scholarly journals Kainate Acts at Presynaptic Receptors to Increase GABA Release From Hypothalamic Neurons

1999 ◽  
Vol 82 (2) ◽  
pp. 1059-1062 ◽  
Author(s):  
Qing-Song Liu ◽  
Peter R. Patrylo ◽  
Xiao-Bing Gao ◽  
Anthony N. van den Pol
Keyword(s):  
Transmitter Release ◽  
Hippocampal Neurons ◽  
Gaba Release ◽  
Presynaptic Receptors ◽  
Inhibitory Neurons ◽  
Kainate Receptors ◽  
Nmda Receptor Antagonists ◽  
Presynaptic Site ◽  
Site Of Action ◽  
Inhibitory Transmitter

Recent reports suggest that kainate acting at presynaptic receptors reduces the release of the inhibitory transmitter GABA from hippocampal neurons. In contrast, in the hypothalamus in the presence of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor antagonists [1-(4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) and d,l-2-amino-5-phosphonopentanoic acid (AP5)], kainate increased GABA release. In the presence of tetrodotoxin, the frequency, but not the amplitude, of GABA-mediated miniature inhibitory postsynaptic currents (IPSCs) was enhanced by kainate, consistent with a presynaptic site of action. Postsynaptic activation of kainate receptors on cell bodies/dendrites was also found. In contrast to the hippocampus where kainate increases excitability by reducing GABA release, in the hypothalamus where a much higher number of GABAergic cells exist, kainate-mediated activation of transmitter release from inhibitory neurons may reduce the level of neuronal activity in the postsynaptic cell.

scholarly journals Desensitization-resistant and -sensitive GPCR-mediated inhibition of GABA release occurs by Ca2+-dependent and -independent mechanisms at a hypothalamic synapse

2016 ◽  
Vol 115 (5) ◽  
pp. 2376-2388 ◽  
Author(s):  
Reagan L. Pennock ◽  
Shane T. Hentges
Keyword(s):  
G Protein ◽  
Opioid Receptors ◽  
Transmitter Release ◽  
Presynaptic Inhibition ◽  
Calcium Influx ◽  
Gaba Release ◽  
Presynaptic Receptors ◽  
Postsynaptic Currents ◽  
Independent Mechanism ◽  
Μ Opioid Receptors

Whereas the activation of Gαi/o-coupled receptors commonly results in postsynaptic responses that show acute desensitization, the presynaptic inhibition of transmitter release caused by many Gαi/o-coupled receptors is maintained during agonist exposure. However, an exception has been noted where GABAB receptor (GABABR)-mediated inhibition of inhibitory postsynaptic currents (IPSCs) recorded in mouse proopiomelanocortin (POMC) neurons exhibit acute desensitization in ∼25% of experiments. To determine whether differential effector coupling confers sensitivity to desensitization, voltage-clamp recordings were made from POMC neurons to compare the mechanism by which μ-opioid receptors (MORs) and GABABRs inhibit transmitter release. Neither MOR- nor GABABR-mediated inhibition of release relied on the activation of presynaptic K+ channels. Both receptors maintained the ability to inhibit release in the absence of external Ca2+ or in the presence of ionomycin-induced Ca2+ influx, indicating that inhibition of release can occur through a Ca2+-independent mechanism. Replacing Ca2+ with Sr2+ to disrupt G-protein-mediated inhibition of release occurring directly at the release machinery did not alter MOR- or GABAB -mediated inhibition of IPSCs, suggesting that reductions in evoked release can occur through the inhibition of Ca2+ channels. Additionally, both receptors inhibited evoked IPSCs in the presence of selective blockers of N- or P/Q-type Ca2+ channels. Altogether, the results show that MORs and GABABRs can inhibit transmitter release through the inhibition of calcium influx and by direct actions at the release machinery. Furthermore, since both the desensitizing and nondesensitizing presynaptic receptors are similarly coupled, differential effector coupling is unlikely responsible for differential desensitization of the inhibition of release.

Physiological Properties of Late Inspiratory Neurons and Their Possible Involvement in Inspiratory Off-Switching in Cats

2002 ◽  
Vol 87 (2) ◽  
pp. 1057-1067 ◽  
Author(s):  
Akira Haji ◽  
Mari Okazaki ◽  
Hiromi Yamazaki ◽  
Ryuji Takeda
Keyword(s):  
Nmda Receptors ◽  
Gaba Release ◽  
Membrane Depolarization ◽  
Inhibitory Neurons ◽  
Acid Decarboxylase ◽  
Postsynaptic Potentials ◽  
Inspiratory Neurons ◽  
Small Constant ◽  
Physiological Properties ◽  
Decerebrate Cats

To assess the functional significance of late inspiratory (late-I) neurons in inspiratory off-switching (IOS), membrane potential and discharge properties were examined in vagotomized, decerebrate cats. During spontaneous IOS, late-I neurons displayed large membrane depolarization and associated discharge of action potentials that started in late inspiration, peaked at the end of inspiration, and ended during postinspiration. Depolarization was decreased by iontophoresis of dizocilpine and eliminated by tetrodotoxin. Stimulation of the vagus nerve or the nucleus parabrachialis medialis (NPBM) also evoked depolarization of late-I neurons and IOS. Waves of spontaneous chloride-dependent inhibitory postsynaptic potentials (IPSPs) preceded membrane depolarization during early inspiration and followed during postinspiration and stage 2 expiration of the respiratory cycle. Iontophoresed bicuculline depressed the IPSPs. Intravenous dizocilpine caused a greatly prolonged inspiratory discharge of the phrenic nerve (apneusis) and suppressed late-inspiratory depolarization as well as early-inspiratory IPSPs, resulting in a small constant depolarization throughout the apneusis. NPBM or vagal stimulation after dizocilpine produced small, stimulus-locked excitatory postsynaptic potentials (EPSPs) in late-I neurons. Neurobiotin-labeled late-I neurons revealed immunoreactivity for glutamic acid decarboxylase as well as N-methyl-d-aspartate (NMDA) receptors. These results suggest that late-I neurons are GABAergic inhibitory neurons, while the effects of bicuculline and dizocilpine indicate that they receive periodic waves of GABAergic IPSPs and glutamatergic EPSPs. The data lead to the conclusion that late-I neurons play an important inhibitory role in IOS. NMDA receptors are assumed to augment and/or synchronize late-inspiratory depolarization and discharge of late-I neurons, leading to GABA release and consequently off-switching of bulbar inspiratory neurons and phrenic motoneurons.

Influence of presynaptic receptors on neuromuscular transmission in rat

1982 ◽  
Vol 242 (5) ◽  
pp. C366-C372 ◽  
Author(s):  
D. F. Wilson
Keyword(s):  
Transmitter Release ◽  
Action Potentials ◽  
Physiological Function ◽  
Motor Nerve ◽  
Presynaptic Receptors ◽  
End Plate ◽  
Feedback Pathway ◽  
Partial Blockade ◽  
Ach Receptors

The presence and physiological significance of acetylcholine (ACh) receptors on motor nerve terminals was examined at the rat diaphragm neuromuscular junction. Intracellular recording techniques were used to monitor end-plate potentials (EPP), miniature end-plate potentials (MEPP), and resting potentials of the muscle fibers. Muscle action potentials were blocked by the cut-muscle technique. Quantal release was determined by the ratio EPP/MEPP, after correcting for nonlinear summation. Blockade of acetylcholinesterase with eserine and neostigmine was tested to determine the influence of residual ACh on transmitter release. Partial blockade of ACh receptors with curare was examined to further clarify the role of these presynaptic receptors. The experiments demonstrate that residual ACh inhibits transmitter release and that blockade of ACh receptors enhances transmitter release. It is concluded that presynaptic ACh receptors exist and that they serve an important physiological function. It is suggested that the presynaptic ACh receptors normally serve to limit transmitter release in a negative feedback pathway.

Dynamics of Excitatory Transmitter Release: Analysis of Synaptic Responses in CA3 Hippocampal Neurons After Repetitive Stimulation of Afferent Fibers

1998 ◽  
Vol 79 (4) ◽  
pp. 1977-1988 ◽  
Author(s):  
Marco Canepari ◽  
Enrico Cherubini
Keyword(s):  
Transmitter Release ◽  
Hippocampal Neurons ◽  
Repetitive Stimulation ◽  
Patch Clamp Technique ◽  
Afferent Fibers ◽  
Presynaptic Mechanisms ◽  
Release Analysis ◽  
Excitatory Transmitter ◽  
Stimulation Of ◽  
Synaptic Responses

Canepari, Marco and Enrico Cherubini. Dynamics of excitatory transmitter release: analysis of synaptic responses in CA3 hippocampal neurons after repetitive stimulation of afferent fibers. J. Neurophysiol. 79: 1977–1988, 1998. The patch-clamp technique (whole cell configuration) was used to record excitatory postsynaptic currents (EPSCs) evoked by repetitive stimulation (4 pulses at 50-ms intervals) of afferent fibers in the stratum lucidum-radiatum. Different synaptic behaviors (EPSC patterns) were classified in terms of facilitation or depression of the mean amplitude of the second, third, and fourth EPSC with respect to the previous one. A large variety of EPSC patterns was observed by stimulating different afferent fibers. Experiments with the mGluR2/mGluR3 agonist 2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) (1 μM), a compound that reduces release at mossy but not at associative commissural fibers and therefore allows to identify the origin of synaptic responses, showed that particular EPSC patterns could not be associated to the activation of a specific type of synaptic input. To investigate the role of the probability of release in the dynamics of synaptic activity, the extracellular calcium concentration was varied from 0.8 to 4 mM in several experiments. EPSC patterns dominated by depression, characteristics of high release probability conditions, could be observed in the majority of the cases in the presence of higher calcium concentrations. A quantitative model for dynamics of transmitter release has been developed. Experimental results were compared with data computed with the model taking into account the probability of release and the time course of reavailability. This work indicates that short-term changes of presynaptic conditions occurring during a train of action potentials can account for the high variability of EPSC responses. The model that is proposed also suggests a general method of experimental data analysis to investigate the possible presynaptic mechanisms underlying long-lasting changes in synaptic efficacy.

Calcium From Internal Stores Triggers GABA Release From Retinal Amacrine Cells

2005 ◽  
Vol 94 (6) ◽  
pp. 4196-4208 ◽  
Author(s):  
Ajithkumar Warrier ◽  
Salvador Borges ◽  
David Dalcino ◽  
Cameron Walters ◽  
Martin Wilson
Keyword(s):  
Transmitter Release ◽  
Metabotropic Glutamate Receptor ◽  
Amacrine Cell ◽  
Ryanodine Receptors ◽  
Amacrine Cells ◽  
Gaba Release ◽  
Voltage Gated ◽  
Metabotropic Glutamate ◽  
Inositol 1,4,5 Trisphosphate ◽  
Evoked Transmitter Release

The Ca2+ that promotes transmitter release is generally thought to enter presynaptic terminals through voltage-gated Ca2+channels. Using electrophysiology and Ca2+ imaging, we show that, in amacrine cell dendrites, at least some of the Ca2+ that triggers transmitter release comes from endoplasmic reticulum Ca2+ stores. We show that both inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) are present in these dendrites and both participate in the elevation of cytoplasmic [Ca2+] during the brief depolarization of a dendrite. Only the Ca2+ released through IP3Rs, however, seems to promote the release of transmitter. Antagonists for the IP3R reduced transmitter release, whereas RyR blockers had no effect. Application of an agonist for metabotropic glutamate receptor, known to liberate Ca2+ from internal stores, enhanced both spontaneous and evoked transmitter release.

scholarly journals Paradoxical Anti-Epileptic Effects of a GluR5 Agonist of Kainate Receptors

2002 ◽  
Vol 88 (1) ◽  
pp. 523-527 ◽  
Author(s):  
Ilgam Khalilov ◽  
June Hirsch ◽  
Rosa Cossart ◽  
Yehezkel Ben-Ari
Keyword(s):  
Propionic Acid ◽  
Therapeutic Approach ◽  
Hippocampal Neurons ◽  
Selective Excitation ◽  
Kainate Receptors ◽  
Kainate Receptor ◽  
Tert Butyl ◽  
Principal Cells ◽  
Selective Agonist

Kainate generates in adult hippocampal neurons a seizure but also a massive excitation of interneurons and a dramatic increase of the inhibitory drive that impinges on principal cells. This “overinhibition” is largely mediated by GluR5-containing kainate receptors that are enriched on interneurons. Here, using the neonatal intact hippocampus in vitro and the triple chamber, we first show that this mechanism is fully operative in neonatal neurons. We then report that application to one hippocampus of ( RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid—a relatively selective agonist of GluR5 containing kainate receptors—depresses the propagation of seizure generated in the opposite hippocampus by a convulsive agent. We conclude that the selective excitation of interneurons by GluR5-containing kainate receptor agonists opens a new therapeutic approach for the epilepsies.

scholarly journals 5-HT1B Receptor-Mediated Presynaptic Inhibition of GABA Release in the Suprachiasmatic Nucleus

2005 ◽  
Vol 93 (6) ◽  
pp. 3157-3164 ◽  
Author(s):  
Jayne R. Bramley ◽  
Patricia J. Sollars ◽  
Gary E. Pickard ◽  
F. Edward Dudek
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Receptor Agonist ◽  
Gaba Release ◽  
Presynaptic Receptors ◽  
Clear Effect ◽  
Whole Cell Patch Clamp ◽  
Bath Application ◽  
Hypothalamic Slices ◽  
Photic Input ◽  
Serotonergic Innervation

The suprachiasmatic nucleus (SCN) receives a dense serotonergic innervation that modulates photic input to the SCN via serotonin 1B (5-HT1B) presynaptic receptors on retinal glutamatergic terminals. However, the majority of 5-HT1B binding sites in the SCN are located on nonretinal terminals and most axonal terminals in the SCN are GABAergic. We therefore tested the hypothesis that 5-HT1B receptors might also be located on SCN GABAergic terminals by examining the effects of the highly selective 5-HT1B receptor agonist CP-93,129 on SCN miniature inhibitory postsynaptic currents (mIPSCs). Whole cell patch-clamp recordings of mIPSCs were obtained from rat and mouse SCN neurons in hypothalamic slices. Using CsCl-containing microelectrodes with QX314, we isolated mPSCs that were sensitive to the GABAA receptor antagonist, bicuculline. Bath application of CP-93,129 (1 μM) decreased the frequency of mIPSCs by an average of 22% ( n = 7) in rat SCN neurons and by an average of 30% ( n = 8) in mouse SCN neurons with no clear effect on mIPSC amplitude. In mice lacking functional 5-HT1B receptors, CP-93,129 (1 μM) had no clear effect on the frequency or the amplitude of mIPSCs recorded in any of the cells tested ( n = 4). The decrease in the frequency of mIPSCs of SCN neurons produced by the selective 5-HT1B receptor agonist CP-93,129 is consistent with the interpretation that 5-HT1B receptors are located on GABA terminals in the SCN and that 5-HT inhibits GABA release via a 5-HT1B presynaptic receptor-mediated mechanism.

scholarly journals Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yuki Matsushita ◽  
Yasunari Sakai ◽  
Mitsunori Shimmura ◽  
Hiroshi Shigeto ◽  
Miki Nishio ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Focal Cortical Dysplasia ◽  
Mossy Fibers ◽  
Premature Death ◽  
Mtor Pathway ◽  
Conditional Knockout ◽  
Inhibitory Neurons ◽  
Sequencing Data ◽  
Functional Roles ◽  
Synaptic Markers

Abstract Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8–10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6–8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain.

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