Kindling is an animal model of epilepsy that can provide information about the neural network and potentially the molecular basis underlying seizures. Abundant evidence suggests that the substantia nigra (SN) promotes seizure propagation in kindling and other models of seizures. Because the SN and the entopeduncular nucleus (EPN), the rodent equivalent of the primate internal pallidum, are the two output relay nuclei of the basal ganglia, the EPN may also play a role in seizure propagation. Preliminary evidence supports this hypothesis in the pilocarpine model of seizures. This project will test the hypothesis that the EPN regulates seizure propagation, and will compare the postulated role of the EPN with that of the SN. Several lines of experimental evidence will be used. Microinjection of a GABA agonist into the EPN will be used to inhibit its outflow and thereby examine its effect on electroshock and kindled seizures in rats. Microinjection of an excitatory amino acid, NMDA, into the EPN will be used to enhance EPN outflow, and to examine the effect on the threshold and duration of kindled seizures. Simultaneous extracellular single-unit recording in the EPN and one of its monosynaptic targets, the lateral habenular nucleus, will verify that intra-EPN microinjection of these compounds produces the inhibition and excitation presumed. The effect of the EPN on the development of kindling will be tested by lesioning the structure before kindling is established. Finally, the monosynaptic targets of the EPN will be selectively lesioned to discover which is (are) necessary for the role of the EPN in seizure regulation. Results of these studies will add to the known role of the SN in seizure regulation. Once the full neural network(s) underlying seizure expression is (are) known, better pharmacologic or surgical manipulation of human seizures may be possible.
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