Febrile (fever-induced) seizures are the most common forms of childhood seizures, affecting 3%-5% of infants and young children in the United States and worldwide. In spite of the extremely high incidence of fever-induced seizures, whether and how febrile seizures in the developing brain alter neuronal circuits is not well understood. Indeed, one of the most controversial issues in epilepsy is the relationship of convulsions in infancy to the subsequent development of temporal lobe epilepsy. Retrospective clinical studies indicated that a large fraction of patients with intractable temporal lobe epilepsy have a history of febrile seizures as infants. However, prospective studies have failed to find this association. Recently, an appropriate-aged rodent model of hyperthermia-induced seizures have been introduce, suitable for studying the mechanisms and sequelae of febrile seizures. We propose to use this model of hyperthermia-induced for studying the mechanisms and sequelae of febrile seizures. We propose to use this model of hyperthermia-induced seizure to test the central hypothesis that hyperthermia-induced seizures early I life cause long-lasting alterations in limbic neuronal excitability, and we propose to identify mechanisms which may contribute to long- lasting pot-seizure changes in limbic excitability. The central hypothesis will be tested by the three specific aims, using path clamp electrophysiological techniques in brain slice preparations of the hippocampus and dentate gyrus of the rat. Two types of controls will be used: 1) age-matched, normothermic sham controls, and 2) age-matched, hyperthermic controls, in which the seizures were blocked using pharmacological agents. Preliminary data indicate that the fee-forward GABA A receptor mediated inhibitory control of hippocampus pyramidal cells is enhanced in a long-term manner following hypothermia-induced seizures, but not following hyperthermia alone. Further more, preliminary experiments suggest that the excitatory drive onto hippocampal interneurons is increased following febrile seizures, which, together with a persistently unregulated hyperpolarization-activated depolarizing current(a ubiquitous regulator of excitability, often referred to as the """"""""pacemaker"""""""": current for rats role in cardiac and thalamic membrane potential oscillations), may greatly contribute to the seizure-induced long-term potential of GABAergic inhibition. The data obtained from the proposed experiments will unequivocally determine whether hyperthermia-induced seizures in the developing brain cause long-term alterations in limbic excitability in this modes, and will help to identify novel mechanisms which could be targeted for anti-epileptic drug therapies in children.
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