SYSTEMS PATHOPHYSIOLOGY

University Of California Los Angeles, Los Angeles CA

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Abstract

The primary goal of this proposal is to investigate abnormal interictal and ictal oscillations that are common to both human mesial temporal lobe epilepsy (MTLE) and our at model of MTLE which develops chronic, spontaneous seizures several months after unilateral intra-hippocampal injection of kainic acid (KA). We propose to use in vivo microelectrode and microdialysis, as well as in vitro slice techniques in the interictal epileptiform oscillations: the first, "fast ripples" (200 to 500 Hz), is unique to areas generating spontaneous seizures; the other, "tail gamma" (2o to 100 Hz), is more widely. These events appear activity or large amplitude hypersynchronous activity. Using parallel experimental protocols in KA rat and human hippocampus, we will test three primary hypotheses: 1. Epileptiform fast ripples and tail gamma oscillations recorded from dentate gyrus in rat and human reflect abnormal reorganization or excitatory and inhibitory local circuits intrinsic to this structure, and are modulated by afferent input from entorhinal cortex and septal area. 2. The appearance over a period of months, of fast ripples, tall gamma and spontaneous seizures follows a specific sequence correlated with development of anatomical reorganization in KA-rat hippocampus and DG detectable by neo-Timm's stain of mossy fibers, and GD interneuron immunohistochemistry (IHC). 3. Sleep-cycle related changes in neurotransmitter release modulate the occurrence of fast ripples, tail gamma and seizures in KA-rats and patients with MTLE. This subproject of our program project is particularly concerned with the pathophysiological mechanisms and anatomical substrates underlying the appearance of these epileptiform oscillations. It makes use of a unique opportunity provided by the clinical need to implant depth electrodes in surgical candidates, to also study fundamental human neuronal mechanisms, allowing us to validate animal models of temporal lobe epilepsy. It is anticipated that elucidation of mechanisms underlying hippocampal epileptogenesis and seizure generation will lead to new concepts for the diagnosis, treatment, and prevention of human MTLE.