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1
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 (May 1, 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 (January 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 (August 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, and 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, no. 2 (October 29, 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, Linn Hege Nilsen, Inger Schousboe, Arne Schousboe, Ursula Sonnewald, and Helle S. Waagepetersen. "Knockout of GAD65 has Major Impact on Synaptic GABA Synthesized from Astrocyte-Derived Glutamine." Journal of Cerebral Blood Flow & Metabolism 31, no. 2 (July 28, 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 (February 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 (February 1, 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 (July 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 (August 1, 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 (September 1, 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.
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Wang, Huaixing, and Julie S. Haas. "GABABR Modulation of Electrical Synapses and Plasticity in the Thalamic Reticular Nucleus." International Journal of Molecular Sciences 22, no. 22 (November 9, 2021): 12138. http://dx.doi.org/10.3390/ijms222212138.
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Two distinct types of neuronal activity result in long-term depression (LTD) of electrical synapses, with overlapping biochemical intracellular signaling pathways that link activity to synaptic strength, in electrically coupled neurons of the thalamic reticular nucleus (TRN). Because components of both signaling pathways can also be modulated by GABAB receptor activity, here we examined the impact of GABAB receptor activation on the two established inductors of LTD in electrical synapses. Recording from patched pairs of coupled rat neurons in vitro, we show that GABAB receptor inactivation itself induces a modest depression of electrical synapses and occludes LTD induction by either paired bursting or metabotropic glutamate receptor (mGluR) activation. GABAB activation also occludes LTD from either paired bursting or mGluR activation. Together, these results indicate that afferent sources of GABA, such as those from the forebrain or substantia nigra to the reticular nucleus, gate the induction of LTD from either neuronal activity or afferent glutamatergic receptor activation. These results add to a growing body of evidence that the regulation of thalamocortical transmission and sensory attention by TRN is modulated and controlled by other brain regions. Significance: We show that electrical synapse plasticity is gated by GABAB receptors in the thalamic reticular nucleus. This effect is a novel way for afferent GABAergic input from the basal ganglia to modulate thalamocortical relay and is a possible mediator of intra-TRN inhibitory effects.
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Moulder, K. L., X. Jiang, A. A. Taylor, W. Shin, K. D. Gillis, and S. Mennerick. "Vesicle Pool Heterogeneity at Hippocampal Glutamate and GABA Synapses." Journal of Neuroscience 27, no. 37 (September 12, 2007): 9846–54. http://dx.doi.org/10.1523/jneurosci.2803-07.2007.
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Lalo, Ulyana, Jemma Andrew, Oleg Palygin, and Yuriy Pankratov. "Ca2+-dependent modulation of GABAA and NMDA receptors by extracellular ATP: implication for function of tripartite synapse." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1407–11. http://dx.doi.org/10.1042/bst0371407.
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The importance of communication between neuronal and glial cells for brain function is recognized by a modern concept of ‘tripartite synapse’. Astrocytes enwrap synapses and can modulate their activity by releasing gliotransmitters such as ATP, glutamate and D-serine. One of the regulatory pathways in the tripartite synapse is mediated by P2X purinoreceptors. Release of ATP from synaptic terminals and astrocytes activates Ca2+ influx via P2X purinoreceptors which co-localize with NMDA (N-methyl-D-aspartate) and GABA (γ-aminobutyric acid) receptors and can modulate their activity via intracellular cascades which involve phosphatase II and PKA (protein kinase A).
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Case, Daniel T., and Deda C. Gillespie. "Pre- and postsynaptic properties of glutamatergic transmission in the immature inhibitory MNTB-LSO pathway." Journal of Neurophysiology 106, no. 5 (November 2011): 2570–79. http://dx.doi.org/10.1152/jn.00644.2010.
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The lateral superior olive (LSO) integrates excitatory inputs driven by sound arriving at the ipsilateral ear with inhibitory inputs driven by sound arriving at the contralateral ear in order to compute interaural intensity differences needed for localizing high-frequency sound sources. Specific mechanisms necessary for developmental refinement of the inhibitory projection, which arises from the medial nucleus of the trapezoid body (MNTB), have only been partially deciphered. The demonstration that immature MNTB-LSO synapses release glutamate has led to a model in which early glutamate neurotransmission plays a major role in inhibitory plasticity. We used whole cell electrophysiology in acute auditory brain stem slices of neonatal rats to examine glutamatergic transmission in the developing MNTB-LSO pathway. Unexpectedly, AMPA receptor (AMPAR)-mediated responses were prevalent at the earliest ages. We found a salient developmental profile for NMDA receptor (NMDAR) activation, described both by the proportion of total glutamate current and by current durations, and we found evidence for distinct release probabilities for GABA/glycine and glutamate in the MNTB-LSO pathway. The developmental profile of NMDAR is consistent with the possibility that the inhibitory MNTB-LSO pathway experiences a sensitive period, driven by cochlear activity and mediated by GluN2B-containing NMDARs, between postnatal days 3 and 9. Differing neurotransmitter release probabilities could allow the synapse to switch between GABA/glycinergic transmission and mixed glutamate/GABA/glycinergic transmission in response to changing patterns of spiking activity.
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Ben-Ari, Yehezkel, Jean-Luc Gaiarsa, Roman Tyzio, and Rustem Khazipov. "GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations." Physiological Reviews 87, no. 4 (October 2007): 1215–84. http://dx.doi.org/10.1152/physrev.00017.2006.
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Developing networks follow common rules to shift from silent cells to coactive networks that operate via thousands of synapses. This review deals with some of these rules and in particular those concerning the crucial role of the neurotransmitter γ-aminobuytric acid (GABA), which operates primarily via chloride-permeable GABAAreceptor channels. In all developing animal species and brain structures investigated, neurons have a higher intracellular chloride concentration at an early stage leading to an efflux of chloride and excitatory actions of GABA in immature neurons. This triggers sodium spikes, activates voltage-gated calcium channels, and acts in synergy with NMDA channels by removing the voltage-dependent magnesium block. GABA signaling is also established before glutamatergic transmission, suggesting that GABA is the principal excitatory transmitter during early development. In fact, even before synapse formation, GABA signaling can modulate the cell cycle and migration. The consequence of these rules is that developing networks generate primitive patterns of network activity, notably the giant depolarizing potentials (GDPs), largely through the excitatory actions of GABA and its synergistic interactions with glutamate signaling. These early types of network activity are likely required for neurons to fire together and thus to “wire together” so that functional units within cortical networks are formed. In addition, depolarizing GABA has a strong impact on synaptic plasticity and pathological insults, notably seizures of the immature brain. In conclusion, it is suggested that an evolutionary preserved role for excitatory GABA in immature cells provides an important mechanism in the formation of synapses and activity in neuronal networks.
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Hoffpauir, Brian K., and Evanna L. Gleason. "Activation of mGluR5 Modulates GABAA Receptor Function in Retinal Amacrine Cells." Journal of Neurophysiology 88, no. 4 (October 1, 2002): 1766–76. http://dx.doi.org/10.1152/jn.2002.88.4.1766.
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Amacrine cells in the vertebrate retina receive glutamatergic input from bipolar cells and make synapses onto bipolar cells, ganglion cells, and other amacrine cells. Recent studies indicate that amacrine cells express metabotropic glutamate receptors (mGluRs) and that signaling within the inner plexiform layer (IPL) of the retina might be modulated by mGluR activity. This study tests the hypothesis that activation of mGluR5 modulates GABAA receptor function in retinal amacrine cells. Whole cell voltage-clamp recordings were combined with pharmacology to establish the identity of the ionotropic GABA receptors expressed in primary cultures of chick amacrine cells and to determine how mGluR5 activity affected the behavior of those receptors. Application of GABA (20 μM) produced currents that reversed at −58.2 ± 0.9 mV, near the predicted Cl−reversal potential of −59 mV. The GABAA receptor antagonist, bicuculline (50 μM), completely blocked the GABA-gated currents. cis-4-Aminocrotonic acid (CACA; 100 μM), a GABAC receptor agonist, produced small currents that were not blocked by the GABAC antagonist, (1,2,5,6-tetrahydropyridine-4-yl) methylphosphinic acid (TPMPA; 20 μM), but were completely blocked by bicuculline. These results indicate that cultured amacrine cells express GABAA receptors exclusively. Activating mGluR5 with ( RS)-2-chloro-5-hydroxyphenylglycine (CHPG; 300 μM) enhanced GABA-gated currents by 10.0 ± 1.5%. Buffering internal Ca2+ with BAPTA (10 mM) blocked the CHPG-dependent enhancement. Activation of PKC with the cell-permeable PKC activators (−)-7-octylindolactam V, phorbol 12-myristate 13 acetate (PMA), or 1-oleoyl-2-acetyl-sn-glycerol (OAG) also enhanced GABA-gated currents in a dose-dependent manner. Preactivation of PKC occluded the mGluR5-dependent enhancement, and inhibition of Ca-dependent PKC isotypes with Gö6976 (35 nM) suppressed the effects of mGluR5 activation, suggesting that mGluR5 and PKC are part of the same pathway. To determine if mGluR5-dependent enhancement occurred at synaptic GABAA receptors, postsynaptic currents were recorded in the presence of CHPG. On average, the mean amplitudes of the quantal events were increased by about 18% when mGluR5 was activated. These results indicate that activation of mGluR5 enhances GABA-gated current in cultured amacrine cells in a manner that is both Ca2+- and PKC-dependent. These results support the possibility that glutamate released from bipolar cells can modulate the function of GABAergic amacrine cells and alter signaling in the inner plexiform layer.
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Keable, Ryan, Iryna Leshchyns’ka, and Vladimir Sytnyk. "Trafficking and Activity of Glutamate and GABA Receptors: Regulation by Cell Adhesion Molecules." Neuroscientist 26, no. 5-6 (May 23, 2020): 415–37. http://dx.doi.org/10.1177/1073858420921117.
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The efficient targeting of ionotropic receptors to postsynaptic sites is essential for the function of chemical excitatory and inhibitory synapses, constituting the majority of synapses in the brain. A growing body of evidence indicates that cell adhesion molecules (CAMs), which accumulate at synapses at the earliest stages of synaptogenesis, are critical for this process. A diverse variety of CAMs assemble into complexes with glutamate and GABA receptors and regulate the targeting of these receptors to the cell surface and synapses. Presynaptically localized CAMs provide an additional level of regulation, sending a trans-synaptic signal that can regulate synaptic strength at the level of receptor trafficking. Apart from controlling the numbers of receptors present at postsynaptic sites, CAMs can also influence synaptic strength by modulating the conductivity of single receptor channels. CAMs thus act to maintain basal synaptic transmission and are essential for many forms of activity dependent synaptic plasticity. These activities of CAMs may underlie the association between CAM gene mutations and synaptic pathology and represent fundamental mechanisms by which synaptic strength is dynamically tuned at both excitatory and inhibitory synapses.
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Hirasawa, Hajime, Massimo Contini, and Elio Raviola. "Extrasynaptic release of GABA and dopamine by retinal dopaminergic neurons." Philosophical Transactions of the Royal Society B: Biological Sciences 370, no. 1672 (July 5, 2015): 20140186. http://dx.doi.org/10.1098/rstb.2014.0186.
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In the mouse retina, dopaminergic amacrine (DA) cells synthesize both dopamine and GABA. Both transmitters are released extrasynaptically and act on neighbouring and distant retinal neurons by volume transmission. In simultaneous recordings of dopamine and GABA release from isolated perikarya of DA cells, a proportion of the events of dopamine and GABA exocytosis were simultaneous, suggesting co-release. In addition, DA cells establish GABAergic synapses onto AII amacrine cells, the neurons that transfer rod bipolar signals to cone bipolars. GABA A but not dopamine receptors are clustered in the postsynaptic membrane. Therefore, dopamine, irrespective of its site of release—synaptic or extrasynaptic—exclusively acts by volume transmission. Dopamine is released upon illumination and sets the gain of retinal neurons for vision in bright light. The GABA released at DA cells' synapses probably prevents signals from the saturated rods from entering the cone pathway when the dark-adapted retina is exposed to bright illumination. The GABA released extrasynaptically by DA and other amacrine cells may set a ‘GABAergic tone’ in the inner plexiform layer and thus counteract the effects of a spillover of glutamate released at the bipolar cell synapses of adjacent OFF and ON strata, thus preserving segregation of signals between ON and OFF pathways.
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Otis, T. S., and I. Mody. "Differential activation of GABAA and GABAB receptors by spontaneously released transmitter." Journal of Neurophysiology 67, no. 1 (January 1, 1992): 227–35. http://dx.doi.org/10.1152/jn.1992.67.1.227.
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1. Whole-cell patch-clamp techniques were used to record from dentate gyrus granule cells in adult rat brain slices when N-methyl-D-aspartate (NMDA) and non-NMDA type glutamate receptors were blocked by D-2-amino-5-phosphonovaleric acid (D-AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively. Spontaneous inhibitory postsynaptic currents (sIPSCs), each presumably due to vesicular release of gamma-aminobutyric acid (GABA), selectively activated GABAA-type receptors. None of the individual sIPSCs showed a slow-onset potassium current characteristic of GABAB receptor activation. 2. In contrast, stimulation in the molecular layer with a bipolar stimulating electrode or bath application of the convulsant drug 4-aminopyridine (4-AP, 10-30 microM) elicited fast GABAA IPSCs followed by slower outward currents that were sensitive to the selective GABAB antagonist CGP 35348 (0.1-1 mM) and that reversed polarity near the potassium equilibrium potential. 3. CGP 35348 (0.5-1 mM) or the GABAB agonist (-)baclofen (1 microM) had no significant effect on the frequency or average amplitude of sIPSCs. However, either bath application of (-)baclofen (1 microM) or a preceding conditioning stimulus caused large reductions in the amplitude of stimulus-evoked IPSCs, suggesting a strong GABAB-mediated presynaptic inhibition of stimulus-evoked GABA release. 4. We conclude that under normal conditions spontaneous transmitter release does not activate GABAB receptors in dentate gyrus slices. These findings are consistent with either of two general possibilities. Separate groups of interneurons with different basal firing rates may selectively form GABAA and GABAB synapses.(ABSTRACT TRUNCATED AT 250 WORDS)
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Heinmiller, Andrew, Ryan Ting-A-Kee, Hector Vargas-Perez, Andrew Yeh, and Derek van der Kooy. "Tegmental pedunculopontine glutamate and GABA-B synapses mediate morphine reward." Behavioral Neuroscience 123, no. 1 (2009): 145–55. http://dx.doi.org/10.1037/a0014015.
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Stewart, R. R., D. J. Zou, J. M. Treherne, K. Mollgard, N. R. Saunders, and J. G. Nicholls. "The intact central nervous system of the newborn opossum in long-term culture: fine structure and GABA-mediated inhibition of electrical activity." Journal of Experimental Biology 161, no. 1 (November 1, 1991): 25–41. http://dx.doi.org/10.1242/jeb.161.1.25.
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1. The entire central nervous system (CNS) of the newly born, South American opossum (Monodelphis domestica) was isolated and maintained in basal medium, Eagle's (BME) with 0.2% foetal calf serum and antibiotics. Isolated CNS preparations remained electrically excitable for up to 10 days. The fine structure of the spinal cord was normal after 5 days in culture: axons, synapses, dendrites and glia were virtually unchanged. Signs of degeneration were evident only in dorsal areas of the spinal cord, which had been denervated by removal of the dorsal root ganglia during dissection. 2. Amino acid transmitters such as glycine, glutamate, N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA), applied to the bathing fluid, rapidly and reversibly inhibited synaptic transmission in cervical segments of the spinal cord. GABA (10–100 mumol l-1) produced a dose-dependent reduction in the magnitude of ventral root responses evoked by dorsal root stimulation. GABA also inhibited synaptically activated compound action potentials produced by spinal cord stimulation. Dose-response curves for GABA obtained in different preparations were highly reproducible. 3. Both GABAA and GABAB receptors were reversibly activated by selective agonists and inhibited by specific antagonists. The actions of GABA were potentiated by benzodiazepines, competitively antagonised by bicuculline (a selective GABAA antagonist) and mimicked by muscimol (a GABAA agonist). Baclofen (a specific GABAB agonist) also inhibited electrical activity and was competitively antagonised by the GABAB antagonist, CGP 35348. 4. After 5 days of culture in BME or minimal essential medium (MEM), GABA dose-response curves were unchanged from those observed immediately after removal of the CNS. The inhibitory potency of baclofen was also unaffected by culture in BME. By contrast, after 5 days of culture in MEM, baclofen no longer inhibited electrical activity. This difference between BME and MEM could be attributed to the higher content of L-histidine in MEM. Thus, addition of 150 mumol l-1 L-histidine to BME produced similar results to culture in MEM: the inhibitory action of baclofen was virtually abolished after 3–5 days. L-Histidine had no effect on freshly dissected preparations. Chronic application of L-histidine did not affect glycine or glutamate responses after 5 days. Addition of D-histidine or other amino acids, such as arginine, to BME did not abolish the responses to baclofen. 5. These results show that the isolated CNS of the newborn opossum survives well in long-term culture and that it provides a useful preparation to study receptor development and plasticity of an intact mammalian CNS in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)
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Verkhratsky, Alexei, and Maiken Nedergaard. "The homeostatic astroglia emerges from evolutionary specialization of neural cells." Philosophical Transactions of the Royal Society B: Biological Sciences 371, no. 1700 (August 5, 2016): 20150428. http://dx.doi.org/10.1098/rstb.2015.0428.
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Evolution of the nervous system progressed through cellular diversification and specialization of functions. Conceptually, the nervous system is composed from electrically excitable neuronal networks connected with chemical synapses and non-excitable glial cells that provide for homeostasis and defence. Astrocytes are integrated into neural networks through multipartite synapses; astroglial perisynaptic processes closely enwrap synaptic contacts and control homeostasis of the synaptic cleft, supply neurons with glutamate and GABA obligatory precursor glutamine and contribute to synaptic plasticity, learning and memory. In neuropathology, astrocytes may undergo reactive remodelling or degeneration; to a large extent, astroglial reactions define progression of the pathology and neurological outcome. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.
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Speed, Haley E., and Lynn E. Dobrunz. "Developmental Decrease in Short-Term Facilitation at Schaffer Collateral Synapses in Hippocampus Is mGluR1 Sensitive." Journal of Neurophysiology 99, no. 2 (February 2008): 799–813. http://dx.doi.org/10.1152/jn.00625.2007.
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Developmental changes can occur in the dynamic properties of synapses, known as short-term plasticity. Using rat acute hippocampal slices at room temperature, we have previously shown a decrease in short-term facilitation at Schaffer collateral synapses from young adults compared with juveniles in response to temporally complex natural stimulus patterns such as synapses receive in vivo. Here we show that this developmental decrease in facilitation is also seen at 32°C and investigate the underlying mechanism. Addition of the mGluR1 antagonist LY367385 increases short-term facilitation in response to the natural stimulus pattern, showing that mGluR1 is activated by synaptically released glutamate. Although synaptic activation of mGluR1 occurs at both ages, the effect is larger in young adults. Furthermore, blocking mGluR1 eliminates most of the developmental decrease in short-term facilitation during the natural stimulus pattern. We investigated possible retrograde/downstream messengers involved after synaptic activation of mGluR1. Blocking cannabinoid receptors has no effect on the response during the natural stimulus pattern, indicating that the reduction in facilitation during synaptic activation of mGluR1 does not occur through release of endocannabinoids. We find that blocking GABAB receptors increases facilitation during the natural stimulus pattern and occludes the effect of the mGluR1 antagonist, indicating a role for the modulation of GABA release from inhibitory interneurons by mGluR1 activation. These data suggest a model where synaptic activation of mGluR1 on inhibitory interneurons causes an increase in GABA release by inhibitory interneurons, which activates GABAB receptors on Schaffer collateral synapses and inhibits short-term facilitation during the natural stimulus pattern.
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LIN, BIN, PAUL R. MARTIN, and ULRIKE GRÜNERT. "Expression and distribution of ionotropic glutamate receptor subunits on parasol ganglion cells in the primate retina." Visual Neuroscience 19, no. 4 (July 2002): 453–65. http://dx.doi.org/10.1017/s0952523802194077.
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The response properties of postreceptoral sensory neurones are determined by the properties of their input neurones, by intrinsic membrane properties, and by the properties of neurotransmitter receptors on the soma and dendritic tree. We previously showed that inhibitory neurotransmitter (GABAA and glycine) receptors on a well-characterised sensory neurone, the parasol ganglion cell in the primate retina, are segregated towards the distal part of the dendritic tree. Here we studied the distribution of excitatory ionotropic glutamate receptor subunits on the dendrites of parasol cells in the retina of a New World monkey, the marmoset, Callithrix jacchus. Individual ganglion cells were intracellularly injected in an in vitro retinal wholemount preparation. Ionotropic glutamate receptor subunits, including AMPA (GluR1-4), kainate (GluR6/7), NMDA (NR1C2′) subunits, and the orphan receptors δ1 and δ2 were visualized with immunocytochemical methods. Immunoreactive puncta that colocalized with the dendrites of ganglion cells were analyzed using standard and/or confocal light microscopy. Colocalized puncta were present on parasol dendrites for all subunits studied, but their density was much lower (approximately 1/5) than previously reported for inhibitory (GABA and glycine) receptors. Segregation of the glutamate receptor clusters (GluR1, GluR6/7 subunits) to the peripheral dendrites was less marked than that shown for GABA and glycine receptor clusters. No sign of segregation of colocalized puncta to the peripheral part of the dendritic field was seen with antibodies to the GluR2, GluR2/3, GluR4, δ1/2, or NR1C2′ subunits. The results suggest that although there is diverse expression of glutamate receptor subtypes, the glutamatergic synapses form only a small proportion of the total synaptic input to primate ganglion cells. They further suggest that the processes which control distribution of excitatory and inhibitory synapses on the dendritic field of ganglion cells are, at least to some extent, independent.
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Han, Victor Z., Kirsty Grant, and Curtis C. Bell. "Rapid Activation of GABAergic Interneurons and Possible Calcium Independent GABA Release in the Mormyrid Electrosensory Lobe." Journal of Neurophysiology 83, no. 3 (March 1, 2000): 1592–604. http://dx.doi.org/10.1152/jn.2000.83.3.1592.
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The primary afferent fibers from the electroreceptors of mormyrid electric fish terminate centrally in the granular layer of the electrosensory lobe (ELL). This study examines the excitatory and inhibitory processes that take place in this layer using an in vitro slice preparation and field potentials evoked by stimulation of primary afferent fibers in the deep fiber layer of ELL. The postsynaptic response to stimulation of the afferent fibers was still present after blocking chemical transmission in three different ways: by adding glutamate receptor antagonists to the medium, by substituting a nominally calcium-free medium for normal medium, and by blocking calcium channels with cadmium. Blockade of chemical transmission was demonstrated by disappearance of control responses to parallel fiber stimulation. The continued presence of a postsynaptic response in the absence of chemical excitation is consistent with previous anatomic and physiological evidence for electrical synapses between afferent fibers and granular cells in ELL. Granular cell activation by primary afferent fibers was followed by a powerful, short-latency inhibition mediated by GABA and GABAA receptors, as indicated by a large increase in the postsynaptic response to afferent fiber stimulation following application of the GABAA receptor antagonist, bicuculline. Bicuculline caused a marked increase of the postsynaptic response even after chemical synaptic excitation had been blocked by glutamate receptor antagonists, by a calcium-free medium, or by cadmium. Thus activation of the inhibitory interneurons responsible for GABA release did not require chemical excitation. Nonchemical excitation of the inhibitory interneurons could be mediated either by electrical synapses between afferent fibers and inhibitory interneurons, or by nonsynaptic activation of the large GABAergic terminals that are known to be present on granular cells. The marked increase of the postsynaptic response caused by bicuculline in a calcium-free medium or in the presence of cadmium suggests that the release of GABA by inhibitory terminals was not entirely dependent on calcium influx. This effect of bicuculline on the postsynaptic response in a calcium-free medium or in the presence of cadmium was markedly reduced by prior addition of the GABA transporter antagonist, nipecotic acid. Thus calcium-independent release of GABA may occur in ELL and may be partly dependent on reversal of a GABA transporter. Rapid and powerful inhibition at the first stage in the processing of electrosensory information could serve to enhance the small differences in latency among afferent fibers that appear to encode small differences in stimulus intensity.
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Ghatpande, Ambarish S., and Alan Gelperin. "Presynaptic Muscarinic Receptors Enhance Glutamate Release at the Mitral/Tufted to Granule Cell Dendrodendritic Synapse in the Rat Main Olfactory Bulb." Journal of Neurophysiology 101, no. 4 (April 2009): 2052–61. http://dx.doi.org/10.1152/jn.90734.2008.
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The mammalian olfactory bulb receives multiple modulatory inputs, including a cholinergic input from the basal forebrain. Understanding the functional roles played by the cholinergic input requires an understanding of the cellular mechanisms it modulates. In an in vitro olfactory bulb slice preparation we demonstrate cholinergic muscarinic modulation of glutamate release onto granule cells that results in γ-aminobutyric acid (GABA) release onto mitral/tufted cells. We demonstrate that the broad-spectrum cholinergic agonist carbachol triggers glutamate release from mitral/tufted cells that activates both AMPA and NMDA receptors on granule cells. Activation of the granule cell glutamate receptors leads to calcium influx through voltage-gated calcium channels, resulting in spike-independent, asynchronous GABA release at reciprocal dendrodendritic synapses that granule cells form with mitral/tufted cells. This cholinergic modulation of glutamate release persists through much of postnatal bulbar development, suggesting a functional role for cholinergic inputs from the basal forebrain in bulbar processing of olfactory inputs and possibly in postnatal development of the olfactory bulb.
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Strecker, George J., Jean-Pierre Wuarin, and F. Edward Dudek. "GABAA-Mediated Local Synaptic Pathways Connect Neurons in the Rat Suprachiasmatic Nucleus." Journal of Neurophysiology 78, no. 4 (October 1, 1997): 2217–20. http://dx.doi.org/10.1152/jn.1997.78.4.2217.
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Strecker, George J., Jean-Pierre Wuarin, and F. EdwardDudek. GABAA-mediated local synaptic pathways connect neurons in the rat suprachiasmatic nucleus. J. Neurophysiol. 78: 2217–2220, 1997. The suprachiasmatic nucleus (SCN) in mammals functions as the biological clock controlling circadian rhythms, but the synaptic circuitry of the SCN is largely unexplored. Most SCN neurons use the neurotransmitter γ-aminobutyric acid (GABA), and anatomic studies indicate many GABAergic synapses and local axon collaterals; however, physiological evidence for synaptic communication among SCN neurons is indirect. We have used three approaches to investigate local circuitry in the SCN in acute hypothalamic slices from rat. First, tetrodotoxin was used to block action-potential-dependent synaptic release, which resulted in a decrease in the frequency of spontaneous synaptic currents in SCN neurons, suggesting that spontaneously active neurons in the slice connect synaptically to SCN neurons. Postsynaptic currents in SCN neurons were also evoked by the selective stimulation of other SCN neurons with glutamate, which avoids direct activation of axons that might originate outside the SCN. Two different methods of glutamate microapplication (i.e., pressure ejection and ultraviolet photolysis of caged glutamate) indicated that SCN neurons receive GABAA-receptor-mediated synaptic input from other SCN neurons. In contrast, glutamate-receptor-mediated synaptic connections between SCN neurons were not detected. The GABAergic synapses that comprise the network described here could conceivably be a substrate for the synchronization and amplification of the circadian rhythm of SCN firing. Alternatively, this circuitry might mediate other aspects of clock function such as the integration of environmental and physiological information.
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Dai, Shuiping, Misha Perouansky, and Robert A. Pearce. "Isoflurane Enhances Both Fast and Slow Synaptic Inhibition in the Hippocampus at Amnestic Concentrations." Anesthesiology 116, no. 4 (April 1, 2012): 816–23. http://dx.doi.org/10.1097/aln.0b013e31824be0e3.
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Background Inhibition mediated by γ-aminobutyric acid type A (GABA A) receptors has long been considered an important target for a variety of general anesthetics. In the hippocampus, two types of phasic GABA A receptor-mediated inhibition coexist: GABA A,fast, which is expressed primarily at peri-somatic sites, and GABAA,slow, which is expressed primarily in the dendrites. Their spatial segregation suggests distinct functions: GABA A,slow may control plasticity of dendritic synapses, whereas GABA A,fast controls action potential initiation at the soma. We examined modulation of GABA A,fast and GABA A,slow inhibition by isoflurane at amnesic concentrations, and compared it with modulation by behaviorally equivalent doses of the GABA A receptor-selective drug etomidate. Methods Whole cell recordings were obtained from pyramidal cells in organotypic hippocampal cultures prepared from C57BL/6 × 129/SvJ F1 hybrid mice. GABA A receptor-mediated currents were isolated using glutamate receptor antagonists. GABAA,slow currents were evoked by electrical stimulation in the stratum lacunosum-moleculare. Miniature GABA A,fast currents were recorded in the presence of tetrodotoxin. Results 100 μM isoflurane (approximately EC50,amnesia) slowed fast- and slow-inhibitory postsynaptic current decay by approximately 25%. Higher concentrations, up to 400 μM, produced proportionally greater effects without altering current amplitudes. The effects on GABA A,slow were approximately one-half those produced by equi-amnesic concentrations of etomidate. Conclusions Isoflurane enhances both types of phasic GABA A receptor-mediated inhibition to similar degrees at amnesic concentrations. This pattern differs from etomidate, which at low concentrations selectively enhances slow inhibition. These effects of isoflurane are sufficiently large that they may contribute substantially to its suppression of hippocampal learning and memory.
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Redman, Stephen J., and Robert Porter. "David Roderick Curtis 1927–2017." Historical Records of Australian Science 31, no. 2 (2020): 152. http://dx.doi.org/10.1071/hr19016.
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David Curtis was a pioneer in the identification of excitatory and inhibitory transmitters released at synapses in the central nervous system. He made major contributions to the identification of gamma-amino butyric acid (GABA) and glycine as inhibitory transmitters released at inhibitory synapses. His work laid the foundation for the subsequent acceptance that L-glutamate was the major excitatory transmitter. David’s scientific work led to him receiving many accolades and honours, including Fellowships of the Australian Academy of Sciences, the Royal Society and a Companion of the Order of Australia.
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LINDSTROM, SARAH H., NASON AZIZI, CYNTHIA WELLER, and MARTIN WILSON. "Retinal input to efferent target amacrine cells in the avian retina." Visual Neuroscience 27, no. 3-4 (July 2010): 103–18. http://dx.doi.org/10.1017/s0952523810000155.
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AbstractThe bird visual system includes a substantial projection, of unknown function, from a midbrain nucleus to the contralateral retina. Every centrifugal, or efferent, neuron originating in the midbrain nucleus makes synaptic contact with the soma of a single unique amacrine cell, the target cell (TC). By labeling efferent neurons in the midbrain, we have been able to identify their terminals in retinal slices and make patch-clamp recordings from TCs. TCs generate Na+-based action potentials (APs) triggered by spontaneous EPSPs originating from multiple classes of presynaptic neurons. Exogenously applied glutamate elicited inward currents having the mixed pharmacology of NMDA, kainate, and inward rectifying AMPA receptors. Exogenously applied GABA elicited currents entirely suppressed by GABAzine and therefore mediated by GABAA receptors. Immunohistochemistry showed the vesicular glutamate transporter, vGluT2, to be present in the characteristic synaptic boutons of efferent terminals, whereas the GABA synthetic enzyme, GAD, was present in much smaller processes of intrinsic retinal neurons. Extracellular recording showed that exogenously applied GABA was directly excitatory to TCs and, consistent with this, NKCC, the Cl− transporter often associated with excitatory GABAergic synapses, was identified in TCs by antibody staining. The presence of excitatory retinal input to TCs implies that TCs are not merely slaves to their midbrain input; instead, their output reflects local retinal activity and descending input from the midbrain.
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Giustizieri, Michela, Giorgio Bernardi, Nicola B. Mercuri, and Nicola Berretta. "Distinct Mechanisms of Presynaptic Inhibition at GABAergic Synapses of the Rat Substantia Nigra Pars Compacta." Journal of Neurophysiology 94, no. 3 (September 2005): 1992–2003. http://dx.doi.org/10.1152/jn.00171.2005.
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We investigated the mechanisms of presynaptic inhibition of GABAergic neurotransmission by group III metabotropic glutamate receptors (mGluRs) and GABAB receptors, in dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Both the group III mGluRs agonist l-(+)-2-amino-4-phosphonobutyric acid (AP4, 100 μM) and the GABAB receptor agonist baclofen (10 μM) reversibly depressed the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) to 48.5 ± 2.7 and 79.3 ± 1.6% (means ± SE) of control, respectively. On the contrary, the frequency of action potential-independent miniature IPSCs (mIPSCs), recorded in tetrodotoxin (TTX, 1 μM) and cadmium (100 μM) were insensitive to AP4 but were reduced by baclofen to 49.7 ± 8.6% of control. When the contribution of voltage-dependent calcium channels (VDCCs) to synaptic transmission was boosted with external barium (1 mM), AP4 became effective in reducing TTX-resistant mIPSCs to 65.4 ± 3.9% of control, thus confirming a mechanism of presynaptic inhibition involving modulation of VDCCs. Differently from AP4, baclofen inhibited to 58.5 ± 6.7% of control the frequency mIPSCs recorded in TTX and the calcium ionophore ionomycin (2 μM), which promotes Ca2+-dependent, but VDCC-independent, transmitter release. Moreover, in the presence of α-latrotoxin (0.3 nM), to promote a Ca2+-independent vesicular release of GABA, baclofen reduced mIPSC frequency to 48.1 ± 3.2% of control, while AP4 was ineffective. These results indicate that group III mGluRs depress GABA release to DA neurons of the SNc through inhibition of presynaptic VDCCs, while presynaptic GABAB receptors directly impair transmitter exocytosis.
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El Khoueiry, Corinne, Cristina Alba-Delgado, Myriam Antri, Maria Gutierrez-Mecinas, Andrew J. Todd, Alain Artola, and Radhouane Dallel. "GABAA and Glycine Receptor-Mediated Inhibitory Synaptic Transmission onto Adult Rat Lamina IIi PKCγ-Interneurons: Pharmacological but Not Anatomical Specialization." Cells 11, no. 8 (April 15, 2022): 1356. http://dx.doi.org/10.3390/cells11081356.
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Mechanical allodynia (pain to normally innocuous tactile stimuli) is a widespread symptom of inflammatory and neuropathic pain. Spinal or medullary dorsal horn (SDH or MDH) circuits mediating tactile sensation and pain need to interact in order to evoke mechanical allodynia. PKCγ-expressing (PKCγ+) interneurons and inhibitory controls within SDH/MDH inner lamina II (IIi) are pivotal in connecting touch and pain circuits. However, the relative contribution of GABA and glycine to PKCγ+ interneuron inhibition remains unknown. We characterized inhibitory inputs onto PKCγ+ interneurons by combining electrophysiology to record spontaneous and miniature IPSCs (sIPSCs, mIPSCs) and immunohistochemical detection of GABAARα2 and GlyRα1 subunits in adult rat MDH. While GlyR-only- and GABAAR-only-mediated mIPSCs/sIPSCs are predominantly recorded from PKCγ+ interneurons, immunohistochemistry reveals that ~80% of their inhibitory synapses possess both GABAARα2 and GlyRα1. Moreover, nearly all inhibitory boutons at gephyrin-expressing synapses on these cells contain glutamate decarboxylase and are therefore GABAergic, with around half possessing the neuronal glycine transporter (GlyT2) and therefore being glycinergic. Thus, while GABA and glycine are presumably co-released and GABAARs and GlyRs are present at most inhibitory synapses on PKCγ+ interneurons, these interneurons exhibit almost exclusively GABAAR-only and GlyR-only quantal postsynaptic inhibitory currents, suggesting a pharmacological specialization of their inhibitory synapses.
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Farzana, F., R. Zalm, N. Chen, K. W. Li, Seth G. N. Grant, A. B. Smit, R. F. Toonen, and M. Verhage. "Neurobeachin Regulates Glutamate- and GABA-Receptor Targeting to Synapses via Distinct Pathways." Molecular Neurobiology 53, no. 4 (May 2, 2015): 2112–23. http://dx.doi.org/10.1007/s12035-015-9164-8.
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Masugi-Tokita, Miwako, and Ryuichi Shigemoto. "High-resolution quantitative visualization of glutamate and GABA receptors at central synapses." Current Opinion in Neurobiology 17, no. 3 (June 2007): 387–93. http://dx.doi.org/10.1016/j.conb.2007.04.012.
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Gao, Fan, Bruce R. Maple, and Samuel M. Wu. "I4AA-Sensitive Chloride Current Contributes to the Center Light Responses of Bipolar Cells in the Tiger Salamander Retina." Journal of Neurophysiology 83, no. 6 (June 1, 2000): 3473–82. http://dx.doi.org/10.1152/jn.2000.83.6.3473.
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Light-evoked currents in depolarizing and hyperpolarizing bipolar cells (DBCs and HBCs) were recorded under voltage-clamp conditions in living retinal slices of the larval tiger salamander. Responses to illumination at the center of the DBCs' and HBCs' receptive fields were mediated by two postsynaptic currents: Δ I C, a glutamate-gated cation current with a reversal potential near 0 mV, and Δ I Cl, a chloride current with a reversal potential near −60 mV. In DBCs Δ I C was suppressed byl-2-amino-4-phosphonobutyric acid (l-AP4), and in HBCs it was suppressed by 6,7-dinitroquinoxaline-2,3-dione (DNQX). In both DBCs and HBCs Δ I Cl was suppressed by imidazole-4-acetic acid (I4AA), a GABA receptor agonist and GABAC receptor antagonist. In all DBCs and HBCs examined, 10 μM I4AA eliminated Δ I Cl and the light-evoked current became predominately mediated by Δ I C. The addition of 20 μM l-AP4 to the DBCs or 50 μM DNQX to HBCs completely abolished Δ I C. Focal application of glutamate at the inner plexiform layer elicited chloride currents in bipolar cells by depolarizing amacrine cells that release GABA at synapses on bipolar cell axon terminals, and such glutamate-induced chloride currents in DBCs and HBCs could be reversibly blocked by 10 μM I4AA. These experiments suggest that the light-evoked, I4AA-sensitive chloride currents (Δ I Cl) in DBCs and HBCs are mediated by narrow field GABAergic amacrine cells that activate GABACreceptors on bipolar cell axon terminals. Picrotoxin (200 μM) or (1,2,5,6-tetrahydropyridine-4yl) methyphosphinic acid (TPMPA) (2 other GABAC receptor antagonists) did not block (but enhanced and broadened) the light-evoked Δ I Cl, although they decreased the chloride current induced by puff application of GABA or glutamate. The light response of narrow field amacrine cells were not affected by I4AA, but were substantially enhanced and broadened by picrotoxin. These results suggest that there are at least two types of GABACreceptors in bipolar cells: one exhibits stronger I4AA sensitivity than the other, but both can be partially blocked by picrotoxin. The GABA receptors in narrow field amacrine cells are I4AA insensitive and picrotoxin sensitive. The light-evoked Δ I Cl in bipolar cells are mediated by the more strongly I4AA-sensitive GABAC receptors. Picrotoxin, although acting as a partial GABAC receptor antagonist in bipolar cells, does not suppress Δ I Clbecause its presynaptic effects on amacrine cell light responses override its antagonistic postsynaptic actions.
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Ulrich, Daniel, Valérie Besseyrias, and Bernhard Bettler. "Functional Mapping of GABAB-Receptor Subtypes in the Thalamus." Journal of Neurophysiology 98, no. 6 (December 2007): 3791–95. http://dx.doi.org/10.1152/jn.00756.2007.
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The thalamus plays an important role in attention mechanisms and the generation of brain rhythms. γ-Aminobutyric acid type B (GABAB) receptors are known to regulate the main output neurons of the thalamus, the thalamocortical relay (TCR) cells. However, the contributions of the two predominant GABAB-receptor subtypes, GABAB(1a,2) and GABAB(1b,2), to the control of TCR cell activity are unknown. Here, we used genetic and electrophysiological methods to investigate subtype-specific GABAB effects at the inputs to TCR cells. We found that mainly GABAB(1a,2) receptors inhibit the release of glutamate from corticothalamic fibers impinging onto TCR cells. In contrast, both GABAB(1a,2) and GABAB(1b,2) receptors efficiently inhibit the release of GABA from thalamic reticular nucleus (TRN) neurons onto TCR neurons. Likewise, both GABAB(1a,2) and GABAB(1b,2) receptors efficiently activate somatodendritic K+ currents in TCR cells. In summary, our data show that GABAB(1b,2) receptors cannot compensate for the absence of GABAB(1a,2) receptors at glutamatergic inputs to TCR cells. This shows that the predominant association of GABAB(1a,2) receptors with glutamatergic terminals is a feature that is preserved at several brain synapses. Furthermore, our data indicate that the cognitive deficits observed with mice lacking GABAB(1a,2) receptors could to some extent relate to attention deficits caused by disinhibited release of glutamate onto TCR neurons.
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Palmer, Mary J., and Jenni Harvey. "Honeybee Kenyon cells are regulated by a tonic GABA receptor conductance." Journal of Neurophysiology 112, no. 8 (October 15, 2014): 2026–35. http://dx.doi.org/10.1152/jn.00180.2014.
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The higher cognitive functions of insects are dependent on their mushroom bodies (MBs), which are particularly large in social insects such as honeybees. MB Kenyon cells (KCs) receive multisensory input and are involved in associative learning and memory. In addition to receiving sensory input via excitatory nicotinic synapses, KCs receive inhibitory GABAergic input from MB feedback neurons. Cultured honeybee KCs exhibit ionotropic GABA receptor currents, but the properties of GABA-mediated inhibition in intact MBs are currently unknown. Here, using whole cell recordings from KCs in acutely isolated honeybee brain, we show that KCs exhibit a tonic current that is inhibited by picrotoxin but not by bicuculline. Bath application of GABA (5 μM) and taurine (1 mM) activate a tonic current in KCs, but l-glutamate (0.1–0.5 mM) has no effect. The tonic current is strongly potentiated by the allosteric GABAA receptor modulator pentobarbital and is reduced by inhibition of Ca2+ channels with Cd2+ or nifedipine. Noise analysis of the GABA-evoked current gives a single-channel conductance value for the underlying receptors of 27 ± 3 pS, similar to that of resistant to dieldrin (RDL) receptors. The amount of injected current required to evoke action potential firing in KCs is significantly lower in the presence of picrotoxin. KCs recorded in an intact honeybee head preparation similarly exhibit a tonic GABA receptor conductance that reduces neuronal excitability, a property that is likely to contribute to the sparse coding of sensory information in insect MBs.
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Redman, S. J., and R. Porter. "David Roderick Curtis. 3 June 1927—11 December 2017." Biographical Memoirs of Fellows of the Royal Society 69 (August 26, 2020): 133–43. http://dx.doi.org/10.1098/rsbm.2020.0025.
Full textAbstract:
David Curtis was a pioneer in the identification of excitatory and inhibitory transmitters released at synapses in the central nervous system. He made major contributions to the identification of gamma-amino butyric acid (GABA) and glycine as inhibitory transmitters released at inhibitory synapses. His work laid the foundation for the subsequent acceptance that l -glutamate was the major excitatory transmitter. David's scientific work led to him receiving many accolades and honours, including fellowships of the Australian Academy of Sciences and the Royal Society and a Companion of the Order of Australia. Note: This memoir was commissioned by the Historical Records of Australian Science and is published here with minor amendments. It was published in June 2020 and is available at https://doi.org/10.1071/HR19016 .
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Wang, Na, and Junyu Xu. "Functions of Kinesin Superfamily Proteins in Neuroreceptor Trafficking." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/639301.
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Synaptic plasticity is widely regarded as the cellular basis of learning and memory. Understanding the molecular mechanism of synaptic plasticity has been one of center pieces of neuroscience research for more than three decades. It has been well known that the trafficking ofα-amino-3-hydroxy-5-methylisoxazoloe-4-propionic acid- (AMPA-) type, N-methyl-D-aspartate- (NMDA-) type glutamate receptors to and from synapses is a key molecular event underlying many forms of synaptic plasticity. Kainate receptors are another type of glutamate receptors playing important roles in synaptic transmission. In addition, GABA receptors also play important roles in modulating the synaptic plasticity. Kinesin superfamily proteins (also known as KIFs) transport various cargos in both anterograde and retrograde directions through the interaction with different adaptor proteins. Recent studies indicate that KIFs regulate the trafficking of NMDA receptors, AMPA receptors, kainate receptors, and GABA receptors and thus play important roles in neuronal activity. Here we review the essential functions of KIFs in the trafficking of neuroreceptor and synaptic plasticity.
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Colbert, C. M., and W. B. Levy. "Electrophysiological and pharmacological characterization of perforant path synapses in CA1: mediation by glutamate receptors." Journal of Neurophysiology 68, no. 1 (July 1, 1992): 1–8. http://dx.doi.org/10.1152/jn.1992.68.1.1.
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1. With the use of hippocampal slices from adult rats, we studied monosynaptic potentials in CA1 evoked by stimulating either the perforant pathway or the Schaffer collaterals. Excision of region CA3 and the dentate gyrus prevented polysynaptic excitation of CA1 and facilitated interpretation of the extracellular potentials. 2. Laminar profiles distinguished the population excitatory postsynaptic potentials (pEPSPs) in CA1 evoked by stimulating the Schaffer collaterals and the perforant path. Stimulating the perforant path evoked short-latency negative-going pEPSPs in s. lacunosum-moleculare of CA1 and positive-going pEPSPs in s. radiatum. Stimulating the Schaffer collaterals evoked negative-going pEPSPs in s. radiatum. 3. A pharmacological manipulation also distinguished the two pathways in CA1. The selective GABAB agonist baclofen greatly decreased the slope of pEPSPs evoked by stimulating the Schaffer collaterals but did not decrease the slope of pEPSPs evoked by stimulating the perforant path. 4. Combined bath application of the glutamate receptor antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 2-amino-5-phosphonopentanoic acid (APV) abolished the negative-going pEPSPs in s. lacunosum-moleculare evoked by stimulating the perforant pathway. This application of DNQX and APV revealed a positive-going field potential that was blocked by bath application of the gamma-aminobutyric acid (GABA) receptor antagonists picrotoxin or bicuculline. 5. Although the glutamate-mediated component of the response evoked by stimulating the perforant path was apparently excitatory, we never observed a population spike in s. pyramidal evoked by stimulating the perforant path.(ABSTRACT TRUNCATED AT 250 WORDS)
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Kim, Jieun, Ju Hwan Yang, In Soo Ryu, Sumin Sohn, Sunghyun Kim, and Eun Sang Choe. "Interactions of Glutamatergic Neurotransmission and Brain-Derived Neurotrophic Factor in the Regulation of Behaviors after Nicotine Administration." International Journal of Molecular Sciences 20, no. 12 (June 16, 2019): 2943. http://dx.doi.org/10.3390/ijms20122943.
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Nicotine causes tobacco dependence, which may result in fatal respiratory diseases. The striatum is a key structure of forebrain basal nuclei associated with nicotine dependence. In the striatum, glutamate release is increased when α7 nicotinic acetylcholine receptors expressed in the glutamatergic terminals are exposed to nicotine, and over-stimulates glutamate receptors in gamma amino-butyric acid (GABA)ergic neurons. These receptor over-stimulations in turn potentiate GABAergic outputs to forebrain basal nuclei and contribute to the increase in psychomotor behaviors associated with nicotine dependence. In parallel with glutamate increases, nicotine exposure elevates brain-derived neurotrophic factor (BDNF) release through anterograde and retrograde targeting of the synapses of glutamatergic terminals and GABAergic neurons. This article reviews nicotine-exposure induced elevations of glutamatergic neurotransmission, the bidirectional targeting of BDNF in the striatum, and the potential regulatory role played by BDNF in behavioral responses to nicotine exposure.
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Llewellyn-Smith, I. J., J. B. Minson, P. M. Pilowsky, L. F. Arnolda, and J. P. Chalmers. "The One Hundred Percent Hypothesis: Glutamate Or Gaba in Synapses on Sympathetic Preganglionic Neurons." Clinical and Experimental Hypertension 17, no. 1-2 (January 1995): 323–33. http://dx.doi.org/10.3109/10641969509087074.
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Kang, Ning, Li Jiang, Wei He, Jun Xu, Maiken Nedergaard, and Jian Kang. "Presynaptic Inactivation of Action Potentials and Postsynaptic Inhibition of GABAA Currents Contribute to KA-Induced Disinhibition in CA1 Pyramidal Neurons." Journal of Neurophysiology 92, no. 2 (August 2004): 873–82. http://dx.doi.org/10.1152/jn.01231.2003.
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Kainate-type glutamate ionotropic receptors (KAR) mediate either depression or potentiation of inhibitory transmission. The mechanisms underlying the depressant effect of KAR agonists have been controversial. Under dual patch-clamp recording techniques in synaptically coupled pairs of CA1 interneurons and pyramidal neurons in hippocampal slices, micromolar concentrations of KAR agonists, kainic acid (KA, 10 μM) and ATPA (10 μM), induced inactivation of action potentials (APs) in 58 and 50% of presynaptic interneurons, respectively. Inactivation of interneuronal APs might have significantly contributed to KA-induced decreases in evoked inhibitory postsynaptic currents (eIPSCs) that are obtained by stimulating the stratum radiatum. With controlled interneuronal APs, KAR agonists induced a decrease in the potency (mean amplitude of successful events) and mean amplitude (including failures) of unitary inhibitory postsynaptic currents (uIPSCs) without significantly changing the success rate (Ps) at perisomatic high-Ps synapses. In contrast, KAR agonists induced a decrease in both the Ps and potency of uIPSCs at dendritic high-Ps synapses. KAR agonists induced an inhibition of GABAA currents by activating postsynaptic KARs in pyramidal neurons; this was more prominent at dendrites than at soma. Both the exogenous GABA-induced current and the amplitude of miniature IPSCs (mIPSCs) were attenuated by KAR agonists. Thus the postsynaptic KAR-mediated inhibition of GABAA currents may contribute to the KAR agonist-induced decrease in the potency of uIPSCs and KA-induced disinhibition.
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Egashira, Yoshihiro, Miki Takase, Shoji Watanabe, Junji Ishida, Akiyoshi Fukamizu, Ryosuke Kaneko, Yuchio Yanagawa, and Shigeo Takamori. "Unique pH dynamics in GABAergic synaptic vesicles illuminates the mechanism and kinetics of GABA loading." Proceedings of the National Academy of Sciences 113, no. 38 (September 6, 2016): 10702–7. http://dx.doi.org/10.1073/pnas.1604527113.
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GABA acts as the major inhibitory neurotransmitter in the mammalian brain, shaping neuronal and circuit activity. For sustained synaptic transmission, synaptic vesicles (SVs) are required to be recycled and refilled with neurotransmitters using an H+ electrochemical gradient. However, neither the mechanism underlying vesicular GABA uptake nor the kinetics of GABA loading in living neurons have been fully elucidated. To characterize the process of GABA uptake into SVs in functional synapses, we monitored luminal pH of GABAergic SVs separately from that of excitatory glutamatergic SVs in cultured hippocampal neurons. By using a pH sensor optimal for the SV lumen, we found that GABAergic SVs exhibited an unexpectedly higher resting pH (∼6.4) than glutamatergic SVs (pH ∼5.8). Moreover, unlike glutamatergic SVs, GABAergic SVs displayed unique pH dynamics after endocytosis that involved initial overacidification and subsequent alkalization that restored their resting pH. GABAergic SVs that lacked the vesicular GABA transporter (VGAT) did not show the pH overshoot and acidified further to ∼6.0. Comparison of luminal pH dynamics in the presence or absence of VGAT showed that VGAT operates as a GABA/H+ exchanger, which is continuously required to offset GABA leakage. Furthermore, the kinetics of GABA transport was slower (τ > 20 s at physiological temperature) than that of glutamate uptake and may exceed the time required for reuse of exocytosed SVs, allowing reuse of incompletely filled vesicles in the presence of high demand for inhibitory transmission.
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Huang, M. H., F. M. Smith, and J. A. Armour. "Amino acids modify activity of canine intrinsic cardiac neurons involved in cardiac regulation." American Journal of Physiology-Heart and Circulatory Physiology 264, no. 4 (April 1, 1993): H1275—H1282. http://dx.doi.org/10.1152/ajpheart.1993.264.4.h1275.
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The effects of amino acids on intrinsic cardiac neuronal activity identified in 10 anesthetized dogs were investigated. Local injection of small volumes (1-10 microliters) of the excitatory amino acids, glutamate (100 mM) and aspartate (10 mM), and the inhibitory amino acids, gamma-aminobutyric acid (GABA; 10 mM) and glycine (10 mM), modified the activity of 39 of 50 identified neurons. Spontaneous activity of eight neurons was modified by both excitatory and inhibitory amino acids. Cardiodynamic responses accompanied neuronal activity modification in 15 instances. After acute decentralization, repeat doses of amino acids altered the activity of 21 neurons and elicited cardiovascular responses in 7 instances. Neuronal and cardiovascular responses were elicited after atropine administration. Neuronal but not cardiac responses were elicited after subsequent timolol administration. In other animals, GABA but not other amino acids elicited neuronal and cardiodynamic responses after hexamethonium administration in decentralized preparations, indicating that non-nicotinic synapses were involved in some GABA-induced responses. These results demonstrate that excitatory and inhibitory amino acids can modify intrinsic cardiac neuronal activity such that, as a consequence, cardiac variables can be modified.
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Partridge, John G., Megan J. Janssen, David Y. T. Chou, Ken Abe, Zofia Zukowska, and Stefano Vicini. "Excitatory and Inhibitory Synapses in Neuropeptide Y–Expressing Striatal Interneurons." Journal of Neurophysiology 102, no. 5 (November 2009): 3038–45. http://dx.doi.org/10.1152/jn.00272.2009.
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Although rare, interneurons are pivotal in governing striatal output by extensive axonal arborizations synapsing on medium spiny neurons. Using a genetically modified mouse strain in which a green fluorescent protein (GFP) is driven to be expressed under control of the neuropeptide Y (NPY) promoter, we identified NPY interneurons and compared them with striatal principal neurons. We found that the bacteria artificial chromosome (BAC)- npy mouse expresses GFP with high fidelity in the striatum to the endogenous expression of NPY. Patch-clamp analysis from NPY neurons showed a heterogeneous population of striatal interneurons. In the majority of cells, we observed spontaneous firing of action potentials in extracellular recordings. On membrane rupture, most NPY interneurons could be classified as low-threshold spiking interneurons and had high-input resistance. Voltage-clamp recordings showed that both GABA and glutamate gated ion channels mediate synaptic inputs onto these striatal interneurons. AMPA receptor–mediated spontaneous excitatory postsynaptic currents (sEPSCs) were small in amplitude and infrequent in NPY neurons. Evoked EPSCs did not show short-term plasticity but some rectification. Evoked N-methyl-d-aspartate (NMDA) EPSCs had fast decay kinetics and were poorly sensitive to an NR2B subunit containing NMDA receptor blocker. Spontaneous inhibitory postsynaptic currents (sIPSCs) were mediated by GABAA receptors and were quite similar among all striatal neurons studied. On the contrary, evoked IPSCs decayed faster in NPY neurons than in other striatal neurons. These data report for the first time specific properties of synaptic transmission to NPY striatal interneurons.
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Zhao, Liangfang, and Eric S. Levine. "BDNF-endocannabinoid interactions at neocortical inhibitory synapses require phospholipase C signaling." Journal of Neurophysiology 111, no. 5 (March 1, 2014): 1008–15. http://dx.doi.org/10.1152/jn.00554.2013.
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Endogenous cannabinoids (endocannabinoids) and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), are potent synaptic modulators that are expressed throughout the forebrain and play critical roles in many behavioral processes. Although the effects of BDNF at excitatory synapses have been well characterized, the mechanisms of action of BDNF at inhibitory synapses are not well understood. Previously we have found that BDNF suppresses presynaptic GABA release in layer 2/3 of the neocortex via postsynaptic tropomyosin-related kinase receptor B (trkB) receptor-induced release of endocannabinoids. To examine the intracellular signaling pathways that underlie this effect, we used pharmacological approaches and whole cell patch-clamp techniques in layer 2/3 pyramidal neurons of somatosensory cortex in brain slices from juvenile Swiss CD1 mice. Our results indicated that phospholipase Cγ (PLCγ) is involved in the CB1 receptor-mediated synaptic effect of BDNF, because the BDNF effect was blocked in the presence of the broad-spectrum PLC inhibitors U-73122 and edelfosine, whereas the inactive analog U-73343 did not alter the suppressive effect of BDNF at inhibitory synapses. Endocannabinoid release can also be triggered by metabotropic glutamate receptor (mGluR)-mediated activation of PLCβ, and BDNF has been shown to enhance spontaneous glutamate release. An mGluR antagonist, E4CPG, however, did not block the BDNF effect. In addition, the effect of BDNF was independent of other signaling pathways downstream of trkB receptor activation, namely, mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, as well as protein kinase C signaling.
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Ishibashi, Hitoshi, Junya Yamaguchi, Yoshihisa Nakahata, and Junichi Nabekura. "Dynamic regulation of glycine-GABA co-transmission at spinal inhibitory synapses by neuronal glutamate transporter." Journal of Physiology 591, no. 16 (June 17, 2013): 3821–32. http://dx.doi.org/10.1113/jphysiol.2012.250647.
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Llewellyn-Smith, I. J., L. F. Arnolda, P. M. Pilowsky, J. P. Chalmers, and J. B. Minson. "GABA- and glutamate-immunoreactive synapses on sympathetic preganglionic neurons projecting to the superior cervical ganglion." Journal of the Autonomic Nervous System 71, no. 2-3 (July 1998): 96–110. http://dx.doi.org/10.1016/s0165-1838(98)00069-1.
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van Marle, J., T. Piek, Th Lammertse, A. Lind, and J. van Weeren-Kramer. "Selectivity of the uptake of glutamate and GABA in two morphologically distinct insect neuromuscular synapses." Brain Research 348, no. 1 (November 1985): 107–11. http://dx.doi.org/10.1016/0006-8993(85)90365-8.
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