Mechanisms of regulation of excitability in immature CNS

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DESCRIPTION (provided by applicant): Prolonged, continuous seizure activity (status epilepticus) is associated with significant mortality and morbidity, particularly in children. In humans and animal models of epilepsy the immature brain is highly susceptible to seizures. The neurotransmitter systems in the developing brain are weighted toward excitation and the inhibitory systems present in developing brain to dampen excitation are not well characterized. In adult brain potassium channels are major determinants of membrane excitability in neurons. One particular potassium channel, Kv4.2 is localized to the dendrites of hippocampal neurons where they form the transient A-type K+ current. In this region where the neurons receive synaptic input, the voltage-dependent activation of Kv4.2 channels provides a critical mechanism for regulating postsynaptic excitability. A number of voltage-dependent potassium channels are not expressed early in developing brain; however our pilot studies show that Kv4.2 channels are expressed at adult levels in immature brain. Thus, we hypothesize that the potassium channel Kv4.2 is expressed early in development and may be critical for dampening excitability in the immature brain. We propose the following aims: Aim 1: Investigation of the role of Kv4.2 channels in the regulation of excitability in the immature brain. We will evaluate expression levels and localization of Kv4.2 channel subunits in immature compared with adult mice. To assess the role of Kv4.2 channels in seizure susceptibility in immature brain we will perform convulsant stimulation in Kv4.2 knockout compared with heterozygote and wildtype mice. Aim 2: Investigation of the role of Kv4.2 channels in the development of long-term changes after early-life seizures. We will evaluate whether early-life status epilepticus leads to more profound long-term alterations in Kv4.2 knockout compared to wildtype and heterozygous mice. Long-term parameters that we will monitor are development of spontaneous seizures, neuroanatomical changes in hippocampus, and spatial learning deficits. The overall goal of this proposal to elucidate candidate mechanisms involved in regulating excitability and seizure susceptibility in immature brain and the long-term consequences of early-life status epilepticus. Relevance: Status epilepticus (uncontrollable continuous seizures) is one of the most common diagnoses for children transported to the Pediatric Intensive Care Units at a number of major children's hospitals and is associated with serious long-term consequences. Our studies are anticipated to provide insights into the mechanisms involved in regulating seizure susceptibility and status epilepticus in the developing brain and thereby may identify novel candidate targets for therapeutics in childhood epilepsy.