Academic literature on the topic 'GABA, glutamate,synapses'
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Journal articles on the topic "GABA, glutamate,synapses"
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Khatri, Shailesh N., Wan-Chen Wu, Ying Yang, and Jason R. Pugh. "Direction of action of presynaptic GABAA receptors is highly dependent on the level of receptor activation." Journal of Neurophysiology 121, no. 5 (2019): 1896–905. http://dx.doi.org/10.1152/jn.00779.2018.
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Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABAA receptors. However, reports of the functional consequences of presynaptic GABAA receptor activation are variable across synapses, from inhibition to enhancement of transmitter release. We find that presynaptic GABAA receptor function is bidirectional at parallel fiber synapses depending on GABA concentration and modulation of GABAA receptors in mice. Activation of GABAA receptors by low GABA concentrations enhances glutamate release, whereas activation of receptors by higher GABA concentrations inhibits release. Furthermore, blocking GABAB receptors reduces GABAA receptor currents and shifts presynaptic responses toward greater enhancement of release across a wide range of GABA concentrations. Conversely, enhancing GABAA receptor currents with ethanol or neurosteroids shifts responses toward greater inhibition of release. The ability of presynaptic GABAA receptors to enhance or inhibit transmitter release at the same synapse depending on activity level provides a new mechanism for fine control of synaptic transmission by GABA and may explain conflicting reports of presynaptic GABAA receptor function across synapses. NEW & NOTEWORTHY GABAA receptors are widely expressed at presynaptic terminals in the central nervous system. However, previous reports have produced conflicting results on the function of these receptors at different synapses. We show that presynaptic GABAA receptor function is strongly dependent on the level of receptor activation. Low levels of receptor activation enhance transmitter release, whereas higher levels of activation inhibit release at the same synapses. This provides a novel mechanism by which presynaptic GABAA receptors fine-tune synaptic transmission.
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Gundersen, Vidar, Frode Fonnum, Ole Petter Ottersen, and Jon Storm-Mathisen. "Redistribution of Neuroactive Amino Acids in Hippocampus and Striatum during Hypoglycemia: A Quantitative Immunogold Study." Journal of Cerebral Blood Flow & Metabolism 21, no. 1 (2001): 41–51. http://dx.doi.org/10.1097/00004647-200101000-00006.
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Postembedding immunocytochemistry was used to localize aspartate, glutamate, gamma-aminobutyric acid (GABA), and glutamine in hippocampus and striatum during normo- and hypoglycemia in rat. In both brain regions, hypoglycemia caused aspartatelike immunoreactivity to increase. In hippocampus, this increase was evident particularly in the terminals of known excitatory afferents—in GABA-ergic neurons and myelinated axons. Aspartate was enriched along with glutamate in nerve terminals forming asymmetric synapses on spines and with GABA in terminals forming symmetric synapses on granule and pyramidal cell bodies. In both types of terminal, aspartate was associated with clusters of synaptic vesicles. Glutamate and glutamine immunolabeling were markedly reduced in all tissue elements in both brain regions, but less in the terminals than in the dendrosomatic compartments of excitatory neurons. In glial cells, glutamine labeling showed only slight attenuation. The level of GABA immunolabeling did not change significantly during hypoglycemia. The results support the view that glutamate and glutamine are used as energy substrates in hypoglycemia. Under these conditions both excitatory and inhibitory terminals are enriched with aspartate, which may be released from these nerve endings and thus contribute to the pattern of neuronal death characteristic of hypoglycemia.
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Kaneda, Katsuyuki, and Hitoshi Kita. "Synaptically Released GABA Activates Both Pre- and Postsynaptic GABAB Receptors in the Rat Globus Pallidus." Journal of Neurophysiology 94, no. 2 (2005): 1104–14. http://dx.doi.org/10.1152/jn.00255.2005.
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The globus pallidus (GP) contains abundant GABAergic synapses and GABAB receptors. To investigate whether synaptically released GABA can activate pre- and postsynaptic GABAB receptors in the GP, physiological recordings were performed using rat brain slice preparations. Cell-attached recordings from GABAA antagonist-treated preparations revealed that repetitive local stimulation induced a GABAB antagonist-sensitive pause in spontaneous firings of GP neurons. Whole cell recordings revealed that the repetitive stimulation evoked fast excitatory postsynaptic potentials followed by a slow inhibitory postsynaptic potential (IPSP) in GP neurons. The slow IPSP was insensitive to a GABAA receptor antagonist, increased in amplitude with the application of ionotropic glutamate receptor antagonists, and was suppressed by the GABAB antagonist CGP55845 . The reversal potential of the slow IPSP was close to the potassium equilibrium potential. These results suggest that synaptically released GABA activated postsynaptic GABAB receptors and induced the pause and the slow IPSP. On the other hand, in the neurons that were treated to block postsynaptic GABAB responses, CGP55845 increased the amplitudes of repetitive local stimulation-induced GABAA-mediated inhibitory postsynaptic currents (IPSCs) but not the ionotropic glutamate-mediated excitatory postsynaptic currents. Moreover, the GABAB receptor specific agonist baclofen reduced the frequency of miniature IPSCs without altering their amplitude distributions. These results suggest that synaptically released GABA also activated presynaptic GABAB autoreceptors, resulting in decreased GABA release in the GP. Together, we infer that both pre- and postsynaptic GABAB receptors may play crucial roles in the control of GP neuronal activity.
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DeFazio, R. Anthony, Ami P. Raval, Hung W. Lin, Kunjan R. Dave, David Della-Morte та Miguel A. Perez-Pinzon. "GABA Synapses Mediate Neuroprotection after Ischemic and εPKC Preconditioning in Rat Hippocampal Slice Cultures". Journal of Cerebral Blood Flow & Metabolism 29, № 2 (2008): 375–84. http://dx.doi.org/10.1038/jcbfm.2008.126.
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Delayed neuroprotection against ischemic challenges is conferred by both ischemic preconditioning (IPC) and preconditioning by activation of the ε-isoform of protein kinase C (εPKC-PC). In vivo, ischemic preconditioning enhances GABA release and ameliorates glutamate release during lethal cerebral ischemia. We tested the hypothesis that IPC and εPKC-PC confer neuroprotection by GABA synapses in rat organotypic hippocampal slices. Ischemic preconditioning or εPKC-PC was induced with 15 mins oxygen-glucose deprivation (OGD) or ψεRACK, a selective εPKC activator; and test ischemia consisted of 40 mins OGD. At the time of peak neuroprotection (48 h after preconditioning), we recorded GABAA receptor-mediated miniature postsynaptic currents (GABA mPSCs) in vulnerable CA1 pyramidal neurons using whole-cell voltage clamp techniques. The frequency and amplitude of GABA mPSCs significantly increased 48 h after IPC. In contrast, εPKC-PC enhanced only the amplitude of GABA mPSCs with no effect on frequency. We next asked if neuroprotection depended on these changes in GABA synapses. Weak antagonism of the GABAA receptor with bicuculline (100 nmol/L) decreased the amplitude of GABA mPSCs by 20.9±6.1%. When applied during test ischemia, 100nmol/L bicuculline abolished neuroprotection conferred by either IPC or εPKC-PC. We conclude that neuroprotection conferred by preconditioning depends on functional modifications of GABA synapses.
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Walls, Anne B., Elvar M. Eyjolfsson, Olav B. Smeland, et al. "Knockout of GAD65 has Major Impact on Synaptic GABA Synthesized from Astrocyte-Derived Glutamine." Journal of Cerebral Blood Flow & Metabolism 31, no. 2 (2010): 494–503. http://dx.doi.org/10.1038/jcbfm.2010.115.
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γ-Aminobutyric acid (GABA) synthesis from glutamate is catalyzed by glutamate decarboxylase (GAD) of which two isoforms, GAD65 and GAD67, have been identified. The GAD65 has repeatedly been shown to be important during intensified synaptic activity. To specifically elucidate the significance of GAD65 for maintenance of the highly compartmentalized intracellular and intercellular GABA homeostasis, GAD65 knockout and corresponding wild-type mice were injected with [1-13C]glucose and the astrocyte-specific substrate [1,2-13C]acetate. Synthesis of GABA from glutamine in the GABAergic synapses was further investigated in GAD65 knockout and wild-type mice using [1,2-13C]acetate and in some cases c-vinylGABA (GVG, Vigabatrin), an inhibitor of GABA degradation. A detailed metabolic mapping was obtained by nuclear magnetic resonance (NMR) spectroscopic analysis of tissue extracts of cerebral cortex and hippocampus. The GABA content in both brain regions was reduced by ~20%. Moreover, it was revealed that GAD65 is crucial for maintenance of biosynthesis of synaptic GABA particularly by direct synthesis from astrocytic glutamine via glutamate. The GAD67 was found to be important for synthesis of GABA from glutamine both via direct synthesis and via a pathway involving mitochondrial metabolism. Furthermore, a severe neuronal hypometabolism, involving glycolysis and tricarboxylic acid (TCA) cycle activity, was observed in cerebral cortex of GAD65 knockout mice.
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Liao, Fei, Haitao Liu, Santiago Milla-Navarro, Pedro de la Villa, and Francisco Germain. "Origin of Retinal Oscillatory Potentials in the Mouse, a Tool to Specifically Locate Retinal Damage." International Journal of Molecular Sciences 24, no. 4 (2023): 3126. http://dx.doi.org/10.3390/ijms24043126.
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To determine the origin of oscillatory potentials (OPs), binocular electroretinogram (ERG) recordings were performed under light and dark adaptation on adult healthy C57BL/6J mice. In the experimental group, 1 μL of PBS was injected into the left eye, while the right eye was injected with 1 μL of PBS containing different agents: APB, GABA, Bicuculline, TPMPA, Glutamate, DNQX, Glycine, Strychnine, or HEPES. The OP response depends on the type of photoreceptors involved, showing their maximum response amplitude in the ERG induced by mixed rod/cone stimulation. The oscillatory components of the OPs were affected by the injected agents, with some drugs inducing the complete abolition of oscillations (APB, GABA, Glutamate, or DNQX), whereas other drugs merely reduced the oscillatory amplitudes (Bicuculline, Glycine, Strychnine, or HEPES) or did not even affect the oscillations (TPMPA). Assuming that rod bipolar cells (RBC) express metabotropic Glutamate receptors, GABAA, GABAC, and Glycine receptors and that they release glutamate mainly on Glycinergic AII amacrine cells and GABAergic A17 amacrine cells, which are differently affected by the mentioned drugs, we propose that RBC-AII/A17 reciprocal synapses are responsible for the OP generation in the ERG recordings in the mice. We conclude that the reciprocal synapses between RBC and AII/A17 are the basis of the ERG OP oscillations of the light response, and this fact must be taken into consideration in any ERG test that shows a decrease in the OPs’ amplitude.
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Yamamoto, Ryo, Takafumi Furuyama, Tokio Sugai, Munenori Ono, Denis Pare, and Nobuo Kato. "Serotonergic control of GABAergic inhibition in the lateral amygdala." Journal of Neurophysiology 123, no. 2 (2020): 670–81. http://dx.doi.org/10.1152/jn.00500.2019.
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Much evidence implicates the serotonergic regulation of the amygdala in anxiety. Thus the present study was undertaken to characterize the influence of serotonin (5-HT) on principal neurons (PNs) of the rat lateral amygdala (LA), using whole cell recordings in vitro. Because inhibition is a major determinant of PN activity, we focused on the control of GABAergic transmission by 5-HT. IPSCs were elicited by local electrical stimulation of LA in the presence of glutamate receptor antagonists. We found that 5-HT reduces GABAA inhibitory postsynaptic currents (IPSCs) via presynaptic 5-HT1B receptors. While the presynaptic inhibition of GABA release also attenuated GABAB currents, this effect was less pronounced than for GABAA currents because 5-HT also induced a competing postsynaptic enhancement of GABAB currents. That is, GABAB currents elicited by pressure application of GABA or baclofen were enhanced by 5-HT. In addition, we obtained evidence suggesting that 5-HT differentially regulates distinct subsets of GABAergic synapses. Indeed, GABAA IPSCs were comprised of two components: a relatively 5-HT-insensitive IPSC that had a fast time course and a 5-HT-sensitive component that had a slower time course. Because the relative contribution of these two components varied depending on whether neurons were recorded at proximity versus at a distance from the stimulating electrodes, we speculate that distinct subtypes of local-circuit cells contribute the two contingents of GABAergic synapses. Overall, our results indicate that 5-HT is a potent regulator of synaptic inhibition in LA. NEW & NOTEWORTHY We report that 5-HT, acting via presynaptic 5-HT1B receptors, attenuates GABAA IPSCs by reducing GABA release in the lateral amygdala (LA). In parallel, 5-HT enhances GABAB currents postsynaptically, such that GABAB inhibitory postsynaptic currents (IPSCs) are relatively preserved from the presynaptic inhibition of GABA release. We also found that the time course of 5-HT-sensitive and -insensitive GABAA IPSCs differ. Together, these results indicate that 5-HT is a potent regulator of synaptic inhibition in LA.
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Sethuramanujam, Santhosh, and Malcolm M. Slaughter. "Disinhibitory recruitment of NMDA receptor pathways in retina." Journal of Neurophysiology 112, no. 1 (2014): 193–203. http://dx.doi.org/10.1152/jn.00817.2013.
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Glutamate release at bipolar to ganglion cell synapses activates NMDA and AMPA/kainic acid (KA) ionotropic glutamate receptors. Their relative strength determines the output signals of the retina. We found that this balance is tightly regulated by presynaptic inhibition that preferentially suppresses NMDA receptor (NMDAR) activation. In transient ON-OFF neurons, block of GABA and glycine feedback enhanced total NMDAR charge by 35-fold in the ON response and 9-fold in the OFF compared with a 1.7-fold enhancement of AMPA/KA receptors. Blocking only glycine receptors enhanced the NMDAR excitatory postsynaptic current 10-fold in the ON and 2-fold in the OFF pathway. Blocking GABAA or GABAC receptors (GABACRs or GABAARs) produced small changes in total NMDAR charge. When both GABAARs and GABACRs were blocked, the total NMDAR charge increased ninefold in the ON and fivefold in the OFF pathway. This exposed a strong GABACR feedback to bipolar cells that was suppressed by serial amacrine cell synapses mediated by GABAARs. The results indicate that NMDAR currents are large but latent, held in check by dual GABA and glycine presynaptic inhibition. One example of this controlled NMDAR activation is the cross talk between ON and OFF pathways. Blocking the ON pathway increased NMDAR relative strength in the OFF pathway. Stimulus prolongation similarly increased the NMDAR relative strength in the OFF response. This NMDAR enhancement was produced by a diminution in GABA and glycine feedback. Thus the retinal network recruits NMDAR pathways through presynaptic disinhibition.
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Chéry, Nadège, and Yves De Koninck. "GABAB Receptors Are the First Target of Released GABA at Lamina I Inhibitory Synapses in the Adult Rat Spinal Cord." Journal of Neurophysiology 84, no. 2 (2000): 1006–11. http://dx.doi.org/10.1152/jn.2000.84.2.1006.
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We have previously provided functional evidence that glycine and GABA are contained in the same synaptic vesicles and coreleased at the same synapses in lamina I of the rat spinal dorsal horn. However, whereas both glycine receptors (GlyRs) and GABAA receptors (GABAARs) are expressed on the postsynaptic target, under certain conditions inhibitory events appeared to be mediated by GlyRs only. We therefore wanted to test whether GABAB receptors could be activated in conditions where GABA released was insufficient to activate GABAARs. Focal stimulation in the vicinity of visually identified lamina I neurons elicited monosynaptic IPSCs in the presence of ionotropic glutamate receptor antagonists. Pairs of stimuli were given at different interstimulus intervals (ISI), ranging from 25 ms to 1 s to study the depression of the second of evoked IPSCs (paired pulse depression; PPD). Maximal PPD of IPSCs was 60 ± 14% (SE) (of the conditioning pulse amplitude), at ISI between 150 and 200 ms. PPD was observed with IPSCs evoked at stimulus intensities where they had no GABAAR component. PPD of small evoked IPSCs was not affected by the GABAAR antagonist bicuculline but significantly attenuated by 10–30 μM CGP52432, a specific GABAB receptor antagonist. These data indicate that, under conditions where GABA released is insufficient to affect postsynaptic GABAARs at lamina I inhibitory synapses, significant activation of presynaptic GABABreceptors can occur.
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Aroniadou-Anderjaska, Vassiliki, Fu-Ming Zhou, Catherine A. Priest, Matthew Ennis, and Michael T. Shipley. "Tonic and Synaptically Evoked Presynaptic Inhibition of Sensory Input to the Rat Olfactory Bulb Via GABABHeteroreceptors." Journal of Neurophysiology 84, no. 3 (2000): 1194–203. http://dx.doi.org/10.1152/jn.2000.84.3.1194.
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Olfactory receptor neurons of the nasal epithelium send their axons, via the olfactory nerve (ON), to the glomeruli of the olfactory bulb (OB), where the axon terminals form glutamatergic synapses with the apical dendrites of mitral and tufted cells, the output cells of the OB, and with juxtaglomerular (JG) interneurons. Many JG cells are GABAergic. Here we show that, despite the absence of conventional synapses, GABA released from JG cells activates GABAB receptors on ON terminals and inhibits glutamate release both tonically and in response to ON stimulation. Field potential recordings and current-source density analysis, as well as intracellular and whole cell recording techniques were used in rat OB slices. Baclofen (2–5 μM), a GABAB agonist, completely suppressed ON-evoked synaptic responses of both mitral/tufted cells and JG cells, with no evidence for postsynaptic effects. Baclofen (0.5–1 μM) also reversed paired-pulse depression (PPD) of mitral/tufted cell responses to paired-pulse facilitation (PPF), and reduced depression of JG cell excitatory postsynaptic currents (EPSCs) during repetitive ON stimulation. These results suggest that baclofen reduced the probability of glutamate release from ON terminals. The GABAB antagonists CGP35348 or CGP55845A increased mitral/tufted cell responses evoked by single-pulse ON stimulation, suggesting that glutamate release from ON terminals is tonically suppressed via GABAB receptors. The same antagonists reduced PPD of ON-evoked mitral/tufted cell responses at interstimulus intervals 50–400 ms. This finding suggests that a single ON impulse evokes sufficient GABA release, presumably from JG cells, to activate GABAB receptors on ON terminals. Thus GABAB heteroreceptors on ON terminals are activated by ambient levels of extrasynaptic GABA, and by ON input to the OB. The time course of ON-evoked, GABABpresynaptic inhibition suggests that neurotransmission to M/T cells and JG cells will be significantly suppressed when ON impulses arrive in glomeruli at 2.5–20 Hz. GABAB receptor–mediated presynaptic inhibition of sensory input to the OB may play an important role in shaping the activation pattern of the OB glomeruli during olfactory coding.
Dissertations / Theses on the topic "GABA, glutamate,synapses"
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Monassier, Laurent. "Approche pharmacologique de la modulation des synapses glutamatergiques du systeme nerveux sympathique : une cible pour des drogues cardioprotectrices ?" Strasbourg 1, 1997. http://www.theses.fr/1997STR15026.
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Pin, Jean-Philippe. "Interaction glutamate/GABA : mécanismes et pharmacologie de la libération de GABA des neurones de striatum en culture primaire : effets des acides aminés excitateurs." Montpellier 2, 1987. http://www.theses.fr/1987MON20211.
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Boulland, Jean-Luc. "Recycling the amino acid neurotransmitter glutamate in the CNS : l'alchimie du glutamate et de la glutamine." Paris 6, 2004. http://www.theses.fr/2004PA066017.
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El, Khoury Rita. "Deux syndromes, un même gène : conséquences d'un mauvais dosage de MeCP2 sur la transmission synaptique et le comportement chez la souris." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5075.
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MeCP2 est une protéine multifonctionnelle agissant à de nombreux niveaux de contrôle des programmes génétiques. Un mauvais dosage de MeCP2 cause un groupe de maladies neurologiques dont le point commun est une déficience intellectuelle sévère. Des mutations ou une délétion de MECP2 causent le syndrome de Rett chez les filles, alors que sa surexpression cause chez les garçons le syndrome de duplication de MECP2. Plusieurs modèles murins de Mecp2-pathies ont été générés qui permettent d’expliciter les mécanismes qui sous-tendent l’apparition des symptômes dans ces différentes maladies. Dans notre laboratoire, deux modèles murins sont utilisés: le modèle Mecp2tm1Bird qui présente une déficience en Mecp2 et le modèle Mecp2Tg1 présentant une surexpression de Mecp2. Ce travail de thèse a permis de caractériser l’évolution postnatale des déficits moteurs et physiologique affectant la souris Mecp2Tg1. Nos résultats montrent que la surexpression de Mecp2 conduit à l’apparition de problèmes moteurs, et des convulsions chez la souris. En parallèle, nous avons étudié les déficits neuronaux affectants la voie GABAergique et glutamatergique chez la souris déficiente en Mecp2. Nous avons montré que la déficience en Mecp2 cause une dérégulation de la transmission synaptique dépendante du ‘territoire’ et de l’âge de la maladie. Ces dérégulations sous-tendent vraisemblablement des différences neurophysiologiques importantes entre les régions du cerveau qu’il nous reste encore à découvrir. Par ailleurs, nous avons constaté que la stimulation pharmacologique du système GABAergique par la Tiagabine, permet d’augmenter la survie des animaux Mecp2-déficients<br>MeCP2 is a multifunctional protein acting on many levels of control of genetic programs. Thus, an abnormal dosage of MeCP2 protein causes a group of neurological disorders with a common feature of severe intellectual disability. Mutations or deletions in MECP2 gene cause Rett Syndrome in females, whereas in boys its overexpression causes the MECP2-duplication Syndrome. Several mouse models of MECP2-pathologies were generated. The use of these models is crucial for understanding the mechanisms underlying the onset of symptoms related to the pathology. In our laboratory, two mouse models are under study: The Mecp2tm1Bird model with an Mecp2 deficiency and the transgenic Mecp2Tg1 model with a double expression of Mecp2. My thesis work enabled the characterization of the postnatal physiological and motor deficits affecting Mecp2Tg1 mice. My work led to a better understanding of the gene dosage effect. Our results showed that overexpression of Mecp2 in mice, led to the occurrence of motor problems, and seizures. In parallel, we studied the neural deficits affecting the GABA and the glutamate pathway in several structures of the Mecp2 deficient brain (Mecp2tm1bird). We showed that Mecp2-deficiency causes deregulation of the synaptic transmission, which is dependent on the area, and the age of the study. These deregulations underlie significant neurophysiological differences between the different regions of the brain that we still have to uncover. Furthermore, we found that pharmacological stimulation of the GABA system with Tiagabine, a molecule capable of acting on GABA transporters to prevent its uptake, increases the survival of Mecp2-deficients animals
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Malinina, Evgenya. "Neurotransmission and functional synaptic plasticity in the rat medial preoptic nucleus." Doctoral thesis, Umeå : Umeå university, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-25874.
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Piot, Laura. "Nouveaux éléments sur la structure, fonction et pharmacologie des récepteurs delta (GluD)." Thesis, Sorbonne université, 2021. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2021SORUS522.pdf.
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Les récepteurs ionotropiques du glutamate (iGluRs) sont les principaux médiateurs de la transmission excitatrice dans le système nerveux central (SNC) des Vertébrés. Il a longtemps été considéré que les réponses biologiques provoquées par les iGluRs étaient nécessairement liées au flux d’ions à travers leur canal, d’où l’appellation « ionotropique ». Toutefois de nombreuses données indiquent que plusieurs membres de cette classe de récepteurs peuvent provoquer des signalisations intracellulaires sans ouverture de leur canal. C’est le cas des récepteurs delta, classe comprenant deux membres (GluD1 et GluD2) et qui joue des rôles clé dans la formation des synapses et la régulation de la transmission synaptique par le biais de signalisations non ionotropiques. Toutefois les mécanismes moléculaires de fonctionnement et de signalisation des récepteurs GluD, ainsi que leur pharmacologie, restent mal compris à ce jour, par manque d’outils appropriés pour leur étude. Durant ma thèse, j’ai développé deux méthodes d’étude des récepteurs GluD1: (i) un mutant ouvert de façon constitutive permettant l’étude de GluD1 par électrophysiologie cellulaire classique, et (ii) une technique de fluorescence dite de ‘voltage-clamp fluorometry’ ou VCF pour détecter en temps réel des changements de conformation locaux au sein de GluD1. Ces outils offrent un moyen sans précédent d’étude de la pharmacologie et des mécanismes moléculaires de transduction du signal dans cette classe de récepteurs. J’ai ainsi pu caractériser et quantifier la sensibilité des récepteurs GluD1 à une série de ligands synthétiques et naturels<br>Ionotropic glutamate receptors (iGluRs) are the main mediators of excitatory transmission in the vertebrate central nervous system (CNS). It has long been considered that the biological responses elicited by iGluRs were necessarily related to the flow of ions through their channel, hence the name "ionotropic". However, many data indicate that several members of this class of receptors can induce intracellular signaling without opening their channel. This is the case of delta receptors, a class comprising two members (GluD1 and GluD2) which plays key roles in synapse formation and the regulation of synaptic transmission through non-ionotropic signaling. However, the molecular mechanisms of GluD receptor function and signaling, as well as their pharmacology, still remain poorly understood, due to a lack of appropriate tools for their study. During my thesis, I developed two methods to study GluD1 receptors: (i) a constitutively open mutant allowing the study of GluD1 by classical cell electrophysiology, and (ii) a fluorescence technique called 'voltage-clamp fluorometry' or VCF to detect in real time local conformational changes within GluD1. These tools offer an unprecedented means to study the pharmacology and molecular mechanisms of signal transduction in this class of receptors. I was thus able to characterize and quantify the sensitivity of GluD1 receptors to a series of synthetic and natural ligands
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Tora, Amélie. "Modulation endogène des récepteurs métabotropiques du glutamate : bases moléculaires et implications fonctionnelles de la sensibilité au chlore extracellulaire." Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTT032.
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Les récepteurs métabotropiques du glutamate (mGluRs) sont des récepteurs couplés aux protéines G (RCPGs) modulant la transmission synaptique au sein du système nerveux central. D'un point de vue structural, ils ont la particularité de posséder un large domaine extracellulaire, le Venus Flytrap (VFT), où se lie leur ligand endogène, le glutamate. Leur domaine transmembranaire à 7 hélices, commun à tous les RCPGs, est connu pour être la cible d'une nouvelle classe de molécules à visée thérapeutique, les modulateurs allostériques. Au contraire, le VFT est le siège du développement de ligands compétitifs du glutamate et peu de choses sont connues quant à l'existence de modulateurs allostériques du VFT. Des études récentes ont mis en évidence une sensibilité des mGluRs aux ions extracellulaires et en particulier au chlore (Cl-), sans que son site de liaison ne soit identifié. Dans ce contexte, ce travail de thèse explore la possibilité d'une modulation allostérique endogène des mGluRs par les ions Cl-, en identifiant leur(s) site(s) de liaison(s) et leur effet sur la dynamique conformationnelle et la fonction des récepteurs. En combinant une approche pharmacologique, biophysique basée sur la technique de FRET, et la modélisation, nous avons tout d'abord confirmé que le Cl- potentialise l'action du glutamate sur tous les mGluRs et qu'il favorise la conformation active des récepteurs en se liant au niveau du VFT. Les mGluRs présentent également une sensibilité différente au Cl-, mGlu4 étant le plus sensible et mGlu2 le moins. Ceci s'explique notamment par le nombre de sites fonctionnels, tous les mGluRs dont mGlu4 possédant 2 sites par monomère à l'exception de mGlu2 qui n'en possède qu'un, en raison d'une mutation « clé » d'une sérine en aspartate dans le lobe 1 du VFT. D'autre part, le récepteur mGlu3 est apparu comme un cas particulier ayant une sensibilité accrue au Cl-, son domaine VFT cumulant la présence et l'orientation adéquate d'acides aminés formant un « verrou » Cl-, qui favorise de manière drastique la conformation active et une activité basale élevée de ce récepteur. Enfin, la modélisation de la variation de la concentration extracellulaire en Cl- lors d'une activité synaptique GABAergique est compatible avec une modulation des mGluRs les plus sensibles. En conclusion, le Cl- est un modulateur allostérique endogène des mGluRs et l'exploitation de ses sites de liaison au sein du VFT pourrait permettre le développement de nouveaux agents thérapeutiques<br>Metabotropic glutamate receptors (mGluRs) are G coupled-protein receptors (GPCRs) playing key roles in synaptic transmission in the central nervous system. They display a large extracellular domain, the Venus Flytrap (VFT) where the endogenous ligand, glutamate, binds. Their 7 transmembrane helices spanning domain, common to all GPCRs, is known to be the target of new therapeutic compounds, called allosteric modulators. In contrast, VFT domain is used to develop glutamate competitive ligands and there are only few data about allosteric modulators targeting the VFT. Recent studies have shown mGluRs are sensitive to extracellular ions, particularly to chloride (Cl-), although its binding site has not been elucidated. This thesis work explores the possibility of an endogenous allosteric modulation of mGluRs by Cl-, aiming to delineate its binding site(s) and its effect on receptor conformational dynamics and function. Using pharmacological, FRET based biophysical approaches and modelling, we have first confirmed that Cl- potentiates glutamate action in all mGluRs and that this ion favors agonist induced active conformation by binding to the VFT. mGluRs are also differently sensitive to Cl-, mGlu4 being the most and mGlu2 the least. This difference is notably explained by the number of Cl- functional sites within the VFT, all mGluRs including mGlu4 displaying 2 sites per monomer whereas mGlu2 has only 1 site due to a serine-aspartate “key” mutation in VFT lobe 1. Besides, mGlu3 receptor appears to be a “special case”, as this receptor is highly sensitive to Cl- because its VFT domain is carrying amino acids creating a “Cl- lock”, which dramatically favors active conformation and a high level of basal activity. Finally, modelling of extracellular Cl- concentration variations in a GABAergic synapse is compatible with a modulation of the most sensitive mGluRs. In conclusion, Cl- is an endogenous allosteric modulator of mGluRs and exploiting its binding sites may yield to the development of innovative therapeutic tools
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Majdoubi, Mohammed el. "Etude neuroanatomique des innervations des neurones magnocellulaires à ocytocine et à vasopressine et de leur contribution à la plasticité synaptique induite par l'allaitement." Bordeaux 2, 1996. http://www.theses.fr/1996BOR28435.
Full textBook chapters on the topic "GABA, glutamate,synapses"
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Gillespie, Deda C., and Karl Kandler. "GABA, Glycine, and Glutamate Co-Release at Developing Inhibitory Synapses." In Co-Existence and Co-Release of Classical Neurotransmitters. Springer US, 2008. http://dx.doi.org/10.1007/978-0-387-09622-3_5.
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