Although complex partial seizures of temporal lobe origin can occur as the apparent result of tumors, arteriovenous malformations, and disorders of cortical development, they often occur """"""""spontaneously,"""""""" in the absence of any obvious cause. In these """"""""cryptogenic"""""""" patients, an antecedent episode of prolonged febrile seizures, infection, or head trauma is often reported, but of unproved causation. This clinical history led to the hypothesis that an initial injury alters the temporal lobe/hippocampal network in such a way that it ultimately becomes a source of seizure discharges. Experimental studies on this subject can be extrapolated to the human condition because the structural and functional properties of the mammalian temporal lobe have been highly conserved phylogenetically. This application describes experiments designed to test the hypothes:is that post-injury non-principal cell (interneuron) death or dysfunction causes hippocampal principal cell disinhibition and. hyperexcitability. The proposed experiments have been designed to: 1) continue to elucidate the normal structural and functional organization of the hippocampal formation with particular reference to the identification of the interneuron populations that have distant axonal projections necessary for establishing """"""""lateral'' inbibition; 2) determine whether parvalbumin-positive inhibitory basket cells die as a consequence of prolonged seizures, or simply stop expressing parvalbumin; 3) determine if interneuron loss per se induces principal cell disinhibition and hyperexcitability, and; 4) utilize experimental epilepsy models to elucidate the structural and functional changes that follow injury, and precede and follow synaptic reorganization and the development of spontaneous seizures. The first experiments involve the characterization of normal hippocampal interneuron populations in terms of their longitudinal/associational and commissural projections, as well as the neuroactive substances they contain. These studies utilize retrograde and anterograde tracer injections and double fluorescence immunocytochemistry. The second experiments utilize electron nucroscopy and colocalization immunocytochemistry to determine if a subset of basket cells dies or survives after seizures. The third set of experiments involve saporin-based neurotoxins that target different interneuron populations relatively selectively. These studies directly address the """"""""interneuron loss"""""""" and """"""""lateral inhibition't' hypotheses proposed previous,ly by the applicant. The f inal set of experiments utilizes the perforant path stimulation-, and pilocarpine models to deterrrune which structural network defects may give rise to abnorrnal network excitability and spontaneous seizures. These studies involve both anesthetized and awake recording, as well as anatomical and irnmunocytochernical methods designed to elucidate the functional and structural basis of epileptogenesis.
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