Genetic Approaches to the Neurobiology of Electroconvulsive Therapy

Abstract

Although electroconvulsive therapy effectively treats severe psychiatric disorders, its neurobiologic mechanisms are not fully understood. Also unclear is the basis for variability in seizure threshold and duration among patients. We used multiple strains of rats and mice to test for genetic variation in the properties of seizures induced by electroconvulsive shock (ECS). We specifically measured seizure duration, sensitivity to proconvulsant actions of caffeine, and relative refractoriness to postictal induction of further seizures, all of which showed significant interstrain variability. In addition, tonic-clonic seizure durations correlated with rates of immediate mortality, suggesting variations in underlying levels of cellular excitability across strains. By using quantitative autoradiography to relate these findings to neurobiologic mechanisms, we found significant correlations between hippocampal A1-receptor binding, cortical and striatal N-methyl-D-aspartate (NMDA)-receptor binding, and the modification of seizure duration by caffeine. These studies suggest that heritable factors modulate the neurobiologic determinants of electrically induced seizures. Furthermore, they suggest that genetic factors may contribute to clinically observed variability in seizure thresholds. Finally, the data provide a basis for future molecular genetic approaches to link ECS-induced changes in seizure properties to relevant transmitter systems.