This project will test the hypothesis that generalized seizures are regulated by specific subcortical neural systems, particularly in the thalamus. The first step will be to define particular thalamic nuclei critical to seizures by examining how discrete microinjections of neuroactive substances which affect major inhibitory or excitatory neurotransmitter systems affect susceptibility to different types of experimental seizures, particularly those induced by chemical convulsants. Following this, multiple and single unit recordings will be performed in these critical nuclei, and this electrophysiological activity will be correlated with behavioral and EEG seizure events. Next, the neurotransmitter systems which control and modulate neuronal activity in these nuclei will be characterized by determining the effects of microinjection of substances with specific, selective receptor mediated effects. Among the neuroactive agents studied will be selected butyrolactones. Finally, we want to define the role in seizure regulation of other brain regions which are connected to these nuclei, in order to define entire systems which regulate seizure expression and susceptibility. Elucidating subcortical substrates which regulate generalized seizures not only would provide greater understanding of the basic processes of generalized epilepsy, but also has relevance to the study and development of antiepileptic drugs, since identification of the site of action of these drugs is a prerequisite for understanding their mechanism.
