This proposal focuses on the mechanisms and consequences of febrile seizures, the most prevalent seizure type in young children. An immature rat model of prolonged febrile seizures, those associated with potential development of limbic epilepsy, has been characterized, and has already shed considerable light on the neuroanatomical basis of these seizures and on their functional consequences. Importantly, it was established that experimental prolonged febrile seizures lead to long-lasting enhanced hippocampal excitability. Surprisingly, this increased excitability was associated with persistent increase in GABA-mediated inhibition of CA1 pyramidal cells. A resolution to this apparent paradox derives from preliminary data showing functional changes in the Hyperpolarization-activated Cation-Nonselective channels (HCNs) in CA1 pyramidal cells of immature rats who had experienced experimental febrile seizures: Slowed HCN channel kinetics permit increased Na+ entry, depolarizing the cell to promote action potential firing, essentially converting the potentiated inhibition to hyper-excitability. Importantly, slowing of HCN kinetics is consistent with a quantitative shift in the subunit make-up of these recently cloned channel molecules, and preliminary mRNA expression data support this notion. Therefore, this proposal will test the hypothesis that experimental prolonged febrile seizures modulate the expression of HCN channel molecules and disrupt their normal developmental expression patterns, leading to persistently enhanced excitability. Three experiments are proposed: 1) To determine the developmental spatio-temporal expression profiles of the 4 HCN subunit isoforms in defined hippocampal cell populations and single neurons, providing the foundation for probing effects of the seizures; (2) To determine the effects of the seizures on HCN expression in defined individual cells and neuronal populations in vivo; 3) To use an in vitro organotypic hippocampal culture to determine the mechapisms for seizure-induced alteration of HCN isoform expression and the consequent ?neuroplastic? changes in hippocampal excitability. The proposed studies should provide novel and important insight into the remarkable age-and seizure-specific effects of prolonged experimental febrile seizures on the developing hippocampus, changes leading to enhanced excitability long-term. In addition, these studies should contribute to our understanding of fundamental aspects of the functional anatomy of these newly characterized ion channel molecules in developing hippocampus, leading to the definition of the roles of these pacemaker channels in the development of the synchronized hippocampal network.
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