia; Padolecchia, Cristina; Grilli, Massimo; Milanese, Marco; Di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Bonanno, Giambattista; Marchi, Mario; Pittaluga, Anna

    2017-01-01

    Fingolimod, the first oral, disease-modifying therapy for MS, has been recently proposed to modulate glutamate transmission in the central nervous system (CNS) of mice suffering from Experimental Autoimmune Encephalomyelitis (EAE) and in MS patients. Our study aims at investigating whether oral fingolimod recovers presynaptic defects that occur at different stages of disease in the CNS of EAE mice. In vivo prophylactic (0.3 mg/kg for 14 days, from the 7th day post immunization, d.p.i, the drug dissolved in the drinking water) fingolimod significantly reduced the clinical symptoms and the anxiety-related behaviour in EAE mice. Spinal cord inflammation, demyelination and glial cell activation are markers of EAE progression. These signs were ameliorated following oral fingolimod administration. Glutamate exocytosis was shown to be impaired in cortical and spinal cord terminals isolated from EAE mice at 21 ± 1 d.p.i., while GABA alteration emerged only at the spinal cord level. Prophylactic fingolimod recovered these presynaptic defects, restoring altered glutamate and GABA release efficiency. The beneficial effect occurred in a dose-dependent, region-specific manner, since lower (0.1-0.03 mg/kg) doses restored, although to a different extent, synaptic defects in cortical but not spinal cord terminals. A delayed reduction of glutamate, but not of GABA, exocytosis was observed in hippocampal terminals of EAE mice at 35 d.p.i. Therapeutic (0.3 mg/kg, from 21 d.p.i. for 14 days) fingolimod restored glutamate exocytosis in the cortex and in the hippocampus of EAE mice at 35 ± 1 d.p.i. but not in the spinal cord, where also GABAergic defects remained unmodified. These results improve our knowledge of the molecular events accounting for the beneficial effects elicited by fingolimod in demyelinating disorders.

  9. Pre-synaptic striatal dopaminergic function in people at high risk of psychosis

    PubMed Central

    Howes, Oliver D; Montgomery, Andrew J; Asselin, Marie-Claude; Murray, Robin M; Grasby, Paul M; McGuire, Philip K

    2013-01-01

    Background The dopamine hypothesis has been the major pathophysiological theory of psychosis in recent decades. Molecular imaging studies have provided in vivo evidence of increased dopamine synaptic availability and increased pre-synaptic dopamine synthesis in the striata of people with psychotic illnesses. These studies support the predictions of the dopamine hypothesis, but it remains to be determined whether dopaminergic abnormalities pre-date or are secondary to the development of psychosis. Method We selectively review the molecular imaging studies of the striatal dopaminergic system in psychosis and link this to models of psychosis and the functional sub-divisions of the striatum to make predictions for dopaminergic system in the prodromal phase of psychosis. Results A fairly consistent body of evidence indicates that pre-synaptic dopamine synthesis and synaptic dopamine availability is increased in the striata of people with psychotic illnesses. There may also be a small increase in striatal D2 dopamine receptor levels, although the evidence is less consistent. No studies to date have investigated striatal dopaminergic function longitudinally in people with psychosis or who are in the prodromal phase of psychosis. Evidence indicates that people with psychosis and at risk of psychosis show characteristic cognitive biases which support models of psychosis that link cognitive processes underlying appraisal to the development of delusions. Conclusions Current findings indicate an association between dopaminergic abnormalities and psychosis, which supports the dopamine hypothesis. However it is not possible to infer a causal relationship from these data. Studies of the dopaminergic system in the prodromal phase of psychosis and over the course of the developing psychotic illness are needed to determine whether dopaminergic abnormalities are secondary or primary, and whether dopaminergic abnormalities underlie the cognitive biases and impairments associated with

  10. Presynaptic GluN2D receptors detect glutamate spillover and regulate cerebellar GABA release

    PubMed Central

    Dubois, Christophe J.; Lachamp, Philippe M.; Sun, Lu; Mishina, Masayoshi

    2015-01-01

    Glutamate directly activates N-methyl-d-aspartate (NMDA) receptors on presynaptic inhibitory interneurons and enhances GABA release, altering the excitatory-inhibitory balance within a neuronal circuit. However, which class of NMDA receptors is involved in the detection of glutamate spillover is not known. GluN2D subunit-containing NMDA receptors are ideal candidates as they exhibit a high affinity for glutamate. We now show that cerebellar stellate cells express both GluN2B and GluN2D NMDA receptor subunits. Genetic deletion of GluN2D subunits prevented a physiologically relevant, stimulation-induced, lasting increase in GABA release from stellate cells [long-term potentiation of inhibitory transmission (I-LTP)]. NMDA receptors are tetramers composed of two GluN1 subunits associated to either two identical subunits (di-heteromeric receptors) or to two different subunits (tri-heteromeric receptors). To determine whether tri-heteromeric GluN2B/2D NMDA receptors mediate I-LTP, we tested the prediction that deletion of GluN2D converts tri-heteromeric GluN2B/2D to di-heteromeric GluN2B NMDA receptors. We find that prolonged stimulation rescued I-LTP in GluN2D knockout mice, and this was abolished by GluN2B receptor blockers that failed to prevent I-LTP in wild-type mice. Therefore, NMDA receptors that contain both GluN2D and GluN2B mediate the induction of I-LTP. Because these receptors are not present in the soma and dendrites, presynaptic tri-heteromeric GluN2B/2D NMDA receptors in inhibitory interneurons are likely to mediate the cross talk between excitatory and inhibitory transmission. PMID:26510761

  11. Palmitoylethanolamide inhibits glutamate release in rat cerebrocortical nerve terminals.

    PubMed

    Lin, Tzu-Yu; Lu, Cheng-Wei; Wu, Chia-Chan; Huang, Shu-Kuei; Wang, Su-Jane

    2015-03-11

    The effect of palmitoylethanolamide (PEA), an endogenous fatty acid amide displaying neuroprotective actions, on glutamate release from rat cerebrocortical nerve terminals (synaptosomes) was investigated. PEA inhibited the Ca²⁺-dependent release of glutamate, which was triggered by exposing synaptosomes to the potassium channel blocker 4-aminopyridine. This release inhibition was concentration dependent, associated with a reduction in cytosolic Ca²⁺ concentration, and not due to a change in synaptosomal membrane potential. The glutamate release-inhibiting effect of PEA was prevented by the Ca(v)2.1 (P/Q-type) channel blocker ω-agatoxin IVA or the protein kinase A inhibitor H89, not affected by the intracellular Ca²⁺ release inhibitors dantrolene and CGP37157, and partially antagonized by the cannabinoid CB1 receptor antagonist AM281. Based on these results, we suggest that PEA exerts its presynaptic inhibition, likely through a reduction in the Ca²⁺ influx mediated by Ca(v)2.1 (P/Q-type) channels, thereby inhibiting the release of glutamate from rat cortical nerve terminals. This release inhibition might be linked to the activation of presynaptic cannabinoid CB1 receptors and the suppression of the protein kinase A pathway.

  12. Hindered submicron mobility and long-term storage of presynaptic dense-core granules revealed by single-particle tracking.

    PubMed

    Scalettar, B A; Jacobs, C; Fulwiler, A; Prahl, L; Simon, A; Hilken, L; Lochner, J E

    2012-09-01

    Dense-core granules (DCGs) are organelles found in neuroendocrine cells and neurons that house, transport, and release a number of important peptides and proteins. In neurons, DCG cargo can include the secreted neuromodulatory proteins tissue plasminogen activator (tPA) and/or brain-derived neurotrophic factor (BDNF), which play a key role in modulating synaptic efficacy in the hippocampus. This function has spurred interest in DCGs that localize to synaptic contacts between hippocampal neurons, and several studies recently have established that DCGs localize to, and undergo regulated exocytosis from, postsynaptic sites. To complement this work, we have studied presynaptically localized DCGs in hippocampal neurons, which are much more poorly understood than their postsynaptic analogs. Moreover, to enhance relevance, we visualized DCGs via fluorescence labeling of exogenous and endogenous tPA and BDNF. Using single-particle tracking, we determined trajectories of more than 150 presynaptically localized DCGs. These trajectories reveal that mobility of DCGs in presynaptic boutons is highly hindered and that storage is long-lived. We also computed mean-squared displacement curves, which can be used to elucidate mechanisms of transport. Over shorter time windows, most curves are linear, demonstrating that DCG transport in boutons is driven predominantly by diffusion. The remaining curves plateau with time, consistent with motion constrained by a submicron-sized corral. These results have relevance to recent models of presynaptic organization and to recent hypotheses about DCG cargo function. The results also provide estimates for transit times to the presynaptic plasma membrane that are consistent with measured times for onset of neurotrophin release from synaptically localized DCGs.

  13. Wnt-7a induces presynaptic colocalization of alpha 7-nicotinic acetylcholine receptors and adenomatous polyposis coli in hippocampal neurons.

    PubMed

    Farías, Ginny G; Vallés, Ana S; Colombres, Marcela; Godoy, Juan A; Toledo, Enrique M; Lukas, Ronald J; Barrantes, Francisco J; Inestrosa, Nibaldo C

    2007-05-16

    Nicotinic acetylcholine receptors (nAChRs) contribute significantly to hippocampal function. Alpha7-nAChRs are present in presynaptic sites in hippocampal neurons and may influence transmitter release, but the factors that determine their presynaptic localization are unknown. We report here that Wnt-7a, a ligand active in the canonical Wnt signaling pathway, induces dissociation of the adenomatous polyposis coli (APC) protein from the beta-catenin cytoplasmic complex and the interaction of APC with alpha7-nAChRs in hippocampal neurons. Interestingly, Wnt-7a induces the relocalization of APC to membranes, clustering of APC in neurites, and coclustering of APC with different, presynaptic protein markers. Wnt-7a also increases the number and size of coclusters of alpha7-nAChRs and APC in presynaptic terminals. These short-term changes in alpha7-nAChRs occur in the few minutes after ligand exposure and involve translocation to the plasma membrane without affecting total receptor levels. Longer-term exposure to Wnt-7a increases nAChR alpha7 subunit levels in an APC-independent manner and increases clusters of alpha7-nAChRs in neurites via an APC-dependent process. Together, these results demonstrate that stimulation through the canonical Wnt pathway regulates the presynaptic localization of APC and alpha7-nAChRs with APC serving as an intermediary in the alpha7-nAChR relocalization process. Modulation by Wnt signaling may be essential for alpha7-nAChR expression and function in synapses.

  14. Presynaptic Ca2+ influx and vesicle exocytosis at the mouse endbulb of Held: a comparison of two auditory nerve terminals

    PubMed Central

    Lin, Kun-Han; Oleskevich, Sharon; Taschenberger, Holger

    2011-01-01

    Abstract The functional properties of mammalian presynaptic nerve endings remain elusive since most terminals of the central nervous system are not accessible to direct electrophysiological recordings. In this study, direct recordings were performed for the first time at endbulb of Held terminals to characterize passive membrane properties, voltage-gated Ca2+ channels (VGCCs) and Ca2+-dependent exocytosis. Endbulb of Held terminals arise from endings of auditory nerve fibres contacting spherical bushy cells (SBCs) in the anterior ventral cochlear nucleus (AVCN). These terminals had a high mean input resistance (1.1 GΩ) and a small mean capacitance (4.3 pF). Presynaptic VGCCs were predominantly of the P/Q type (86%) and expressed at a high density with an estimated average number of 6400 channels per terminal. Presynaptic Ca2+ currents (ICa(V)) activated and deactivated rapidly. Simulations of action potential (AP)-driven gating of VGCCs suggests that endbulb APs trigger brief Ca2+ influx with a mean half-width of 240 μs and a peak amplitude of 0.45 nA which results from the opening of approximately 2600 channels. Unlike Ca2+ currents at the calyx of Held, ICa(V) of endbulb terminals showed no inactivation during trains of AP-like presynaptic depolarizations. Endbulb terminals are endowed with a large readily releasable vesicle pool (1064 vesicles) of which only a small fraction (<10%) is consumed during a single AP-like stimulus. Fast presynaptic APs together with rapidly gating VGCCs will generate brief intracellular Ca2+ transients that favour highly synchronous transmitter release. Collectively these characteristics ensure sustained and precise transmission of timing information from auditory stimuli at the endbulb→SBC synapse. PMID:21746778

  15. Super-Resolution Microscopy Reveals Presynaptic Localization of the ALS/FTD Related Protein FUS in Hippocampal Neurons

    PubMed Central

    Schoen, Michael; Reichel, Jochen M.; Demestre, Maria; Putz, Stefan; Deshpande, Dhruva; Proepper, Christian; Liebau, Stefan; Schmeisser, Michael J.; Ludolph, Albert C.; Michaelis, Jens; Boeckers, Tobias M.

    2016-01-01

    Fused in Sarcoma (FUS) is a multifunctional RNA-/DNA-binding protein, which is involved in the pathogenesis of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A common hallmark of these disorders is the abnormal accumulation of mutated FUS protein in the cytoplasm. Under normal conditions FUS is confined to the nuclear compartment, in neurons, however, additional somatodendritic localization can be observed. In this study, we carefully analyzed the subcellular localization of endogenous FUS at synaptic sites of hippocampal neurons which are among the most affected cell types in FTD with FUS pathology. We could confirm a strong nuclear localization of FUS as well as its prominent and widespread neuronal expression throughout the adult and developing rat brain, particularly in the hippocampus, the cerebellum and the outer layers of the cortex. Intriguingly, FUS was also consistently observed at synaptic sites as detected by neuronal subcellular fractionation as well as by immunolabeling. To define a pre- and/or postsynaptic localization of FUS, we employed super-resolution fluorescence localization microscopy. FUS was found to be localized within the axon terminal in close proximity to the presynaptic vesicle protein Synaptophysin1 and adjacent to the active zone protein Bassoon, but well separated from the postsynaptic protein PSD-95. Having shown the presynaptic localization of FUS in the nervous system, a novel extranuclear role of FUS at neuronal contact sites has to be considered. Since there is growing evidence that local presynaptic translation might also be an important mechanism for plasticity, FUS – like the fragile X mental retardation protein FMRP – might act as one of the presynaptic RNA-binding proteins regulating this machinery. Our observation of presynaptic FUS should foster further investigations to determine its role in neurodegenerative diseases such as ALS and FTD. PMID:26834559

  16. Acetylcholine Facilitates a Depolarization-Induced Enhancement of Inhibition in Rat CA1 Pyramidal Neurons.

    PubMed

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

    2017-01-01

    Cholinergic mechanisms in the hippocampus regulate forms of synaptic plasticity linked with cognition and spatial navigation, but the underlying mechanisms remain largely unknown. Here, in rat hippocampal CA1 pyramidal cells under blockade of ionotropic glutamate receptors, we report that a single acetylcholine pulse and repeated depolarization activated a robust and enduring postsynaptic depolarization-induced enhancement of inhibition (DEI) that masked a presynaptic depolarization-induced suppression of inhibition (DSI). Increased cytosolic Ca2+ and M1-muscarinic receptor activation caused the rise in voltage-sensitive α5βγ2-containing γ-aminobutyric acid type-A receptors that generated DEI. In summary, this muscarinic-mediated activity-dependent plasticity rapidly transfers depolarization effects on inhibition from presynaptic suppression or DSI to postsynaptic enhancement or DEI, a change potentially relevant in behavior.

  17. Neural mechanisms