Glutamatergic Mechanisms Related to Epilepsy

Raymond Dingledine

in Jasper's Basic Mechanisms of the Epilepsies

Fourth edition

Published on behalf of ©Jeffrey L. Noebels, Massimo Avoli, Michael A. Rogawski, Richard W. Olsen, and Antonio V. Delgado-Escueta

Published in print July 2012 | ISBN: 9780199746545
Published online April 2013 | e-ISBN: 9780199322817 | DOI:

Series: Contemporary Neurology Series

Glutamatergic Mechanisms Related to Epilepsy

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The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The past 20 years have been a golden age for glutamate receptor research. Even before that time, in the early 1980s the invention of the first selective antagonists for what would come to be known as N-methyl-d-aspartate (NMDA) receptors1 triggered a flood of investigations as the realization grew that NMDA receptors were critically involved in synaptic plasticity, learning, creation of the proper wiring diagram of the brain during development, excitotoxicity, and a host of neurological disorders involving aberrant circuitry organization, including epilepsy (reviewed in refs. 2 and 3). Cloning of the first glutamate receptor subunit was reported in December 1989,4 and within the next 2 years an additional 15 subunits were cloned.3,5 The subsequent application of molecular and gene ablation technologies has revealed a wealth of subtlety regarding control of synaptic transmission highlighted, perhaps, by a resurgence of interest in how excitatory input patterns to GABAergic interneurons regulate synchronous firing throughout the brain. Over the past decade, our understanding of how these receptors work has been brought to the structural level by successful crystallization of numerous glutamate receptor subunits (see ref. 6). The mechanisms (transcriptional, translational, and post-translational) underlying seizure-induced changes in expression of glutamate receptors have been elucidated. A wealth of new pharmacologic reagents, particularly allosteric receptor modulators, have been introduced that can facilitate study of the roles of specific glutamate receptors in epilepsy. The proposal that reactive astrocytes release glutamate, which then acts to synchronize neuron firing within local microdomains, has been developed. Here I review the functional properties of glutamate receptors and discuss recent data pointing to their potential roles in epilepsy. But first, a word on nomenclature.

Chapter.  4918 words.  Illustrated.

Subjects: Neurology

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