MECHANISMS OF SEIZURE CONTROL IN LIMBIC CIRCUITS

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Seizures that begin in limbic structures (partial complex seizures) remain difficult to adequately control in humans. An animal model that closely replicates these seizures is kindling, The mechanisms that initiate and terminate after-discharges in the kindling model are unknown. Recently, a distinct electrophysiological event linked to kindled seizures has been identified in the anesthetized rat, This event is called maximal dentate activation and consists of the sudden appearance of bursts of large amplitude population spikes of the granule cells in the dentate gyrus. The elicitation of maximal dentate activation has been shown to be a critical step in the production of a hippocampal afterdischarge and in the lengthening of afterdischarges that occur during kindling. The long-term objectives of this project are to understand the synaptic and cellular mechanisms underlying the initiation and termination of maximal dentate activation and, therefore, afterdischarges. Specific aims include: 1) determination of the anatomical regions within the limbic circuit that are necessary for the generation and maintenance of maximal dentate activation, 2) determination of the neurotransmitter or neuromodulator systems that influence the initiation or duration of maximal dentate activation, 3) determination of the cellular basis of maximal dentate activation. The experiments use a combination of in vivo and in vitro techniques to explore these areas. The in vivo experiments in urethane-anesthetized rats use multiple extracellular recordings and lesions to examine the parts of the limbic system that are critical in the control of maximal dentate activation. In all instances recording is done in the dentate gyrus for comparison purposes. Pharmaceutical agents will be used to begin to address the issue of neurotransmitter/neuromodulator influence on the initiation and duration of maximal dentate activation. Drugs that potentiate and inhibit the excitatory and inhibitory systems, as well as agents that alter cholinergic and adenosinergic inputs will be tested. Brain slices that include the hippocampus, subiculum, and entorhinal cortex will be used to examine the cellular basis of maximal dentate activation.