Chapter

Mutated GABA<sub>A</sub> Receptor Subunits in Idiopathic Generalized Epilepsy

Patrick Cossette, Pamela Lachance-Touchette and Guy A. Rouleau

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: http://dx.doi.org/10.1093/med/9780199746545.003.0055

Series: Contemporary Neurology Series

Mutated GABAA Receptor Subunits in Idiopathic Generalized Epilepsy

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An increasing number of genes predisposing to epilepsy have been identified over the past 10 years. Among these genes, mutations in four subunits of the GABAA receptor appear to be important causes of familial epilepsy. So far, the majority of these mutations have been associated with a dramatic decrease of GABA-evoked currents in recombinant receptors. Because GABA is the main inhibitory transmitter in the adult brain, it is generally believed that this loss of function would cause abnormal excitability of cortical neurons, thereby leading to clinical seizures. However, in contrast to the mature central nervous system, GABA is excitatory in the developing brain. This apparent paradox is caused by an inversion in the chloride gradient across the cell membrane that occurs during the first days of life. There is now increasing evidence supporting the hypothesis that excitatory GABA transmission plays a key role in various aspects of brain development, such as neuronal migration, shaping of dendritic trees, and synaptogenesis. It is thus very likely that epilepsy-causing mutations in GABAA receptors would be associated with abnormal development of neuronal networks, which may be one of the critical mechanisms leading to the disease. However, so far, this hypothesis has not been examined. Should it be validated, it would provide an unparalleled advance in our comprehension of the IGEs.

Chapter.  8992 words.  Illustrated.

Subjects: Neurology

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