Febrile (fever-induced) seizures are the most common forms of childhood seizures, affecting three percent to five percent 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 has been introduced, suitable for studying the mechanisms and sequelae of febrile seizures. Under the previous award, we used this model of experimental febrile seizures to determine that experimental febrile seizures in infant rats resulted in a persistent, presynaptic increase in inhibition, but concurrent changes in specific postsynaptic ion channels (h-channels) paradoxically converted the potentiated inhibition to hyperexcitability. Here we propose to test the hypothesis that hyperthermia-induced seizures result in persistent, hyper-synchronous inhibitory synaptic inputs to principal cells in the hippocampus.
The specific aims will be tested using patch clamp electrophysiological, immunocytochemical and computational modeling techniques. Two types of controls will be employed: 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 a specific type of interneuron is involved in the generation of hyper-synchronous inhibitory inputs to postsynaptic cells after experimental febrile seizures. Additional preliminary results suggest that activation of cannabinoid-1 receptors can potently modulate the hyper-synchronous inhibitory inputs to principal cells after the seizures, in agreement with recent reports showing the expression of cannabinoid-l receptors on specific interneuronal axon terminals. The data obtained from the proposed experiments will determine how long-term alterations in the interactions of interneurons and principal cells can be regulated, and will help to identify novel mechanisms that could be targeted for anti-epileptic drug therapies in children.
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