Neurophysiological Study of CA1 Synaptic Reorganization

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DESCRIPTION (provided by applicant): Epilepsy is a major neurologic public health problem that affects an estimated 3 million Americans. Despite its prevalence and several decades of research efforts, our understanding about the cellular mechanisms underlying intractable epilepsy remains limited. Most of the epilepsy research has been focused on the electrophysiological consequences of acute seizures leading to the discovery of several anticonvulsants that are currently available. However, our limited understanding about the mechanisms underlying the chronic alterations of epilepsy has hampered the development of true "anti-epileptic" drugs. It is now recognized that repeated seizures induced morphological alterations in the limbic structures of human temporal lobe epilepsy and in chronic animal models of this condition. These morphological alterations include sprouting of the mossy fiber pathway that forms new recurrent excitatory collaterals leading to a permanent hyperexcitability of the dentate gyrus. The proposed research investigates the exciting possibility that this putative cellular mechanism of epilepsy, sproutinginduced hyperexcitability, is a major contributor in another seizurevulnerable limbic structure, the CA1 region of the hippocampus. I have obtained anatomical evidence of sprouting in the CA1 region in 4 chronic models of epilepsy, thus, providing a rationale for the hypothesis described in this proposal. As the functional consequences of this newly recognized phenomenon in CA1 neurons are not known, I would like to extend my anatomical studies by using neurophysiological techniques to address this question. The hypothesis of this grant proposal extension has not changed and is that seizureinduced synaptic reorganization in the CA1 region is a mechanism that leads to hyperexcitability in this circuitry enhancing the susceptibility to further seizures. We have made progress in recording from CA1 pyramidal neurons, but we still need to determine whether there is a correlation between the anatomical distribution of Kainic acid induced hyperexcitability in the electrophysiological properties of CA1 pyramidal neurons and the anatomical distribution of Kainic acid induced synaptic reorganization in the CA1 region. During the first 18 months of the award, there was no Kainic acid available (worldwide shortage). We evaluated the Pilocarpine model, and we determined that although CA1 synaptic reorganization occurs, it was not robust enough for the proposed studies as compared to prior experiments with Kainic acid. As Kainic acid became available in May 2000, we began to examine the relationship between hyperexcitability and sprouting in the CA1 region of the hippocampus. In August 2000, I accepted a position in UTHSCSA, and I moved in October 2000. The proposed experiments will better define the mechanisms of chronic epileptogenesis in Temporal Lobe Epilepsy (TLE) and may lead to the development of novel pharmacological approaches for the treatment of TLE. For the Educational component of the MCSDA, I now attend the pharmacology seminars at UTHSCSA and have selected Dr. Steven Mifflin as my new mentor owing to his extensive experience in brain slice neurophysiology. I will devote at least 75% of effort to research, and the remaining effort for clinical care in Epilepsy.