Seizures induced by fever are common in the infant and young child. Whether they result in neuronal death and subsequent temporal lobe epilepsy is controversial. Experimental models for febrile seizures used to date have involved older animals, or were unsuitable for long-term studies. Work by the applicant has established an infant rat paradigm of hyperthermia-induced seizures which is age-appropriate and suitable for long-term studies. This model will be used to test the following hypotheses: (1). Hyperthermic seizures result in injury of select limbic neurons, particularly in the central and lateral amygdaloid nuclei. (2). This neuronal injury is mediated by the neuroexcitatory peptide, corticotropin releasing hormone (CRH). To define the distribution and characterize the types of neurons injured, brains will be examined at several time-points following the induction of hyperthermic seizures. Neuronal injury will be determined based on altered staining properties of affected cells. Concurrent experiments will test the hypothesis proposed for the mechanism of this neuronal injury: If neuronal injury produced by hyperthermic seizures is mediated by CRH then i). these seizures should increase the levels of CRH in the involved brain regions and ii). the injury should be prevented by the administration of CRH antagonists. Furthermore, the long-term effects of hyperthermic seizures during infancy on the development of spontaneous seizures (epilepsy) in adulthood will be determined. The proposed studies establish a long-term model for the study of febrile seizures in the infant, a model which had been pursued by investigators focusing on Developmental Epilepsy Research for close to two decades. These studies should yield fundamentally important information regarding the pathogenesis of non-genetic human developmental epilepsies, of which febrile seizures are the most prevalent. The results of the proposed studies may have significant implications for the current management of these seizures in human infants, and could lead to a more aggressive approach to febrile seizures.
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