EARLY GENES AND KINDLING DEVELOPMENT

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Epilepsy is a common neurologic disorder afflicting over two million people in the United States. More than 25% of patients with epilepsy continue to have seizures despite optimal therapy with conventional drugs. Kindling is an animal model of complex partial epilepsy (CPE), the adult seizure type that is most common and often refractory to treatment. Kindling refers to a phenomenon in which repeated, focal application of initially subconvulsive electrical stimulations to the brain eventually results in seizure. Each stimulation must evoke an electrographic seizure (afterdischarge (AD)). Moreover, activation of a subtype of excitatory amino acid receptor, the N-methyl-D-aspartate (NMDA) receptor, during AD is required for kindling to develop. How these transient events generate the long lasting enhanced neuronal excitability is not known. The recent discovery that AD and NMDA receptor activation can trigger increases in c-fos, an immediate early gene (IEG), has been shown to alter the expression of other genes (target genes) by acting as a transcriptional regulator. It is hypothesized that c-fos expression activates target genes which are necessary for the persistent state of neuronal excitability known as kindling. To facilitate testing this hypothesis, we have begun to study the earliest events in kindling development. We showed that a lasting increase in AD duration occurs after only 2 brief stimulation-evoked ADs. We have also demonstrated that AD-evoked c-fos expression occurs in a highly specific pattern uniformly involving the medial amygdaloid nucleus. Initial attempts to test this hypothesis will be performed by blocking transcription and translation of c-fos following AD. Additional experiments will specifically interfere with second messenger systems involved in c-fos induction. Candidate compounds for blocking NMDA- induced c-fos expression will be tested in primary neuronal culture derived from rat dentate gyrus. Those found effective will then be examined for their effect on c-fos expression and increase in AD duration in vivo. The results of these experiments should increase our understanding of the mechanism underlying the development of kindling. The ultimate goal of this line of investigation is to extend the anticipated findings to human CPE, thereby facilitating better understanding and treatment of seizures in humans.