Journal articles on the topic 'GABAergic transmissioni'
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Liu, Tao, Tsugumi Fujita, and Eiichi Kumamoto. "Acetylcholine and norepinephrine mediate GABAergic but not glycinergic transmission enhancement by melittin in adult rat substantia gelatinosa neurons." Journal of Neurophysiology 106, no. 1 (July 2011): 233–46. http://dx.doi.org/10.1152/jn.00838.2010.
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GABAergic and glycinergic inhibitory synaptic transmissions in substantia gelatinosa (SG; lamina II of Rexed) neurons of the spinal dorsal horn play an important role in regulating nociceptive transmission from the periphery. It has not yet been well known whether each of the inhibitory transmissions plays a distinct role in the regulation. We report an involvement of neurotransmitters in GABAergic but not glycinergic transmission enhancement produced by the PLA2 activator melittin, where the whole-cell patch-clamp technique is applied to the SG neurons of adult rat spinal cord slices. Glycinergic but not GABAergic spontaneous inhibitory postsynaptic current (sIPSC) was increased in frequency and amplitude by melittin in the presence of nicotinic, muscarinic acetylcholine, and α1-adrenergic receptor antagonists (mecamylamine, atropine, and WB-4101, respectively). GABAergic transmission enhancement produced by melittin was unaffected by the 5-hydroxytryptamine 3 receptor and P2X receptor antagonists (ICS-205,930 and pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid, respectively). Nicotinic and muscarinic acetylcholine receptor agonists [(−)-nicotine and carbamoylcholine, respectively] and norepinephrine, as well as melittin, increased GABAergic sIPSC frequency and amplitude. A repeated application of (−)-nicotine, carbamoylcholine, and norepinephrine, but not melittin, at an interval of 30 min produced a similar transmission enhancement. These results indicate that melittin produces the release of acetylcholine and norepinephrine, which activate (nicotinic and muscarinic) acetylcholine and α1-adrenergic receptors, respectively, resulting in GABAergic but not glycinergic transmission enhancement in SG neurons. The desensitization of a system leading to the acetylcholine and norepinephrine release is slow in recovery. This distinction in modulation between GABAergic and glycinergic transmissions may play a role in regulating nociceptive transmission.
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Zhu, Ping Jun, and Vincent A. Chiappinelli. "Nicotine Modulates Evoked GABAergic Transmission in the Brain." Journal of Neurophysiology 82, no. 6 (December 1, 1999): 3041–45. http://dx.doi.org/10.1152/jn.1999.82.6.3041.
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The effects of nicotine on evoked GABAergic synaptic transmission were examined using whole cell recordings from neurons of the lateral spiriform nucleus in embryonic chick brain slices. All synaptic activities were abolished by the GABAA receptor antagonist, bicuculline (20 μM). Under voltage-clamp with KCl-filled pipettes (holding potential −70 mV), nicotine (0.1–1.0 μM) increased the frequency of spontaneous GABAergic currents in a dose-dependent manner. Nicotine enhanced electrically evoked GABAergic transmission only at relatively low concentrations of 50–100 nM (but not 25 nM), which approximate the concentrations of nicotine in the blood produced by cigarette smoking. At higher concentrations nicotine had either no effect (0.25 μM) or diminished (0.5–1.0 μM) evoked GABAergic neurotransmission. Nicotine had no significant effect on the postsynaptic current induced by exogenous GABA (30–50 μM). These data imply that nicotine levels attained in smokers are sufficient to enhance evoked GABAergic transmission in the brain, and that this effect is most likely mediated through activation of presynaptic nicotinic receptors.
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Donato, Roberta, and Andrea Nistri. "Relative Contribution by GABA or Glycine to Cl−-Mediated Synaptic Transmission on Rat Hypoglossal Motoneurons In Vitro." Journal of Neurophysiology 84, no. 6 (December 1, 2000): 2715–24. http://dx.doi.org/10.1152/jn.2000.84.6.2715.
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The relative contribution by GABA and glycine to synaptic transmission of motoneurons was investigated using an hypoglossus nucleus slice preparation from neonatal rats. Spontaneous, miniature, or electrically evoked postsynaptic currents (sPSCs, mPSCs, ePSCs, respectively) mediated by glycine or GABA were recorded under whole cell voltage clamp after blocking excitatory glutamatergic transmission with kynurenic acid. The overall majority of Cl−-mediated sPSCs was glycinergic, while only one-third was GABAergic; 70 ± 10% of mPSCs were glycinergic while 22 ± 8% were GABAergic. Tetrodotoxin (TTX) application dramatically reduced the frequency (and slightly the amplitude) of GABAergic events without changing frequency or amplitude of glycinergic sPSCs. These results indicate that, unlike spontaneous GABAergic transmission, glycine-mediated neurotransmission was essentially independent of network activity. There was a consistent difference in the kinetics of GABAergic and glycinergic responses as GABAergic events had significantly slower rise and decay times than glycinergic ones. Such a difference was always present whenever sPSCs, mPSCs, or ePSCs were measured. Finally, GABAergic and glycinergic mPSCs were differentially modulated by activation of glutamate metabotropic receptors (mGluRs), which are abundant in the hypoglossus nucleus. In fact, the broad-spectrum mGluR agonist (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid (50 μM), which in control solution increased the frequency of both GABAergic and glycinergic sPSCs, enhanced the frequency of glycinergic mPSCs only. These results indicate that on brain stem motoneurons, Cl−-mediated synaptic transmission is mainly due to glycine rather than GABA and that GABAergic and glycinergic events differ in terms of kinetics and pharmacological sensitivity to mGluR activation or TTX.
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Rao, G. Prasad. "Anxiety Disorders and Gabaergic Transmission." Indian Journal of Psychological Medicine 28, no. 1 (January 2006): 5–6. http://dx.doi.org/10.1177/0975156420060101.
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Sergeeva, Olga A. "GABAergic transmission in hepatic encephalopathy." Archives of Biochemistry and Biophysics 536, no. 2 (August 2013): 122–30. http://dx.doi.org/10.1016/j.abb.2013.04.005.
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Gafurov, Boris, and Suzanne B. Bausch. "GABAergic transmission facilitates ictogenesis and synchrony between CA3, hilus, and dentate gyrus in slices from epileptic rats." Journal of Neurophysiology 110, no. 2 (July 15, 2013): 441–55. http://dx.doi.org/10.1152/jn.00679.2012.
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The impact of regional hippocampal interactions and GABAergic transmission on ictogenesis remain unclear. Cortico-hippocampal slices from pilocarpine-treated epileptic rats were compared with controls to investigate associations between seizurelike events (SLE), GABAergic transmission, and neuronal synchrony within and between cortico-hippocampal regions. Multielectrode array recordings revealed more prevalent hippocampal SLE in epileptic tissue when excitatory transmission was enhanced and GABAergic transmission was intact [removal of Mg2+ (0Mg)] than when GABAergic transmission was blocked [removal of Mg2+ + bicuculline methiodide (0Mg+BMI)]. When activity within individual regions was analyzed, spectral and temporal slow oscillation/SLE correlations and cross-correlations were highest within the hilus of epileptic tissue during SLE but were similar in 0Mg and 0Mg+BMI. GABAergic facilitation of spectral “slow” oscillation and ripple correlations was most prominent within CA3 of epileptic tissue during SLE. When activity between regions was analyzed, slow oscillation and ripple coherence was highest between the hilus and dentate gyrus as well as between the hilus and CA3 of epileptic tissue during SLE and was significantly higher in 0Mg than 0Mg+BMI. High 0Mg-induced SLE cross-correlations between the hilus and dentate gyrus as well as between the hilus and CA3 were reduced or abolished in 0Mg+BMI. SLE cross-correlation lag measurements provided evidence for a monosynaptic connection from the hilus to the dentate gyrus during SLE. Findings implicate the hilus as an oscillation generator, whose impact on other cortico-hippocampal regions is mediated by GABAergic transmission. Data also suggest that GABAA receptor-mediated transmission facilitates back-propagation from CA3/hilus to the dentate gyrus and that this back-propagation augments SLE in epileptic hippocampus.
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Schubert, Timm, Daniel Kerschensteiner, Erika D. Eggers, Thomas Misgeld, Martin Kerschensteiner, Jeff W. Lichtman, Peter D. Lukasiewicz, and Rachel O. L. Wong. "Development of Presynaptic Inhibition Onto Retinal Bipolar Cell Axon Terminals Is Subclass-Specific." Journal of Neurophysiology 100, no. 1 (July 2008): 304–16. http://dx.doi.org/10.1152/jn.90202.2008.
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Synaptic integration is modulated by inhibition onto the dendrites of postsynaptic cells. However, presynaptic inhibition at axonal terminals also plays a critical role in the regulation of neurotransmission. In contrast to the development of inhibitory synapses onto dendrites, GABAergic/glycinergic synaptogenesis onto axon terminals has not been widely studied. Because retinal bipolar cells receive subclass-specific patterns of GABAergic and glycinergic presynaptic inhibition, they are a good model for studying the development of inhibition at axon terminals. Here, using whole cell recording methods and transgenic mice in which subclasses of retinal bipolar cells are labeled, we determined the temporal sequence and patterning of functional GABAergic and glycinergic input onto the major subclasses of bipolar cells. We found that the maturation of GABAergic and glycinergic synapses onto the axons of rod bipolar cells (RBCs), on-cone bipolar cells (on-CBCs) and off-cone bipolar cells (off-CBCs) were temporally distinct: spontaneous chloride-mediated currents are present in RBCs earlier in development compared with on- and off-CBC, and RBCs receive GABAergic and glycinergic input simultaneously, whereas in off-CBCs, glycinergic transmission emerges before GABAergic transmission. Because on-CBCs show little inhibitory activity, GABAergic and glycinergic events could not be pharmacologically distinguished for these bipolar cells. The balance of GABAergic and glycinergic input that is unique to RBCs and off-CBCs is established shortly after the onset of synapse formation and precedes visual experience. Our data suggest that presynaptic modulation of glutamate transmission from bipolar cells matures rapidly and is differentially coordinated for GABAergic and glycinergic synapses onto distinct bipolar cell subclasses.
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Rubi, Lena, and Jean-Marc Fritschy. "Increased GABAergic transmission in neuropeptide Y-expressing neurons in the dopamine-depleted murine striatum." Journal of Neurophysiology 123, no. 4 (April 1, 2020): 1496–503. http://dx.doi.org/10.1152/jn.00059.2020.
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As the main input nucleus of the basal ganglia, the striatum plays a central role in planning, control, and execution of movement and motor skill learning. More than 90% of striatal neurons, so-called medium spiny neurons (MSN), are GABAergic projection neurons, innervating primarily the substantia nigra pars reticulata or the globus pallidus internus. The remaining neurons are GABAergic and cholinergic interneurons, synchronizing and controlling striatal output by reciprocal connections with MSN. Besides prominent local cholinergic influence, striatal function is globally regulated by dopamine (DA) from the nigrostriatal pathway. Little is known about whether DA depletion, as occurs in Parkinson’s disease, affects the activity of striatal interneurons. Here we focused on neuropeptide Y (NPY)-expressing interneurons, which are among the major subgroups of GABAergic interneurons in the striatum. We investigated the effects of striatal DA depletion on GABAergic transmission in NPY interneurons by electrophysiologically recording GABAergic spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs) in identified NPY interneurons in slices from 6-hydroxydopamine (6-OHDA)- and vehicle-injected transgenic NPY-humanized Renilla green fluorescent protein (hrGFP) mice with the whole cell patch-clamp technique. We report a significant increase in sIPSC and mIPSC frequency as well as the occurrence of giant synaptic and burst sIPSCs in the 6-OHDA group, suggesting changes in GABAergic circuit activity and synaptic transmission. IPSC kinetics remained unchanged, pointing to mainly presynaptic changes in GABAergic transmission. These results show that chronic DA depletion following 6-OHDA injection causes activity-dependent and -independent increase of synaptic GABAergic inhibition onto striatal NPY interneurons, confirming their involvement in the functional impairments of the DA-depleted striatum. NEW & NOTEWORTHY Neuropeptide Y (NPY) interneurons regulate the function of striatal projection neurons and are upregulated upon dopamine depletion in the striatum. Here we investigated how dopamine depletion affects NPY circuits and show electrophysiologically that it leads to the occurrence of giant synaptic and burst GABAergic spontaneous inhibitory postsynaptic currents (IPSCs) and to an activity-independent increase in GABAergic miniature IPSC frequency in NPY neurons. We suggest that degeneration of dopaminergic terminals in the striatum causes functional changes in striatal GABAergic function.
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Petukhova, Elena, Daria Ponomareva, Karin Rustler, Burkhard Koenig, and Piotr Bregestovski. "Action of the Photochrome Glyght on GABAergic Synaptic Transmission in Mouse Brain Slices." International Journal of Molecular Sciences 23, no. 18 (September 12, 2022): 10553. http://dx.doi.org/10.3390/ijms231810553.
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Glyght is a new photochromic compound described as an effective modulator of glycine receptors at heterologous expression, in brain slices and in zebrafish larvae. Glyght also caused weak inhibition of GABAA-mediated currents in a cell line expressing α1/β2/γ2 GABAA receptors. However, the effects of Glyght on GABAergic transmission in the brain have not been analysed, which does not allow a sufficiently comprehensive assessment of the effects of the compound on the nervous system. Therefore, in this study using whole-cell patch-clamp recording, we analysed the Glyght (100 µM) action on evoked GABAergic inhibitory postsynaptic currents (eIPSCs) in mice hippocampal slices. Two populations of cells were found: the first responded by reducing the GABAergic eIPSCs’ amplitude, whereas the second showed no sensitivity to the compound. Glyght did not affect the ionic currents’ amplitude induced by GABA application, suggesting the absence of action on postsynaptic GABA receptors. Additionally, Glyght had no impact on the paired-pulse modulation of GABAergic eIPSCs, indicating that Glyght does not modulate the neurotransmitter release mechanisms. In the presence of strychnine, an antagonist of glycine receptors, the Glyght effect on GABAergic synaptic transmission was absent. Our results suggest that Glyght can modulate GABAergic synaptic transmission via action on extrasynaptic glycine receptors.
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Jo, Young-Hwan, and Lorna W. Role. "Cholinergic Modulation of Purinergic and GABAergic Co-Transmission at In Vitro Hypothalamic Synapses." Journal of Neurophysiology 88, no. 5 (November 1, 2002): 2501–8. http://dx.doi.org/10.1152/jn.00352.2002.
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The lateral hypothalamus (LH) is an important center for the integration of autonomic and limbic information and is implicated in the modulation of visceral motor and sensory pathways, including those underlying feeding and arousal behaviors. LH neurons in vitro release both ATP and GABA. The control of ATP and GABA co-transmission in LH may underlie the participation of LH in basic aspects of arousal and reinforcement. LH neurons receive cholinergic input from the pedunculopontine and laterodorsal tegmental nuclei as well as from cholinergic interneurons within the LH per se. This study presents evidence for nicotinic acetylcholine receptor (nAChR)-mediated enhancement of GABAergic, but not of purinergic, transmission despite the co-transmission of ATP and GABA at LH synapses in vitro. Facilitation of GABAergic transmission by nicotine is inhibited by antagonists of (αβ)*-containing nAChRs, but is unaffected by an α7-selective antagonist, consistent with a nAChR-mediated enhancement of GABA release mediated by non-α7-containing nAChRs. Activation of muscarinic ACh receptors enhances the release of ATP while concomitantly depressing GABAergic transmission. The independent modulation of ATP/GABAergic transmission may provide a new level of synaptic flexibility in which individual neurons utilize more than one neurotransmitter but retain independent control over their synaptic activity.
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Nieto Mendoza, Elizabeth, and Elizabeth Hernández Echeagaray. "Dopaminergic Modulation of Striatal Inhibitory Transmission and Long-Term Plasticity." Neural Plasticity 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/789502.
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Dopamine (DA) modulates glutamatergic synaptic transmission and its plasticity in the striatum; however it is not well known how DA modulates long-term plasticity of striatal GABAergic inhibitory synapses. This work focused on the analysis of both dopaminergic modulation of inhibitory synapses and the synaptic plasticity established between GABAergic afferents to medium spiny neurons (MSNs). Our results showed that low and high DA concentrations mainly reduced the amplitude of inhibitory synaptic response; however detailed analysis of the D1 and D2 participation in this modulation displayed a wide variability in synaptic response. Analyzing DA participation in striatal GABAergic plasticity we observed that high frequency stimulation (HFS) of GABAergic interneurons in the presence of DA at a low concentration (200 nM) favored the expression of inhibitory striatal LTD, whereas higher concentration of DA (20 μM) primarily induced LTP. Interestingly, the plasticity induced in an animal model of striatal degeneration mimicked that induced in the presence of DA at a high concentration, which was not abolished with D2 antagonist but was prevented by PKA blocker.
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Okada, Motohiro, and Kouji Fukuyama. "Interaction between Mesocortical and Mesothalamic Catecholaminergic Transmissions Associated with NMDA Receptor in the Locus Coeruleus." Biomolecules 10, no. 7 (July 1, 2020): 990. http://dx.doi.org/10.3390/biom10070990.
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Noncompetitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonists contribute to the pathophysiology of schizophrenia and mood disorders but improve monoaminergic antidepressant-resistant mood disorder and suicidal ideation. The mechanisms of the double-edged sword clinical action of NMDAR antagonists remained to be clarified. The present study determined the interaction between the NMDAR antagonist (MK801), α1 adrenoceptor antagonist (prazosin), and α2A adrenoceptor agonist (guanfacine) on mesocortical and mesothalamic catecholaminergic transmission, and thalamocortical glutamatergic transmission using multiprobe microdialysis. The inhibition of NMDAR in the locus coeruleus (LC) by local MK801 administration enhanced both the mesocortical noradrenergic and catecholaminergic coreleasing (norepinephrine and dopamine) transmissions. The mesothalamic noradrenergic transmission was also enhanced by local MK801 administration in the LC. These mesocortical and mesothalamic transmissions were activated by intra-LC disinhibition of transmission of γ-aminobutyric acid (GABA) via NMDAR inhibition. Contrastingly, activated mesothalamic noradrenergic transmission by MK801 enhanced intrathalamic GABAergic inhibition via the α1 adrenoceptor, resulting in the suppression of thalamocortical glutamatergic transmission. The thalamocortical glutamatergic terminal stimulated the presynaptically mesocortical catecholaminergic coreleasing terminal in the superficial cortical layers, but did not have contact with the mesocortical selective noradrenergic terminal (which projected terminals to deeper cortical layers). Furthermore, the α2A adrenoceptor suppressed the mesocortical and mesothalamic noradrenergic transmissions somatodendritically in the LC and presynaptically/somatodendritically in the reticular thalamic nucleus (RTN). These discrepancies between the noradrenergic and catecholaminergic transmissions in the mesocortical and mesothalamic pathways probably constitute the double-edged sword clinical action of noncompetitive NMDAR antagonists.
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Kauer, J. A., and L. L. McMahon. "Depressing transmission in GABAergic hippocampal neurons." Molecular Psychiatry 2, no. 6 (October 1997): 434–36. http://dx.doi.org/10.1038/sj.mp.4000283.
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Burket, Jessica A., Maria R. Urbano, and Stephen I. Deutsch. "Sugarcoated Perineuronal Nets Regulate “GABAergic” Transmission." Clinical Neuropharmacology 40, no. 3 (2017): 120–30. http://dx.doi.org/10.1097/wnf.0000000000000209.
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Saitow, Fumihito. "Modulation of Cerebellar GABAergic Synaptic Transmission." Nihon Ika Daigaku Igakkai Zasshi 5, no. 3 (2009): 152–58. http://dx.doi.org/10.1272/manms.5.152.
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Zhan, Yang. "Harnessing GABAergic Transmission for Slow Oscillations." Neuroscience Bulletin 32, no. 5 (August 30, 2016): 501–2. http://dx.doi.org/10.1007/s12264-016-0058-1.
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Sebe, Joy Y., Erika D. Eggers, and Albert J. Berger. "Differential Effects of Ethanol on GABAA and Glycine Receptor-Mediated Synaptic Currents in Brain Stem Motoneurons." Journal of Neurophysiology 90, no. 2 (August 2003): 870–75. http://dx.doi.org/10.1152/jn.00119.2003.
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Ethanol potentiates glycinergic synaptic transmission to hypoglossal motoneurons (HMs). This effect on glycinergic transmission changes with postnatal development in that juvenile HMs (P9–13) are more sensitive to ethanol than neonate HMs (P1–3). We have now extended our previous study to investigate ethanol modulation of synaptic GABAA receptors (GABAARs), because both GABA and glycine mediate inhibitory synaptic transmission to brain stem motoneurons. We tested the effects of ethanol on GABAergic and glycinergic miniature inhibitory postsynaptic currents (mIPSCs) recorded from neonate and juvenile rat HMs in an in vitro slice preparation. Bath application of 30 mM ethanol had no significant effect on the GABAergic mIPSC amplitude or frequency recorded at either age. At 100 mM, ethanol significantly decreased the GABAergic mIPSC amplitude recorded from neonate (6 ± 3%, P < 0.05) and juvenile (16 ± 3%, P < 0.01) HMs. The same concentration of ethanol increased the GABAergic mIPSC frequency recorded from neonate (64 ± 17%, P < 0.05) and juvenile (40 ± 15%, n.s.) HMs. In contrast, 100 mM ethanol robustly potentiated glycinergic mIPSC amplitude in neonate (31 ± 3%, P < 0.0001) and juvenile (41 ± 7%, P < 0.001) HMs. These results suggest that glycine receptors are more sensitive to modulation by ethanol than GABAA receptors and that 100 mM ethanol has the opposite effect on GABAAR-mediated currents in juvenile HMs, that is, inhibition rather than enhancement. Further, comparing ethanol's effects on GABAergic mIPSC amplitude and frequency, ethanol modulates GABAergic synaptic transmission to HMs differentially. Presynaptically, ethanol enhances mIPSC frequency while postsynaptically it decreases mIPSC amplitude.
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Ehrlich, David E., Steven J. Ryan, Rimi Hazra, Ji-Dong Guo, and Donald G. Rainnie. "Postnatal maturation of GABAergic transmission in the rat basolateral amygdala." Journal of Neurophysiology 110, no. 4 (August 15, 2013): 926–41. http://dx.doi.org/10.1152/jn.01105.2012.
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Many psychiatric disorders, including anxiety and autism spectrum disorders, have early ages of onset and high incidence in juveniles. To better treat and prevent these disorders, it is important to first understand normal development of brain circuits that process emotion. Healthy and maladaptive emotional processing involve the basolateral amygdala (BLA), dysfunction of which has been implicated in numerous psychiatric disorders. Normal function of the adult BLA relies on a fine balance of glutamatergic excitation and GABAergic inhibition. Elsewhere in the brain GABAergic transmission changes throughout development, but little is known about the maturation of GABAergic transmission in the BLA. Here we used whole cell patch-clamp recording and single-cell RT-PCR to study GABAergic transmission in rat BLA principal neurons at postnatal day (P)7, P14, P21, P28, and P35. GABAA currents exhibited a significant twofold reduction in rise time and nearly 25% reduction in decay time constant between P7 and P28. This corresponded with a shift in expression of GABAA receptor subunit mRNA from the α2- to the α1-subunit. The reversal potential for GABAA receptors transitioned from depolarizing to hyperpolarizing with age, from around −55 mV at P7 to −70 mV by P21. There was a corresponding shift in expression of opposing chloride pumps that influence the reversal, from NKCC1 to KCC2. Finally, we observed short-term depression of GABAA postsynaptic currents in immature neurons that was significantly and gradually abolished by P28. These findings reveal that in the developing BLA GABAergic transmission is highly dynamic, reaching maturity at the end of the first postnatal month.
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Donato, Roberta, and Andrea Nistri. "Differential Short-Term Changes in GABAergic or Glycinergic Synaptic Efficacy on Rat Hypoglossal Motoneurons." Journal of Neurophysiology 86, no. 2 (August 1, 2001): 565–74. http://dx.doi.org/10.1152/jn.2001.86.2.565.
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Using whole cell patch-clamp recording from hypoglossal motoneurons of a neonatal rat brain slice preparation, we investigated short-term changes in synaptic transmission mediated by GABA or glycine. In 1.5 mM extracellular Ca2+[Ca2+]o, pharmacologically isolated GABAergic or glycinergic currents were elicited by electrical stimulation of the reticular formation. At low stimulation frequency, glycinergic currents were larger and faster than GABAergic ones. GABAergic currents were strongly facilitated by pulse trains at 5 or 10 Hz without apparent depression. This phenomenon persisted after pharmacological block of GABABreceptors. Glycinergic currents were comparatively much less enhanced than GABAergic currents. One possible mechanism to account for this difference is that GABAergic currents decayed so slowly that consecutive responses summated over an incrementing baseline. However, while synaptic summation appeared at ≥10-Hz stimulation, at 5 Hz strong facilitation developed with minimal summation of GABA-mediated currents. Glycinergic currents decayed so fast that summation was minimal. As [Ca2+]o is known to shape short-term synaptic changes, we examined if varying [Ca2+]o could differentially affect facilitation of GABA- or glycine-operated synapses. With 5 mM [Ca2+]o, the frequency of spontaneous GABAergic or glycinergic currents appeared much higher but GABAergic current facilitation was blocked (and replaced by depression), whereas glycinergic currents remained slightly facilitated. [Ca2+]omanipulation thus brought about distinct processes responsible for facilitation of GABAergic or glycinergic transmission. Our data therefore demonstrate an unexpectedly robust, short-term increase in the efficiency of GABAergic synapses that can become at least as effective as glycinergic synapses.
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Li, Ke Y., Yan-zhong Guan, Kresimir Krnjević, and Jiang H. Ye. "Propofol Facilitates Glutamatergic Transmission to Neurons of the Ventrolateral Preoptic Nucleus." Anesthesiology 111, no. 6 (December 1, 2009): 1271–78. http://dx.doi.org/10.1097/aln.0b013e3181bf1d79.
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Background There is much evidence that the sedative component of anesthesia is mediated by gamma-aminobutyric acid type A (GABA(A)) receptors on hypothalamic neurons responsible for arousal, notably in the tuberomammillary nucleus. These GABA(A) receptors are targeted by gamma-aminobutyric acid-mediated (GABAergic) neurons in the ventrolateral preoptic area (VLPO): When these neurons become active, they inhibit the arousal-producing nuclei and induce sleep. According to recent studies, propofol induces sedation by enhancing VLPO-induced synaptic inhibition, making the target cells more responsive to GABA(A). The authors explored the possibility that propofol also promotes sedation less directly by facilitating excitatory inputs to the VLPO GABAergic neurons. Methods Spontaneous excitatory postsynaptic currents were recorded from VLPO cells-principally mechanically isolated, but also in slices from rats. Results In isolated VLPO GABAergic neurons, propofol increased the frequency of glutamatergic spontaneous excitatory postsynaptic currents without affecting their mean amplitude. The action of propofol was mimicked by muscimol and prevented by gabazine, respectively a specific agonist and antagonist at GABA(A) receptors. It was also suppressed by bumetanide, a blocker of Na-K-Cl cotransporter-mediated inward Cl transport. In slices, propofol also increased the frequency of spontaneous excitatory postsynaptic currents and, at low doses, accelerated firing of VLPO cells. Conclusion Propofol induces sedation, at least in part, by increasing firing of GABAergic neurons in the VLPO, indirectly by activation of GABA(A) receptors on glutamatergic afferents: Because these axons/terminals have a relatively high internal Cl concentration, they are depolarized by GABAergic agents such as propofol, which thus enhance glutamate release.
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Jeong, Hyo-Jin, Il-Sung Jang, Junichi Nabekura, and Norio Akaike. "Adenosine A1 Receptor-Mediated Presynaptic Inhibition of GABAergic Transmission in Immature Rat Hippocampal CA1 Neurons." Journal of Neurophysiology 89, no. 3 (March 1, 2003): 1214–22. http://dx.doi.org/10.1152/jn.00516.2002.
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In the mechanically dissociated rat hippocampal CA1 neurons with native presynaptic nerve endings, namely “synaptic bouton” preparation, the purinergic modulation of spontaneous GABAergic miniature inhibitory postsynaptic currents (mIPSCs) was investigated using whole-cell recording mode under the voltage-clamp conditions. In immature neurons, adenosine (10 μM) reversibly decreased GABAergic mIPSC frequency without affecting the mean current amplitude. The inhibitory effect of adenosine transmission was completely blocked by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 nM), a selective Α1 receptor antagonist, and was mimicked by N 6-cyclopentyladenosine (CPA, 1 μM), a selective Α1 receptor agonist. However, CPA had no effect on GABAergic mIPSC frequency in postnatal 30 day neurons. N-ethylmaleimide (10 μM), a guanosine 5′-triphosphate binding protein uncoupler, and Ca2+-free external solution removed the CPA-induced inhibition of mIPSC frequency. K+ channel blockers, 4-aminopyridine (100 μM) and Ba2+ (1 mM), had no effect on the inhibitory effect of CPA on GABAergic mIPSC frequency. Stimulation of adenylyl cyclase with forskolin (10 μM) prevented the CPA action on GABAergic mIPSC frequency. Rp-cAMPS (100 μM), a selective PKA inhibitor, also blocked the CPA action. It was concluded that the activation of presynaptic Α1 receptors modulates the probability of spontaneous GABA release via cAMP- and protein kinase A dependent pathway. This Α1 receptor-mediated modulation of GABAergic transmission may play an important role in the regulation of excitability of immature hippocampal CA1 neurons.
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Saitow, Fumihito, Shin'Ichiro Satake, Junko Yamada, and Shiro Konishi. "β-Adrenergic Receptor-Mediated Presynaptic Facilitation of Inhibitory GABAergic Transmission at Cerebellar Interneuron-Purkinje Cell Synapses." Journal of Neurophysiology 84, no. 4 (October 1, 2000): 2016–25. http://dx.doi.org/10.1152/jn.2000.84.4.2016.
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Norepinephrine (NE) has been shown to elicit long-term facilitation of GABAergic transmission to rat cerebellar Purkinje cells (PCs) through β-adrenergic receptor activation. To further examine the locus and adrenoceptor subtypes involved in the NE-induced facilitation of GABAergic transmission, we recorded inhibitory postsynaptic currents (IPSCs) evoked by focal stimulation with paired-pulse (PP) stimuli from PCs in rat cerebellar slices by whole cell recordings and analyzed the PP ratio of the IPSC amplitude. NE increased the IPSC amplitude with a decease in the variance of the PP ratio, which was mimicked by presynaptic manipulation of the transmission caused by increasing the extracellular Ca2+ concentration, confirming that the presynaptic adrenergic receptors are responsible for the facilitation. Pharmacological tests showed that the β2-adrenoceptor antagonist, ICI118,551, but not the β1-adrenoceptor antagonist, CGP20712A, blocked the NE-induced IPSC facilitation, suggesting that the β2-adrenoceptors on cerebellar interneurons, basket cells (BCs), mediate the noradrenergic facilitation of GABAergic transmission. Double recordings were performed from BCs and PCs to further characterize the regulation of the GABAergic synapses. First, on-cell recordings from BCs showed that the β-agonist isoproterenol (ISP) increased the frequencies of the spontaneous spikes in BCs and the spike-triggered IPSCs in PCs recorded with the whole cell mode. The amplitude of the spike-triggered IPSCs decreased or increased depending on the individual GABAergic synapses examined. Forskolin invariably increased both the amplitude and the frequency of the spike-triggered IPSCs. Double whole cell recordings from BC-PC pairs showed that ISP mainly caused an increase in the amplitude of the IPSCs evoked in the PCs by an action current in the BCs produced in response to voltage steps from −60 to −10 mV. Our data suggest that the noradrenergic facilitation of GABAergic transmission in the rat cerebellar cortex is mediated, at least in part, by depolarization and action potential discharges in the BCs through activation of the β2-adrenoceptors in BCs coupled to intracellular cyclic AMP formation.
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Kirmse, Knut, Christian A. Hübner, Dirk Isbrandt, Otto W. Witte, and Knut Holthoff. "GABAergic Transmission during Brain Development: Multiple Effects at Multiple Stages." Neuroscientist 24, no. 1 (April 5, 2017): 36–53. http://dx.doi.org/10.1177/1073858417701382.
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In recent years, considerable progress has been achieved in deciphering the cellular and network functions of GABAergic transmission in the intact developing brain. First, in vivo studies in non-mammalian and mammalian species confirmed the long-held assumption that GABA acts as a mainly depolarizing neurotransmitter at early developmental stages. At the same time, GABAergic transmission was shown to spatiotemporally constrain spontaneous cortical activity, whereas firm evidence for GABAergic excitation in vivo is currently missing. Second, there is a growing body of evidence indicating that depolarizing GABA may contribute to the activity-dependent refinement of neural circuits. Third, alterations in GABA actions have been causally linked to developmental brain disorders and identified as potential targets of timed prophylactic interventions. In this article, we review these major recent findings and argue that both depolarizing and inhibitory GABA actions may be crucial for physiological brain maturation.
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Park, Chungwon, Xingxiang Chen, Chong-Li Tian, Gyu Nam Park, Nicolas Chenouard, Hunki Lee, Xin Yi Yeo, et al. "Unique dynamics and exocytosis properties of GABAergic synaptic vesicles revealed by three-dimensional single vesicle tracking." Proceedings of the National Academy of Sciences 118, no. 9 (February 23, 2021): e2022133118. http://dx.doi.org/10.1073/pnas.2022133118.
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Maintaining the balance between neuronal excitation and inhibition is essential for proper function of the central nervous system. Inhibitory synaptic transmission plays an important role in maintaining this balance. Although inhibitory transmission has higher kinetic demands compared to excitatory transmission, its properties are poorly understood. In particular, the dynamics and exocytosis of single inhibitory vesicles have not been investigated, due largely to both technical and practical limitations. Using a combination of quantum dots (QDs) conjugated to antibodies against the luminal domain of the vesicular GABA transporter to selectively label GABAergic (i.e., predominantly inhibitory) vesicles together with dual-focus imaging optics, we tracked the real-time three-dimensional position of single GABAergic vesicles up to the moment of exocytosis (i.e., fusion). Using three-dimensional trajectories, we found that GABAergic synaptic vesicles traveled a shorter distance prior to fusion and had a shorter time to fusion compared to synaptotagmin-1 (Syt1)-labeled vesicles, which were mostly from excitatory neurons. Moreover, our analysis revealed that GABAergic synaptic vesicles move more straightly to their release sites than Syt1-labeled vesicles. Finally, we found that GABAergic vesicles have a higher prevalence of kiss-and-run fusion than Syt1-labeled vesicles. These results indicate that inhibitory synaptic vesicles have a unique set of dynamics and exocytosis properties to support rapid synaptic inhibition, thereby maintaining a tightly regulated coordination between excitation and inhibition in the central nervous system.
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Dickinson, Robert, Sara L. M. de Sousa, William R. Lieb, and Nicholas P. Franks. "Selective Synaptic Actions of Thiopental and Its Enantiomers." Anesthesiology 96, no. 4 (April 1, 2002): 884–92. http://dx.doi.org/10.1097/00000542-200204000-00016.
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Background There is conflicting evidence concerning the extent to which the intravenous general anesthetic thiopental acts by enhancing inhibitory gamma-aminobutyric acid-mediated (GABAergic) synaptic transmission or by inhibiting excitatory glutamatergic transmission. Yet there are remarkably few studies on the effects of thiopental on functional synapses. In addition, the degree of stereoselectivity of thiopental acting at synapses has yet to be tested. Methods The actions of thiopental and its enantiomers on GABAergic and glutamatergic synapses were investigated using voltage clamp techniques on microisland cultures of rat hippocampal neurons, a preparation that avoids the confounding effects of complex neuronal networks. Results Racemic thiopental markedly enhanced the charge transfer at GABAergic synapses without significantly affecting the peak of the postsynaptic current. At a surgically relevant concentration (25 microm), charge transfer was increased by approximately 230%. However, even at twice this concentration there were no significant effects on glutamatergic postsynaptic currents. At GABAergic synapses, thiopental acted stereoselectively, with the S(-) enantiomer being approximately twice as effective as the R(+) enantiomer at enhancing charge transfer. Conclusions Thiopental stereoselectively enhances inhibitory GABAergic synaptic transmission in a way that reflects animal potencies, supporting the idea that this is a principal mode of action for this drug. The absence of any effect on glutamatergic synapses at surgically relevant concentrations suggests that the inhibition of these excitatory synapses is not an important factor in producing thiopental general anesthesia.
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Xiao, Zhaoyang, Pan-Yue Deng, Chuanxiu Yang, and Saobo Lei. "Modulation of GABAergic Transmission by Muscarinic Receptors in the Entorhinal Cortex of Juvenile Rats." Journal of Neurophysiology 102, no. 2 (August 2009): 659–69. http://dx.doi.org/10.1152/jn.00226.2009.
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Whereas the entorhinal cortex (EC) receives profuse cholinergic innervations from the basal forebrain and activation of cholinergic receptors has been shown to modulate the activities of the principal neurons and promote the intrinsic oscillations in the EC, the effects of cholinergic receptor activation on GABAergic transmission in this brain region have not been determined. We examined the effects of muscarinic receptor activation on GABAA receptor-mediated synaptic transmission in the superficial layers of the EC. Application of muscarine dose-dependently increased the frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from the principal neurons in layer II/III via activation of M3 muscarinic receptors. Muscarine slightly reduced the frequency but had no effects on the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. Muscarine reduced the amplitude of IPSCs evoked by extracellular field stimulation and by depolarization of GABAergic interneurons in synaptically connected interneuron and pyramidal neuron pairs. Application of muscarine generated membrane depolarization and increased action potential firing frequency but reduced the amplitude of action potentials in GABAergic interneurons. Muscarine-induced depolarization of GABAergic interneurons was mediated by inhibition of background K+ channels and independent of phospholipase C, intracellular Ca2+ release, and protein kinase C. Our results demonstrate that activation of muscarinic receptors exerts diverse effects on GABAergic transmission in the EC.
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Nakamura, Michiko, Il-Sung Jang, Hitoshi Ishibashi, Shigenori Watanabe, and Norio Akaike. "Possible Roles of Kainate Receptors on GABAergic Nerve Terminals Projecting to Rat Substantia Nigra Dopaminergic Neurons." Journal of Neurophysiology 90, no. 3 (September 2003): 1662–70. http://dx.doi.org/10.1152/jn.01165.2002.
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GABAergic afferent inputs are thought to play an important role in the control of the firing pattern of substantia nigra pars compacta (SNc) dopaminergic neurons. We report here the actions of presynaptic kainite (KA) receptors in GABAergic transmission of rat SNc dopaminergic neurons. In mechanically dissociated rat SNc dopaminergic neurons attached with native presynaptic nerve terminals, GABAergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded by use of conventional whole cell patch recording mode. In the voltage-clamp condition, KA (3 μM) significantly increased GABAergic mIPSC frequency without affecting the current amplitude. This facilitatory effect of KA was not affected in the presence of 20 μM GYKI52466, a selective AMPA receptor antagonist, but was completely inhibited in the presence of 20 μM CNQX, an AMPA/KA receptor antagonist. Presynaptic KA receptors on GABAergic terminals were mainly permeable to Na+ but impermeable to Ca2+ because KA-induced facilitation of mIPSC frequency was completely suppressed in either Na+-free or Ca2+-free external solutions, and in the presence of 200 μM Cd2+, a general voltage-dependent Ca2+ channel blocker. In the slice preparation, KA increased GABAergic spontaneous mIPSC frequency, but significantly suppressed evoked IPSC (eIPSC) amplitude. However, this inhibitory action on eIPSCs was reversed by 10 μM CGP55845 , a selective GABAB receptor antagonist, implicating the possible involvement of GABAB autoreceptors in KA-induced modulation of GABAergic transmission. Thus presynaptic KA receptors on GABAergic nerve terminals synapsing onto SNc neurons may play functional roles contributing the fine control of neuronal excitability and firing pattern of SNc.
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Tyagarajan, Shiva K., Himanish Ghosh, Gonzalo E. Yévenes, Irina Nikonenko, Claire Ebeling, Cornelia Schwerdel, Corinne Sidler, et al. "Regulation of GABAergic synapse formation and plasticity by GSK3β-dependent phosphorylation of gephyrin." Proceedings of the National Academy of Sciences 108, no. 1 (December 20, 2010): 379–84. http://dx.doi.org/10.1073/pnas.1011824108.
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Postsynaptic scaffolding proteins ensure efficient neurotransmission by anchoring receptors and signaling molecules in synapse-specific subcellular domains. In turn, posttranslational modifications of scaffolding proteins contribute to synaptic plasticity by remodeling the postsynaptic apparatus. Though these mechanisms are operant in glutamatergic synapses, little is known about regulation of GABAergic synapses, which mediate inhibitory transmission in the CNS. Here, we focused on gephyrin, the main scaffolding protein of GABAergic synapses. We identify a unique phosphorylation site in gephyrin, Ser270, targeted by glycogen synthase kinase 3β (GSK3β) to modulate GABAergic transmission. Abolishing Ser270 phosphorylation increased the density of gephyrin clusters and the frequency of miniature GABAergic postsynaptic currents in cultured hippocampal neurons. Enhanced, phosphorylation-dependent gephyrin clustering was also induced in vitro and in vivo with lithium chloride. Lithium is a GSK3β inhibitor used therapeutically as mood-stabilizing drug, which underscores the relevance of this posttranslational modification for synaptic plasticity. Conversely, we show that gephyrin availability for postsynaptic clustering is limited by Ca2+-dependent gephyrin cleavage by the cysteine protease calpain-1. Together, these findings identify gephyrin as synaptogenic molecule regulating GABAergic synaptic plasticity, likely contributing to the therapeutic action of lithium.
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Sebe, Joy Y., Johannes F. van Brederode, and Albert J. Berger. "Inhibitory Synaptic Transmission Governs Inspiratory Motoneuron Synchronization." Journal of Neurophysiology 96, no. 1 (July 2006): 391–403. http://dx.doi.org/10.1152/jn.00086.2006.
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Neurons within the intact respiratory network produce bursts of action potentials that cause inspiration or expiration. Within inspiratory bursts, activity is synchronized on a shorter timescale to generate clusters of action potentials that occur in a set frequency range and are called synchronous oscillations. We investigated how GABA and glycine modulate synchronous oscillations and respiratory rhythm during postnatal development. We recorded inspiratory activity from hypoglossal nerves using the in vitro rhythmically active mouse medullary slice preparation from P0–P11 mice. Average oscillation frequency increased with postnatal development, from 17 ± 12 Hz in P0–P6 mice ( n = 15) to 38 ± 7 Hz in P7–P11 mice ( n = 37) ( P < 0.0001). Bath application of GABAA and GlyR antagonists significantly reduced oscillation power in neonates (P0–P6) and juveniles (P7–P10) and increased peak integrated activity in both age groups. To test whether elevating slice excitability is sufficient to reduce oscillation power, Substance P was bath applied alone. Substance P, although increasing peak integrated activity, had no significant effect on oscillation power. Prolonging the time course of GABAergic synaptic currents with zolpidem decreased the median oscillation frequency in P9–P10 mouse slices. These data demonstrate that oscillation frequency increases with postnatal development and that both GABAergic and glycinergic transmission contribute to synchronization of activity. Further, the time course of synaptic GABAergic currents is a determinant of oscillation frequency.
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Henderson, L. P., C. A. A. Penatti, B. L. Jones, P. Yang, and A. S. Clark. "Anabolic androgenic steroids and forebrain GABAergic transmission." Neuroscience 138, no. 3 (March 2006): 793–99. http://dx.doi.org/10.1016/j.neuroscience.2005.08.039.
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Schlichting, Joyce L. "Modulation and polytypic signaling in GABAergic transmission." Neurochemical Research 15, no. 2 (February 1990): 131–43. http://dx.doi.org/10.1007/bf00972203.
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Daghfous, Gheylen, François Auclair, Felix Clotten, Jean-Luc Létourneau, Elias Atallah, Jean-Patrick Millette, Dominique Derjean, Richard Robitaille, Barbara S. Zielinski, and Réjean Dubuc. "GABAergic modulation of olfactomotor transmission in lampreys." PLOS Biology 16, no. 10 (October 4, 2018): e2005512. http://dx.doi.org/10.1371/journal.pbio.2005512.
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Saitow, Fumihito, and Hidenori Suzuki. "GABAergic Synaptic Transmission in the Cerebellar Cortex." Nihon Ika Daigaku Igakkai Zasshi 3, no. 2 (2007): 56–57. http://dx.doi.org/10.1272/manms.3.56.
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Rabenstein, Michael, Nico Murr, Andreas Hermann, Arndt Rolfs, and Moritz J. Frech. "Alteration of GABAergic Input Precedes Neurodegeneration of Cerebellar Purkinje Cells of NPC1-Deficient Mice." International Journal of Molecular Sciences 20, no. 24 (December 13, 2019): 6288. http://dx.doi.org/10.3390/ijms20246288.
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Niemann-Pick Disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease belonging to the family of lysosomal storage disorders. NPC1-patients suffer from, amongst other symptoms, ataxia, based on the dysfunction and loss of cerebellar Purkinje cells. Alterations in synaptic transmission are believed to contribute to a pathological mechanism leading to the progressive loss of Purkinje cells observed in NPC1-deficient mice. With regard to inhibitory synaptic transmission, alterations of GABAergic synapses are described but functional data are missing. For this reason, we have examined here the inhibitory GABAergic synaptic transmission of Purkinje cells of NPC1-deficient mice (NPC1−/−). Patch clamp recordings of inhibitory post-synaptic currents (IPSCs) of Purkinje cells revealed an increased frequency of GABAergic IPSCs in NPC1−/− mice. In addition, Purkinje cells of NPC1−/− mice were less amenable for modulation of synaptic transmission via the activation of excitatory NMDA-receptors (NMDA-Rs). Western blot testing disclosed a reduced protein level of phosphorylated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) subunit GluA2 in the cerebella of NPC1−/− mice, indicating a disturbance in the internalization of GluA2-containing AMPA-Rs. Since this is triggered by the activation of NMDA-Rs, we conclude that a disturbance in the synaptic turnover of AMPA-Rs underlies the defective inhibitory GABAergic synaptic transmission. While these alterations precede obvious signs of neurodegeneration of Purkinje cells, we propose a contribution of synaptic malfunction to the initiation of the loss of Purkinje cells in NPC1. Thus, a prevention of the disturbance of synaptic transmission in early stages of the disease might display a target with which to avert progressive neurodegeneration in NPC1.
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Shimizu-Okabe, Chigusa, Shiori Kobayashi, Jeongtae Kim, Yoshinori Kosaka, Masanobu Sunagawa, Akihito Okabe, and Chitoshi Takayama. "Developmental Formation of the GABAergic and Glycinergic Networks in the Mouse Spinal Cord." International Journal of Molecular Sciences 23, no. 2 (January 13, 2022): 834. http://dx.doi.org/10.3390/ijms23020834.
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Gamma-aminobutyric acid (GABA) and glycine act as inhibitory neurotransmitters. Three types of inhibitory neurons and terminals, GABAergic, GABA/glycine coreleasing, and glycinergic, are orchestrated in the spinal cord neural circuits and play critical roles in regulating pain, locomotive movement, and respiratory rhythms. In this study, we first describe GABAergic and glycinergic transmission and inhibitory networks, consisting of three types of terminals in the mature mouse spinal cord. Second, we describe the developmental formation of GABAergic and glycinergic networks, with a specific focus on the differentiation of neurons, formation of synapses, maturation of removal systems, and changes in their action. GABAergic and glycinergic neurons are derived from the same domains of the ventricular zone. Initially, GABAergic neurons are differentiated, and their axons form synapses. Some of these neurons remain GABAergic in lamina I and II. Many GABAergic neurons convert to a coreleasing state. The coreleasing neurons and terminals remain in the dorsal horn, whereas many ultimately become glycinergic in the ventral horn. During the development of terminals and the transformation from radial glia to astrocytes, GABA and glycine receptor subunit compositions markedly change, removal systems mature, and GABAergic and glycinergic action shifts from excitatory to inhibitory.
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Losi, Gabriele, Letizia Mariotti, and Giorgio Carmignoto. "GABAergic interneuron to astrocyte signalling: a neglected form of cell communication in the brain." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1654 (October 19, 2014): 20130609. http://dx.doi.org/10.1098/rstb.2013.0609.
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GABAergic interneurons represent a minority of all cortical neurons and yet they efficiently control neural network activities in all brain areas. In parallel, glial cell astrocytes exert a broad control of brain tissue homeostasis and metabolism, modulate synaptic transmission and contribute to brain information processing in a dynamic interaction with neurons that is finely regulated in time and space. As most studies have focused on glutamatergic neurons and excitatory transmission, our knowledge of functional interactions between GABAergic interneurons and astrocytes is largely defective. Here, we critically discuss the currently available literature that hints at a potential relevance of this specific signalling in brain function. Astrocytes can respond to GABA through different mechanisms that include GABA receptors and transporters. GABA-activated astrocytes can, in turn, modulate local neuronal activity by releasing gliotransmitters including glutamate and ATP. In addition, astrocyte activation by different signals can modulate GABAergic neurotransmission. Full clarification of the reciprocal signalling between different GABAergic interneurons and astrocytes will improve our understanding of brain network complexity and has the potential to unveil novel therapeutic strategies for brain disorders.
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Zheng, Zhongfan, Xiumei Zhang, Junqiang Liu, Ping He, Shan Zhang, Yongning Zhang, Jie Gao, et al. "GABAergic synapses suppress intestinal innate immunity via insulin signaling in Caenorhabditis elegans." Proceedings of the National Academy of Sciences 118, no. 20 (May 10, 2021): e2021063118. http://dx.doi.org/10.1073/pnas.2021063118.
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GABAergic neurotransmission constitutes a major inhibitory signaling mechanism that plays crucial roles in central nervous system physiology and immune cell immunomodulation. However, its roles in innate immunity remain unclear. Here, we report that deficiency in the GABAergic neuromuscular junctions (NMJs) of Caenorhabditis elegans results in enhanced resistance to pathogens, whereas pathogen infection enhances the strength of GABAergic transmission. GABAergic synapses control innate immunity in a manner dependent on the FOXO/DAF-16 but not the p38/PMK-1 pathway. Our data reveal that the insulin-like peptide INS-31 level was dramatically decreased in the GABAergic NMJ GABAAR-deficient unc-49 mutant compared with wild-type animals. C. elegans with ins-31 knockdown or loss of function exhibited enhanced resistance to Pseudomonas aeruginosa PA14 exposure. INS-31 may act downstream of GABAergic NMJs and in body wall muscle to control intestinal innate immunity in a cell-nonautonomous manner. Our results reveal a signaling axis of synapse–muscular insulin–intestinal innate immunity in vivo.
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Awatramani, Gautam B., Rostislav Turecek, and Laurence O. Trussell. "Staggered Development of GABAergic and Glycinergic Transmission in the MNTB." Journal of Neurophysiology 93, no. 2 (February 2005): 819–28. http://dx.doi.org/10.1152/jn.00798.2004.
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Maturation of some brain stem and spinal inhibitory systems is characterized by a shift from GABAergic to glycinergic transmission. Little is known about how this transition is expressed in terms of individual axonal inputs and synaptic sites. We have explored this issue in the rat medial nucleus of the trapezoid body (MNTB). Synaptic responses at postnatal days 5–7 (P5–P7) were small, slow, and primarily mediated by GABAA receptors. By P8–P12, an additional, faster glycinergic component emerged. At these ages, GABAA, glycine, or both types of receptors mediated transmission, even at single synaptic sites. Thereafter, glycinergic development greatly accelerated. By P25, evoked inhibitory postsynaptic currents (IPSCs) were 10 times briefer and 100 times larger than those measured in the youngest group, suggesting a proliferation of synaptic inputs activating fast-kinetic receptors. Glycinergic miniature IPSCs (mIPSCs) increased markedly in size and decay rate with age. GABAergic mIPSCs also accelerated, but declined slightly in amplitude. Overall, the efficacy of GABAergic inputs showed little maturation between P5 and P20. Although gramicidin perforated-patch recordings revealed that GABA or glycine depolarized P5–P7 cells but hyperpolarized P14–P15 cells, the young depolarizing inputs were not suprathreshold. In addition, vesicle-release properties of inhibitory axons also matured: GABAergic responses in immature rats were highly asynchronous, while in older rats, precise, phasic glycinergic IPSCs could transmit even with 500-Hz stimuli. Thus development of inhibition is characterized by coordinated modifications to transmitter systems, vesicle release kinetics, Cl− gradients, receptor properties, and numbers of synaptic inputs. The apparent switch in GABA/glycine transmission was predominantly due to enhanced glycinergic function.
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Uchida, Soko, Eiichiro Noda, Yasuhiro Kakazu, Yoshihito Mizoguchi, Norio Akaike, and Junichi Nabekura. "Allopregnanolone enhancement of GABAergic transmission in rat medial preoptic area neurons." American Journal of Physiology-Endocrinology and Metabolism 283, no. 6 (December 1, 2002): E1257—E1265. http://dx.doi.org/10.1152/ajpendo.00049.2002.
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γ-Aminobutyric acid (GABA)-mediated transmission in the medial preoptic area (MPOA) of the hypothalamus plays an important role in functions such as sex steroid hormone dynamics and control of body temperature. The action of allopregnanolone, the primary metabolite of progesterone, on GABAergic transmission was investigated by employing patch clamp whole cell recording on acutely dissociated rat MPOA neurons with the functional connection of presynaptic terminals. Allopregnanolone enhanced spontaneous GABA release on the MPOA neurons and induced prolonged decay of miniature GABAergic-inhibitory postsynaptic currents (mIPSCs). The facilitation of GABA release from the presynaptic terminals by allopregnanolone disappeared in Ca2+-free extracellular solution. The presynaptic action of this neurosteroid was also blocked by bumetanide, a blocker of cation-Cl− cotransporters, and by removal of extracellular Na+. The results suggest that allopregnanolone enhances GABAergic transmission at the MPOA neurons by pre- and postsynaptic mechanisms. The enhancement of GABA release by allopregnanolone might require a high Cl− concentration in the presynaptic terminal maintained by Na+-dependent, bumetanide-sensitive mechanisms (e.g., Na+-K+-Cl− cotransporter) and might be mediated by Ca2+ influx into presynaptic terminal.
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Lüscher, Bernhard, and Hanns Möhler. "Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience." F1000Research 8 (May 29, 2019): 751. http://dx.doi.org/10.12688/f1000research.18758.1.
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The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABAA receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition. In addition, allopregnanolone may stabilize normal mood by decreasing the activity of stress-responsive dentate granule cells and thereby sustain resilience behavior. Therefore, allopregnanolone may augment and extend its antidepressant activity by fostering resilience. The recent structural resolution of the neurosteroid binding domain of GABAA receptors will expedite the development of more selective ligands as a potential new class of central nervous system drugs.
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Gomes, Francisco Isaac Fernandes, Maria Gerusa Brito Aragão, Mirna Marques Bezerra, and Hellíada Vasconcelos Chaves. "GABAergic transmission and modulation of anxiety: A review on molecular aspects." Brazilian Journal of Biological Sciences 6, no. 12 (2019): 9–16. http://dx.doi.org/10.21472/bjbs.061202.
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Stress responses activate protective mechanisms to achieve homeostasis, but they can be detrimental when such responses become maladaptive. Anxiety relates to risk assessment of a potential threat and involves uncertainty regarding the anticipation of a threatening situation and it dampers quality of life. Gamma-Aminobutyric Acid (GABA) is the major inhibitory system in the central nervous system and plays a key role in the regulation of neuronal transmission in the brain, affecting many physiological and psychological processes. This mini-review aims to summarize key points concerned with the GABAergic transmission and basic aspects related to the GABAergic system in anxiety.
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Hernández-Vázquez, Fabiola, Julieta Garduño, and Salvador Hernández-López. "GABAergic modulation of serotonergic neurons in the dorsal raphe nucleus." Reviews in the Neurosciences 30, no. 3 (April 24, 2019): 289–303. http://dx.doi.org/10.1515/revneuro-2018-0014.
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Abstract The dorsal raphe nucleus (DRN), located in the brainstem, is involved in several functions such as sleep, temperature regulation, stress responses, and anxiety behaviors. This nucleus contains the largest population of serotonin expressing neurons in the brain. Serotonergic DRN neurons receive tonic γ-aminobutyric acid (GABA)inhibitory inputs from several brain areas, as well as from interneurons within the same nucleus. Serotonergic and GABAergic neurons in the DRN can be distinguished by their size, location, pharmacological responses, and electrophysiological properties. GABAergic neurons regulate the excitability of DRN serotonergic neurons and the serotonin release in different brain areas. Also, it has been shown that GABAergic neurons can synchronize the activity of serotonergic neurons across functions such as sleep or alertness. Moreover, dysregulation of GABA signaling in the DRN has been linked to psychiatric disorders such as anxiety and depression. This review focuses on GABAergic transmission in the DRN. The interaction between GABAergic and serotonergic neurons is discussed considering some physiological implications. Also, the main electrophysiological and morphological characteristics of serotonergic and GABAergic neurons are described.
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Imbrosci, Barbara, and Thomas Mittmann. "Functional Consequences of the Disturbances in the GABA-Mediated Inhibition Induced by Injuriesin the Cerebral Cortex." Neural Plasticity 2011 (2011): 1–14. http://dx.doi.org/10.1155/2011/614329.
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Cortical injuries are often reported to induce a suppression of the intracortical GABAergic inhibition in the surviving, neighbouring neuronal networks. Since GABAergic transmission provides the main source of inhibition in the mammalian brain, this condition may lead to hyperexcitability and epileptiform activity of cortical networks. However, inhibition plays also a crucial role in limiting the plastic properties of neuronal circuits, and as a consequence, interventions aiming to reestablish a normal level of inhibition might constrain the plastic capacity of the cortical tissue. A promising strategy to minimize the deleterious consequences of a modified inhibitory transmission without preventing the potential beneficial effects on cortical plasticity may be to unravel distinct GABAergic signaling pathways separately mediating these positive and negative events. Here, gathering data from several recent studies, we provide new insights to better face with this “double coin” condition in the attempt to optimize the functional recovery of patients.
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Baba, Hiroshi, Peter A. Goldstein, Manabu Okamoto, Tatsuro Kohno, Toyofumi Ataka, Megumu Yoshimura, and Koki Shimoji. "Norepinephrine Facilitates Inhibitory Transmission in Substantia Gelatinosa of Adult Rat Spinal Cord (Part 2)." Anesthesiology 92, no. 2 (February 1, 2000): 485. http://dx.doi.org/10.1097/00000542-200002000-00031.
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Background It has been reported previously that norepinephrine, when applied to the spinal cord dorsal horn, excites a subpopulation of dorsal horn neurons, presumably inhibitory interneurons. In the current study, the authors tested whether norepinephrine could activate inhibitory interneurons, specifically those that are "GABAergic." Methods A transverse slice was obtained from a segment of the lumbar spinal cord isolated from adult male Sprague-Dawley rats. Whole-cell patch-clamp recordings were made from substantia gelatinosa neurons using the blind patch-clamp technique. The effects of norepinephrine on spontaneous GABAergic inhibitory postsynaptic currents were studied. Results In the majority of substantia gelatinosa neurons tested, norepinephrine (10-60 microM) significantly increased both the frequency and the amplitude of GABAergic inhibitory postsynaptic currents. These increases were blocked by tetrodotoxin (1 microM). The effects of norepinephrine were mimicked by the alpha1-receptor agonist phenylephrine (10-80 microM) and inhibited by the alpha1-receptor-antagonist WB-4101 (0.5 microM). Primary-afferent-evoked polysynaptic excitatory postsynaptic potentials or excitatory postsynaptic currents in wide-dynamic-range neurons of the deep dorsal horn were also attenuated by phenylephrine (40 microM). Conclusion The observations suggest that GABAergic interneurons possess somatodendritic alpha1 receptors, and activation of these receptors excites inhibitory interneurons. The alpha1 actions reported herein may contribute to the analgesic action of intrathecally administered phenylephrine.
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Jo, Young-Hwan. "Endogenous BDNF regulates inhibitory synaptic transmission in the ventromedial nucleus of the hypothalamus." Journal of Neurophysiology 107, no. 1 (January 2012): 42–49. http://dx.doi.org/10.1152/jn.00353.2011.
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Output from steroidogenic factor-1 (SF-1) neurons in the ventromedial nucleus of the hypothalamus (VMH) is anorexigenic. SF-1 neurons express brain-derived neurotrophic factor (BDNF) that contributes to the regulation of food intake and body weight. Here I show that regulation of GABAergic inputs onto SF-1 neurons by endogenous BDNF determines the anorexigenic outcome from the VMH. Single-cell RT-PCR analysis reveals that one-third of SF-1 neurons express BDNF and that only a subset of BDNF-expressing SF-1 neurons coexpresses the melanocortin receptor type 4. Whole cell patch-clamp analysis of SF-1 neurons in the VMH shows that exogenous BDNF significantly increases the frequency of spontaneous GABAergic inhibitory postsynaptic currents (sIPSCs). This enhancement of GABA drive readily decreases the excitability of SF-1 neurons. However, treatment with BDNF has no significant effect on the frequency of TTX-independent GABAergic IPSCs. Moreover, TrkB receptors are not localized at the postsynaptic sites of GABAergic synapses on SF-1 neurons as there is no change in the amplitude of miniature IPSCs in the presence of BDNF. Dual patch-clamp recordings in mouse hypothalamic slices reveal that stimulation of one SF-1 neuron induces an increase in sIPSC frequency onto the neighboring SF-1 neuron. More importantly, this effect is blocked by a tyrosine kinase inhibitor. Hence, this increased GABA drive onto SF-1 neurons may, in part, explain the cellular mechanisms that mediate the anorexigenic effects of BDNF.
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Dunning, D. D., C. L. Hoover, I. Soltesz, M. A. Smith, and D. K. O'Dowd. "GABAA Receptor–Mediated Miniature Postsynaptic Currents and α-Subunit Expression in Developing Cortical Neurons." Journal of Neurophysiology 82, no. 6 (December 1, 1999): 3286–97. http://dx.doi.org/10.1152/jn.1999.82.6.3286.
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Previous studies have described maturational changes in GABAergic inhibitory synaptic transmission in the rodent somatosensory cortex during the early postnatal period. To determine whether alterations in the functional properties of synaptically localized GABAAreceptors (GABAARs) contribute to development of inhibitory transmission, we used the whole cell recording technique to examine GABAergic miniature postsynaptic currents (mPSCs) in developing cortical neurons. Neurons harvested from somatosensory cortices of newborn mice showed a progressive, eightfold increase in GABAergic mPSC frequency during the first 4 wk of development in dissociated cell culture. A twofold decrease in the decay time of the GABAergic mPSCs, between 1 and 4 wk, demonstrates a functional change in the properties of GABAARs mediating synaptic transmission in cortical neurons during development in culture. A similar maturational profile observed in GABAergic mPSC frequency and decay time in cortical neurons developing in vivo (assessed in slices), suggests that these changes in synaptically localized GABAARs contribute to development of inhibition in the rodent neocortex. Pharmacological and reverse transcription-polymerase chain reaction (RT-PCR) studies were conducted to determine whether changes in subunit expression might contribute to the observed developmental alterations in synaptic GABAARs. Zolpidem (300 nM), a subunit-selective benzodiazepine agonist with high affinity for α1-subunits, caused a reversible slowing of the mPSC decay kinetics in cultured cortical neurons. Development was characterized by an increase in the potency of zolpidem in modulating the mPSC decay, suggesting a maturational increase in percentage of functionally active GABAARs containing α1 subunits. The relative expression of α1 versus α5 GABAAR subunit mRNA in cortical tissue, both in vivo and in vitro, also increased during this same period. Furthermore, single-cell RT-multiplex PCR analysis revealed more rapidly decaying mPSCs in individual neurons in which α1 versus α5 mRNA was amplified. Together these data suggest that changes in α-subunit composition of GABAARs contribute to the maturation of GABAergic mPSCs mediating inhibition in developing cortical neurons.
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Okada, Fukuyama, Nakano, and Ueda. "Pharmacological Discrimination of Effects of MK801 on Thalamocortical, Mesothalamic, and Mesocortical Transmissions." Biomolecules 9, no. 11 (November 18, 2019): 746. http://dx.doi.org/10.3390/biom9110746.
Full textAbstract:
N-methyl-d-aspartate/glutamate receptor (NMDAR) is one of the major voltage-sensitive ligand-gated cation channel. Several noncompetitive NMDAR antagonists contribute to pathophysiology of schizophrenia and mood disorders; however, the effects of inhibition of NMDAR on several transmitter system have not been well clarified. Thus, this study determined the selective NMDAR antagonist, MK801 (dizocilpine), on thalamocortical, mesothalamic, and mesocortical transmissions associated with l-glutamate, GABA, serotonin, norepinephrine, and dopamine using multiprobe microdialysis. Perfusion with MK801 into the medial prefrontal cortex (mPFC) increased and decreased respective regional releases of monoamine and GABA without affecting l-glutamate. The mPFC MK801-induced monoamine release is generated by the regional GABAergic disinhibition. Perfusion with MK801 into the reticular thalamic nucleus (RTN) decreased GABA release in the mediodorsal thalamic nucleus (MDTN) but increased releases of l-glutamate and catecholamine without affecting serotonin in the mPFC. The RTN MK801-induced l-glutamate release in the mPFC was generated by GABAergic disinhibition in the MDTN, but RTN MK801-induced catecholamine release in the mPFC was generated by activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/glutamate receptor (AMPAR) which received l-glutamate release from thalamocortical glutamatergic terminals in the mPFC. Perfusion with MK801 into the dorsal raphe nucleus (DRN) decreased GABA release in the DRN but selectively increased serotonin release in the MDTN and mPFC. These DRN MK801-induced serotonin releases in the both mPFC and MDTN were also generated by GABAergic disinhibition in the DRN. These results indicate that the GABAergic disinhibition induced by NMDAR inhibition plays important roles in the MK801-induced releases of l-glutamate and monoamine in thalamic nuclei and cortex.
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Bleckert, Adam, Chi Zhang, Maxwell H. Turner, David Koren, David M. Berson, Silvia J. H. Park, Jonathan B. Demb, Fred Rieke, Wei Wei, and Rachel O. Wong. "GABA release selectively regulates synapse development at distinct inputs on direction-selective retinal ganglion cells." Proceedings of the National Academy of Sciences 115, no. 51 (December 3, 2018): E12083—E12090. http://dx.doi.org/10.1073/pnas.1803490115.
Full textAbstract:
Synaptic inhibition controls a neuron’s output via functionally distinct inputs at two subcellular compartments, the cell body and the dendrites. It is unclear whether the assembly of these distinct inhibitory inputs can be regulated independently by neurotransmission. In the mammalian retina, γ-aminobutyric acid (GABA) release from starburst amacrine cells (SACs) onto the dendrites of on–off direction-selective ganglion cells (ooDSGCs) is essential for directionally selective responses. We found that ooDSGCs also receive GABAergic input on their somata from other amacrine cells (ACs), including ACs containing the vasoactive intestinal peptide (VIP). When net GABAergic transmission is reduced, somatic, but not dendritic, GABAA receptor clusters on the ooDSGC increased in number and size. Correlative fluorescence imaging and serial electron microscopy revealed that these enlarged somatic receptor clusters are localized to synapses. By contrast, selectively blocking vesicular GABA release from either SACs or VIP ACs did not alter dendritic or somatic receptor distributions on the ooDSGCs, showing that neither SAC nor VIP AC GABA release alone is required for the development of inhibitory synapses in ooDSGCs. Furthermore, a reduction in net GABAergic transmission, but not a selective reduction from SACs, increased excitatory drive onto ooDSGCs. This increased excitation may drive a homeostatic increase in ooDSGC somatic GABAA receptors. Differential regulation of GABAA receptors on the ooDSGC’s soma and dendrites could facilitate homeostatic control of the ooDSGC’s output while enabling the assembly of the GABAergic connectivity underlying direction selectivity to be indifferent to altered transmission.
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Matsuo, Shin-ichiro, Il-Sung Jang, Junichi Nabekura, and Norio Akaike. "α2-Adrenoceptor-Mediated Presynaptic Modulation of GABAergic Transmission in Mechanically Dissociated Rat Ventrolateral Preoptic Neurons." Journal of Neurophysiology 89, no. 3 (March 1, 2003): 1640–48. http://dx.doi.org/10.1152/jn.00491.2002.
Full textAbstract:
The ventrolateral preoptic nucleus (VLPO) is a key nucleus involved in the homeostatic regulation of sleep-wakefulness. Little is known, however, about the cellular mechanisms underlying its role in sleep regulation and how the neurotransmitters, such as GABA and noradrenaline (NA), are involved. In the present study we investigated GABAergic transmission to acutely dissociated VLPO neurons using an enzyme-free, mechanical dissociation procedure in which functional terminals remained adherent and we investigated how this GABAergic transmission was modulated by NA. As previously reported in slices, NA hyperpolarized multipolar VLPO neurons and depolarized bipolar VLPO neurons. NA also inhibited the release of GABA onto multipolar VLPO neurons but had no effect on GABAergic transmission to bipolar neurons. The inhibition of release was mediated by presynaptic α2 adrenoceptors coupled to N-ethylmaleimide (NEM)-sensitive G-proteins which appeared to act via inhibition of adenylate cyclase and subsequent decreases in protein kinase A activity. The inhibition of GABA release did not, however, involve an inhibition of external Ca2+ influx. The results indicate that all VLPO neurons contain GABAergic inputs and that the different morphological subgroups of VLPO neurons are correlated not only to different postsynaptic responses to NA but also to different presynaptic NA responses. Furthermore our results demonstrate an additional mechanism by which NA can modulate the excitability of multipolar VLPO neurons which may have important implications for its role in regulating sleep/wakefulness.
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Shao, Mei, June C. Hirsch, and Kenna D. Peusner. "Emergence of Action Potential Generation and Synaptic Transmission in Vestibular Nucleus Neurons." Journal of Neurophysiology 96, no. 3 (September 2006): 1215–26. http://dx.doi.org/10.1152/jn.00180.2006.
Full textAbstract:
Principal cells of the chick tangential nucleus are vestibular nucleus neurons in the hindbrain. Although detailed information is available on the morphogenesis of principal cells and synaptogenesis of primary vestibular fibers, this is the first study of their early functional development, when vestibular terminals emerge at embryonic days 10 and 13 (E10 and E13). At E10, 60% of principal cells generated spikes on depolarization, whereas 50% exhibited excitatory postsynaptic currents (EPSCs) on vestibular-nerve stimulation. The frequency was 0.2 Hz for glutamatergic spontaneous EPSCs (sEPSCs) at −60 mV, and 0.6 Hz for spontaneous inhibitory postsynaptic current (sIPSC) at +10 mV and completely GABAergic. All of these synaptic events were TTX-insensitive, miniature events. At E13, 50% of principal cells generated spikes on depolarization and 82% exhibited EPSCs on vestibular-nerve stimulation. The frequency was 0.7 Hz for sEPSCs at −60 mV, and 0.8 Hz for sIPSCs at +10 mV. Most principal cells had sIPSCs composed of both GABAergic (75%) and glycinergic (25%) events, but a few cells had only GABAergic sIPSCs. TTX decreased the frequency of EPSCs by 12%, and the IPSCs by 17%. In summary, at E10, some principal cells generated immature spikes on depolarization and EPSCs on vestibular-nerve stimulation. At E10, GABAergic events predominated, AMPA events had low frequencies, and glycinergic activity was absent. By E13, glycinergic events first appeared. This data were compared systematically to that obtained from the late-term embryo and hatchling to reveal the long-term sequence of changes in synaptic events and excitability and offer a broader understanding of how the vestibular system is assembled during development.