Repeated or prolonged seizures may result in a striking behavioral syndrome comprised of cognitive decline and selective impairment of declarative memory. This consequence of seizures is a major cause of long-term morbidity in patients with epilepsy and with isolated convulsions that occur in the setting of metabolic disturbances. Elegant neuropsychological studies have implicated the hippocampus and related structures in the pathophysiology of this acquired behavioral disorder. Human neuropathological studies and animal models of epilepsy have repeatedly demonstrated evidence of selective neuronal vulnerability in hippocampus and other limbic structures after seizures. Nonetheless, the molecular and biochemical mechanisms of neuronal injury with subsequent behavioral disturbance following seizures remain unclear. In preliminary studies using an assay for neuronal injury in an animal model that can be measured and quantitated with cellular resolution, the applicant has demonstrated selective neuroprotective effects of nerve growth factor following kainate-induced seizures. While the trophic properties of NGF appear to require interaction with its high affinity receptor tyrosine kinase, TrkA, NGF also interacts with a low affinity receptor, p75, that is shared with other neurotrophins but whose function is unknown. The mechanisms of trophic factor-mediated neuroprotection remain poorly understood. The proposed studies are designed to understand the mechanism of NGF-mediated neuroprotection in a seizure model, and specifically to examine the hypothesis that NGF neuroprotection in the kainate seizure model is receptor-mediated. The applicant will use anatomic and biochemical assays to examine the neuroprotective properties of several trophic factors, and the distribution and regulation of their respective receptors. As all neurotrophins appear to interact with the low affinity receptor, but each reacts only with a specific high affinity receptor, comparison of protective properties should provide insight as to which, if any, receptor components are necessary. The applicant will also use a transgenic mouse with a defective NGF binding domain and an immunotoxin that selectively lesions p75-bearing neurons to specifically examine the role of the low affinity p75 receptor in neuroprotection.
