NEUROTRANSMITTER MECHANISMS IN EPILEPSY

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This renewal application proposes to continue examining neural mechanisms of generalized seizures in an inherited epilepsy model, the genetically epilepsy-prone rat (GEPR). The GEPR exhibits heightened susceptibility to seizure induction by electroshock, kindling, convulsant drugs and hyperthermia as well as exquisite sensitivity to audiogenic seizures (AGS). Previous studies from our lab and others have shown that intense neuronal firing in inferior colliculus (IC) neurons mediated by increased availability of excitant amino acids (EAAs) and reductions in GABA-mediated inhibition occur during AGS of the GEPR. This proposal will attempt to define the role of neurons in nuclei in the seizure propagation network for AGS in the GEPR and the role of neurotransmitters in these sites. This will involve an examination of neuronal firing abnormalities in nuclei of the AGS pathway and correlation of changes with simultaneously recorded behavior. Preliminary results indicate that abnormally abrupt and intense rises in firing occur in the dorsal cortex of IC and in the reticular formation. Neurotransmitter mechanisms in the nuclei of the AGS network will be evaluated by microinjection of agents that enhance the action of GABA or decrease the action of EAAs into the nuclei of the AGS pathway beyond IC. Preliminary results indicate that agents acting at GABA and EAA receptors are effective in several of these sites in reducing AGS severity in the GEPR. However, the competitive NMDA antagonists greatly decrease IC neuronal response, while the non-competitive NMDA antagonists exert minimal effects on IC neurons, suggesting that these agents affect neurons in different brain sites. The role of endogenous release of GABA and EAAs in these nuclei during AGS will be examined by administration of agents that affect levels of these amino acids. The abnormalities observed in these non-auditory sites may help to explain the mechanisms that subserve the comprehensive epilepsy-prone state of the GEPR. Recent studies indicate that repetitive daily AGS results in a significant increase in seizure severity with epileptiform EEG activity in the GEPR. Our preliminary results suggest that the medial geniculate body (MGB) is crucial to this seizure severity increase. This proposal will evaluate single neuron firing and behavior changes in the IC to MGB pathway in the GEPR that results from daily seizures. Preliminary results indicate the IC firing greatly increases with AGS repetition. Successful completion of these aims should yield significant insight about neuronal and neurotransmitter mechanisms in this naturally-occurring model of generalized seizures that may be valuable in elucidating mechanisms of epileptogenesis and increase our knowledge of the mechanisms and sites of action of new potential anticonvulsant.