Cellular and molecular basis of epilepsy

Abstract

The epilepsies comprise a remarkably diverse collection of disorders that affect 1% of the population in the United States (Hauser and Hesdorffer, 1990). Current therapy is symptomatic. Available drugs reduce seizure frequency in the majority of patients, but only 40% are free of seizures despite optimal treatment (Elwes et al., 1984; Mattson et al., 1985). Neither an effective prophylaxis nor a cure of any of these disorders is available except neurosurgical resection of epileptic tissue in selected instances. There is hope that understanding the cellular and molecular mechanisms of the epilepsies will lead to improved therapies as well as new insights into brain structure and function. Because of the inherent diversity of the epilepsies and their models and the wide range of techniques used for investigating their cellular and molecular basis, I focused on selected rhodels and issues, attempted to bring some coherency to the findings, and sought to draw conclusions that may be generally relevant to epilepsy. I made a special effort to show how investigations of the epilepsies with methods from diverse disciplines can be complementary and mutually reinforcing. By use of the tools of electrophysiology it was initially demonstrated that the epilepsies are disorders of neuronal excitability, which were subsequently characterized in populations of neurons, in individual neurons, and single ion channels. Advances in molecular biology and molecular genetics have elucidated the molecular mechanism of a familial epilepsy. I have attempted to show how these diverse approaches can be mutually reinforcing and explain how electrophysiologic insights into the mechanisms of seizures induced by high K+ provide a plausible connection between the genotype and phenotype in a familial epilepsy. Throughout my account I have addressed the potential therapeutic implications of discerning the underlying mechanisms. The first topic considered is the terminology and classification of epileptic seizures. Next, I address the cellular mechanisms of seizures induced in tissue slices isolated from normal brain. This provides a framework for considering mechanisms that underlie the enduring predisposition of a brain to exhibit a seizure in the absence of an overt extrinsic stimulus. Finally, I present ways