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 high incidence of fever-induced seizures, whether and how febrile seizures in the developing brain alter neuronal circuits is not well understood. Under the previous award, using an appropriate-aged rodent model of febrile seizures, we determined that experimental febrile seizures in infant rats resulted in a persistent increase in the number of cannabinoid receptor type 1- (CB1-) receptors, and an enhancement of the CB1-mediated, activity- dependent, retrograde suppression of the release of the neurotransmitter GABA in the hippocampus. Here we propose to test the hypotheses that 1. febrile seizures selectively alter the intrinsic, synaptic and electrical coupling properties of the CB1-expressing basket cells, without modifying other types of perisomatically projecting interneurons; 2. febrile seizures persistently increase the CB1 receptor-mediated tonic inhibition of GABA-release from basket cell terminals; and that 3. CB1 receptor activation during the experimental febrile seizures in infancy is a key step in causing long-lasting changes in limbic network excitability. These hypotheses will be tested using a combination of electrophysiological methods and immunocytochemical techniques, complemented by large-scale, anatomically and biophysically realistic, computational network modeling approaches that allow the systematic testing of the relative importance of the various, experimentally determined, seizure-induced alterations in hyperexcitability. Two types of controls will be employed: 1) age-matched, normothermic sham controls, and 2) age-matched, hyperthermic controls, in which the seizures are blocked using pharmacological agents. Our Preliminary data indicate that long-term alterations in CB1 receptors, which are the most abundant G-protein-coupled receptors in the mammalian brain, play crucial mechanistic roles in the development and maintenance of increased limbic excitability after experimental febrile seizures. The experiments in this proposal are designed to specifically target major cellular-synaptic mechanisms underlying hyperexcitabilityfollowing febrile seizures in infancy, and it is anticipated that the proposed experiments may provide novel future therapeutic avenues for anti-epileptic drug therapies in children.
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