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Synaptically released glutamate reduces gamma-aminobutyric acid (GABA)ergic inhibition in the hippocampus via kainate receptors.
Proc Natl Acad Sci U S A. 1999 Aug 17; 96(17):9932-7.PN

Abstract

Exogenous application of agonists at the kainate subtype of glutamate receptors has been shown to depress evoked monosynaptic inhibition by gamma-aminobutyric acid (GABA)ergic interneurons in the hippocampus. This observation has led to the hypothesis that synaptic release of endogenous glutamate might have a disinhibitory effect on neuronal circuits, in addition to depolarizing neurons via postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartic acid (NMDA) receptors. It is not known, however, if glutamate released from excitatory neurons has the same kainate receptor-mediated effect on monosynaptic inhibitory transmission as exogenous agonist application. Indeed, the recent demonstration that excitatory synaptic signals elicited in interneurons are partly mediated by kainate receptors suggests that these receptors may have a pro- rather than disinhibitory role. Here, we examine the effect of synaptically released glutamate on monosynaptic inhibitory signaling. In the presence of antagonists to AMPA and NMDA receptors, brief bursts of activity in glutamatergic afferent fibers reduce GABAergic transmission. This depression of inhibition is reversibly abolished by blocking kainate receptors. It persists when GABA(B) receptors are blocked and is enhanced by blocking metabotropic glutamate receptors, possibly explained by presynaptic regulation of glutamate release from excitatory afferents by metabotropic autoreceptors. We conclude that the net kainate receptor-mediated effect of synaptically released glutamate is to reduce monosynaptic inhibition. Since this form of disinhibition may contribute to seizure initiation, kainate receptors may constitute an important target for anticonvulsant drug development.

Authors+Show Affiliations

University Department of Clinical Neurology, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10449797

Citation

Min, M Y., et al. "Synaptically Released Glutamate Reduces Gamma-aminobutyric Acid (GABA)ergic Inhibition in the Hippocampus Via Kainate Receptors." Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 17, 1999, pp. 9932-7.
Min MY, Melyan Z, Kullmann DM. Synaptically released glutamate reduces gamma-aminobutyric acid (GABA)ergic inhibition in the hippocampus via kainate receptors. Proc Natl Acad Sci USA. 1999;96(17):9932-7.
Min, M. Y., Melyan, Z., & Kullmann, D. M. (1999). Synaptically released glutamate reduces gamma-aminobutyric acid (GABA)ergic inhibition in the hippocampus via kainate receptors. Proceedings of the National Academy of Sciences of the United States of America, 96(17), 9932-7.
Min MY, Melyan Z, Kullmann DM. Synaptically Released Glutamate Reduces Gamma-aminobutyric Acid (GABA)ergic Inhibition in the Hippocampus Via Kainate Receptors. Proc Natl Acad Sci USA. 1999 Aug 17;96(17):9932-7. PubMed PMID: 10449797.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synaptically released glutamate reduces gamma-aminobutyric acid (GABA)ergic inhibition in the hippocampus via kainate receptors. AU - Min,M Y, AU - Melyan,Z, AU - Kullmann,D M, PY - 1999/8/18/pubmed PY - 1999/8/18/medline PY - 1999/8/18/entrez SP - 9932 EP - 7 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 96 IS - 17 N2 - Exogenous application of agonists at the kainate subtype of glutamate receptors has been shown to depress evoked monosynaptic inhibition by gamma-aminobutyric acid (GABA)ergic interneurons in the hippocampus. This observation has led to the hypothesis that synaptic release of endogenous glutamate might have a disinhibitory effect on neuronal circuits, in addition to depolarizing neurons via postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartic acid (NMDA) receptors. It is not known, however, if glutamate released from excitatory neurons has the same kainate receptor-mediated effect on monosynaptic inhibitory transmission as exogenous agonist application. Indeed, the recent demonstration that excitatory synaptic signals elicited in interneurons are partly mediated by kainate receptors suggests that these receptors may have a pro- rather than disinhibitory role. Here, we examine the effect of synaptically released glutamate on monosynaptic inhibitory signaling. In the presence of antagonists to AMPA and NMDA receptors, brief bursts of activity in glutamatergic afferent fibers reduce GABAergic transmission. This depression of inhibition is reversibly abolished by blocking kainate receptors. It persists when GABA(B) receptors are blocked and is enhanced by blocking metabotropic glutamate receptors, possibly explained by presynaptic regulation of glutamate release from excitatory afferents by metabotropic autoreceptors. We conclude that the net kainate receptor-mediated effect of synaptically released glutamate is to reduce monosynaptic inhibition. Since this form of disinhibition may contribute to seizure initiation, kainate receptors may constitute an important target for anticonvulsant drug development. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/10449797/Synaptically_released_glutamate_reduces_gamma_aminobutyric_acid__GABA_ergic_inhibition_in_the_hippocampus_via_kainate_receptors_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10449797 DB - PRIME DP - Unbound Medicine ER -