Chapter

The Voltage-Gated Calcium Channel and Absence Epilepsy

Jeffrey L. Noebels

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/9780199746545.003.0054

Series: Contemporary Neurology Series

The Voltage-Gated Calcium Channel and Absence Epilepsy

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Voltage-gated calcium channels were the first of now many genetic starting points for tracing the molecular mechanisms of spike-wave seizures, and in so doing, we have gained equally valuable information regarding the neurobiology of the P/Q-type calcium channel and its family members. Perhaps the most important lesson is that the solution of the neurological phenotype requires two steps: first, analyzing how the mutation affects the biology of the channel in a single neuron; second, determining how and when the misbehavior converts normal rebound bursting patterns in the thalamocortical network into an unstable pathological substrate for epilepsy in the developing brain. The “temporary failure of motor and mental functions” defined by Jackson arises not from enhanced excitatory release, as might be expected in paroxysmal hypersynchronous activity, but from the opposite: reduced synaptic strength within the thalamocortical network due to impaired calcium entry and diminished interactions with transmitter release machinery. This reduction in synaptic strength joins other molecular triggers, such as loss of vesicular exocytosis proteins or postsynaptic AMPA receptors, to induce downstream elevations in low voltage-activated T-type calcium channels, which may suffice to generate a spike-wave seizure phenotype. There is ample clinical and genetic evidence to suggest that there will be no uniform thalamocortical molecular pathology underlying this disorder and that alternative routes to the clinical spectrum of absence epilepsy remain to be discovered. Comparisons of their monogenic mechanisms will prove highly instructive in subsequent attempts to unravel the most elusive causes of sporadic generalized epilepsies, those that arise out of polygenic combinations. This category comprises the majority of individuals with absence seizures, and to them we remain obliged to confess our continuing ignorance of the causes of their condition.

Chapter.  7124 words.  Illustrated.

Subjects: Neurology

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