The long range goal of this project is to study mechanisms of chronic epileptogenesis. The work proposed relates to basic processes operating in chronically epileptic brains, particularly within the hippocampus (HC) and adjacent parahippocampal (pHC) structures as important regions for temporal lobe epilepsy (TLE). Studies are focused on the HC-pHC loop, an epileptic network that initiates and amplifies seizures. Three key regions in the HC-pHC loop, each with its own epileptogenic features, will be examined-- the dentate gyrus (Dg), entorhinal cortex (EC), and CA1 area of the HC. The operation of the HC -pHC loop in generating and intensifying seizures as well s chronic alterations imparting increased epileptogenesis to the three study regions have been defined for chronic models of TLE developed and characterized in our laboratory. In the past period of support, several research aims have been met, including: development of an in vitro slice preparation containing all the chosen study areas of the HC-pHC; implementation of intracellular recordings with sharp electrodes; demonstration of """"""""dormancy"""""""" of GABAergic interneurons in CA1; establishing the ability to study extra- and intracellular aspects of normal and epileptogenic responses in the DG and EC; bringing patch recording and voltage-clamping techniques to athe laboratory; and establishing that at least certain """"""""types"""""""" of chronic TLE, both in our animal models and in humans, display a selective loss of layer III EC neurons that seems responsible for heightened epileptogenesis at remote sites to which the EC projects and, perhaps, in the EC. Our studies will extend this work and test the central hypothesis that checks and balances which normally oppose the high epileptogenic potential of the HC-pHC loop are disturbed in the chronically epileptic brain by changes in functional connectivity. A combination of in vitro and in vivo experiments will test 4 corollaries of this hypothesis: Corollary 1-dormancy of inhibitory interneurons is a general property throughout the HC-pHC loop; Corollary 2-in chronic epilepsy dormancy of inhibitory interneurons is of greater importance for disturbed reactivity of local circuites to excessive excitatory drive but of less importance for resting conditions because of spontaneous activity of GABAergic interneurons; Corollary 3-altered excitatory synapses exist in chronic epilepsy in the HC-pHC loop; Corollary 4-in addition to local circuit changes (Corollaries 1-3), remote site changes occur in chronic epilepsy in the HC-pHC loop. These studies will provide insight that will assist in better treating epileptic patients.
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