GABAB receptors depress glutamate release at C‐fiber afferent synapses in the nucleus of the solitary tract (NTS)
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Cranial visceral primary afferents follow the solitary tract (ST) to synapse on 2 nd order NTS neurons. These afferents consist of both A‐fibers (transient receptor potential vanilloid receptor negative (TRPV1 − )) and C‐fibers (TRPV1 + ). The inhibitory transmitter GABA acts ionotropically at GABA A and metabotropically at GABA B receptors. In horizontal hindbrain slices, ST shocks evoked time‐invariant glutamatergic EPSCs with jitters <200 μs at 2 nd order neurons. Capsaicin (TRPV1 + agonist) blocked C‐fiber afferent transmission. We tested whether the GABA B agonist, baclofen (BAC), reduces glutamate release of TRPV1 + afferents on 2 nd order NTS neurons. During GABA A block with gabazine, BAC (0.001–20 μM) reduced ST‐EPSC amplitudes and rates of sEPSCs or mEPSCs (in TTX), consistent with presynaptic decreases in glutamate release. BAC effects were more pronounced in 1 mM (physiological) than 2 mM bath calcium, consistent with masking effects of increased probability of glutamate release in high calcium. These data are consistent with presynaptic GABA B control of glutamate release at C‐fiber afferent terminals. Future studies will test whether BAC reduces glutamate release at TRPV1 − synapses. Supported by: HL‐088894 (JHP) and HL‐04119 (MCA)Keywords:
Solitary tract
An imbalance between the strengths of excitatory and inhibitory synaptic inputs has been proposed as the cellular basis of autism and related neurodevelopmental disorders. Previous studies examining spontaneous levels of excitatory and inhibitory neurotransmission in the forebrain regions of methyl-CpG-binding protein 2 (Mecp2) mutant mice, models of the autism spectrum disorder Rett syndrome, have identified a decrease in excitatory drive, in some cases coupled with an increase in inhibitory synaptic strength, as a major source of this imbalance. Here, we reevaluated this question by examining the short-term dynamics of evoked neurotransmission between hippocampal neurons cultured from MeCP2 knockout mice and found a marked increase in evoked excitatory neurotransmission that is consistent with an increase in presynaptic release probability. This increase in evoked excitatory drive was not matched with alterations in evoked inhibitory neurotransmission. Moreover, we observed similar excitatory drive specific changes after the loss of key histone deacetylases (histone deacetylase 1 and 2) that form a complex with MeCP2 and mediate transcriptional regulation. These findings suggest a distinct role for MeCP2 and its cofactors in the regulation of evoked excitatory neurotransmission compared with their essential role in basal synaptic activity.
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Effects of synthetic philanthotoxin-4.3.3 (PTX-4.3.3) and of its eleven structural analogues on glutamatergic transmission in the insect muscle, nicotinic transmission in the insect CNS and glutamatergic transmission in the mammalian CNS, are described. Compared with the insect muscle, the insect CNS is about 100 times less sensitive for most of these toxins and the mammalian CNS about 1000 times less reactive. In general, the relative activities of the analogues are comparable except for one toxin: dideaza-PTX-12, which is hardly active in insects and is the most active blocker of synaptic transmission from the Schaffer collaterals to pyramidal cells in the rat hippocampal slices. Dideaza-PTX-12 is also the most active inhibitor of glutamate uptake. It is concluded that the latter compound may be a prototype of a new class of neuroactive drugs affecting the glutamatergic transmission in the mammalian CNS.
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Medium spiny neuron
Postsynaptic Current
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The Caenorhabditis elegans gene eat-4 affects multiple glutamatergic neurotransmission pathways. We find that eat-4 encodes a protein similar in sequence to a mammalian brain-specific sodium-dependent inorganic phosphate cotransporter I (BNPI). Like BNPI in the rat CNS, eat-4 is expressed predominantly in a specific subset of neurons, including several proposed to be glutamatergic. Loss-of-function mutations in eat-4 cause defective glutamatergic chemical transmission but appear to have little effect on other functions of neurons. Our data suggest that phosphate ions imported into glutamatergic neurons through transporters such as EAT-4 and BNPI are required specifically for glutamatergic neurotransmission.
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Chronic stress causes the release of glucocorticoids, which greatly influence cerebral function, especially glutamatergic transmission. These stress-induced changes in neurotransmission could be counteracted by increasing the dietary intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs). Numerous studies have described the capacity of n-3 PUFAs to help protect glutamatergic neurotransmission from damage induced by stress and glucocorticoids, possibly preventing the development of stress-related disorders such as depression or anxiety. The hippocampus contains glucocorticoid receptors and is involved in learning and memory. This makes it particularly sensitive to stress, which alters certain aspects of hippocampal function. In this review, the various ways in which n-3 PUFAs may prevent the harmful effects of chronic stress, particularly the alteration of glutamatergic synapses in the hippocampus, are summarized.
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Research on glutamatergic neurotransmission has focused mainly on the function of presynaptic and postsynaptic neurons, leaving astrocytes with a secondary role only to ensure successful neurotransmission. However, recent evidence indicates that astrocytes contribute actively and even regulate neuronal transmission at different levels. This review establishes a framework by comparing glutamatergic components between neurons and astrocytes to examine how astrocytes modulate or otherwise influence neuronal transmission. We have included the most recent findings about the role of astrocytes in neurotransmission, allowing us to understand the complex network of neuron-astrocyte interactions. However, despite the knowledge of synaptic modulation by astrocytes, their contribution to specific physiological and pathological conditions remains to be elucidated. A full understanding of the astrocyte's role in neuronal processing could open fruitful new frontiers in the development of therapeutic applications.
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Gamma-Aminobutyric Acid
Premovement neuronal activity
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Background The effects of halothane on excitatory synaptic transmission in the central nervous system of mammals have been studied in vivo and in vitro in several investigations with partially contradicting results. Direct measurements of the effects of halothane on isolated glutamate receptor-mediated (glutamatergic) excitatory postsynaptic currents (EPSCs), however, have not been reported to date. Methods The effects of halothane on glutamatergic EPSCs were studied in vitro by using tight-seal, whole-cell recordings from CA1 pyramidal cells in thin slices from the adult mouse hippocampus. The EPSCs were pharmacologically isolated into their non-N-methyl-D-aspartate (non-NMDA) and NMDA receptor-mediated components by using selective antagonists. The effects of halothane on EPSC amplitude and kinetics were analyzed at various membrane potentials and were compared with its effects on currents evoked by exogenously applied glutamatergic agonists. Results Halothane (0.2-5.1%; 0.37-2.78 mM) reversibly blocked non-NMDA and NMDA EPSCs. This effect was voltage independent; concentrations producing 50% inhibition were 0.87% (0.66 mM) and 0.69% (0.57 mM), respectively. Currents induced by bath-applied glutamatergic agonists were not affected even by the high concentrations of halothane. Conclusions Halothane depresses glutamatergic EPSCs irrespective of receptor subtype, most likely by inhibition of glutamate release.
Postsynaptic Current
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