Cellular Mechanisms of Epilepsy and Potential New Treatment Strategies

Abstract

Over the last 15 years, neurobiologists have begun to unravel the cellular mechanisms that underlie epileptiform activity. Such investigations have two main objectives: (1) to develop new methods for treating, "curing," or preventing epilepsy: and (2) to learn more about the normal functioning of the human brain, at the cellular/molecular and the neurological/psychological levels by analyzing abnormal brain functioning. The electroencephalogram (EEG) spike is a marker for the hyperexcitable cortex and arises in or near an area with a high epileptogenic potential. The depolarizing shift (DS) that underlies the interictal discharge (ID) appears to be generated by a combination of excitatory synaptic currents and intrinsic voltage-dependent membrane currents. The hyperpolarization that follows the DS (post-DS HP) limits ID duration, determines ID frequency, and prevents ID deterioration into seizures. The disappearance of the post-DS HP in some models is related to the onset of seizures and the spread of epileptiform activity. During the transition to seizures, the usually self-limited ID spreads in time and anatomical space. Several processes may intervene in the pathophysiological dysfunction. These include enhancing GABA-mediated inhibition, dampening NMDA-mediated excitability, interfering with specific Ca2+ currents in central neurons, and perhaps stimulating "gating" pathways.