1. Brain sodium channelopathy arising from reduced currents through NaV1.1 sodium channels Frank Hong Yu, Ph.D. Dental Research Institute and School of Dentistry, Seoul National University 13:30-14:30, May 12, Thursday, 2011 Room 103, Building 1, DGIST Influx of sodium ions through voltage-gated sodium channels initiates membrane depolarization and the rising phase of the action potential in excitable cells. These integral membrane proteins are comprised of an  -subunit and smaller  -subunits, forming a large multimeric complex that is over 300 kD in size. The  -subunit alone harbors the ion- conducting aqueous pore and is sufficient to demonstrate the essential elements of sodium channel function – channel opening, ion selectivity and rapid inactivation. There are 10 known voltage-gated sodium channel genes in the vertebrate genome. Among epileptic syndromes arising from mutations in specific genes, the brain type I sodium channel (NaV1.1) is most commonly mutated with more than 300 mutations identified for SCN1A. Epileptic syndromes linked to mutations of NaV1.1 channels span a continuum of severity from the relatively mild generalized epilepsy (GEFS+) to severe myoclonic epilepsy in infancy (SMEI). GEFS+ is associated with missense mutations of SCN1A while SMEI results from heterozygous loss of function mutations in SCN1A that lead to haploinsufficiency of NaV1.1 sodium currents. This progressive epilepsy begins in infancy with initially normal development, but at 6–12 months of age affected individuals experience seizures that are frequently associated with fever followed by more severe spontaneous generalized and focal seizures. SMEI is medically refractory with unfavorable long-term outcome. It is a paradox that loss-of-function mutations in NaV1.1 channels, which contribute to action potential generation, cause hyperexcitability and epilepsy. To understand SMEI in more detail, we created a mouse model of SMEI by targeted deletion of one copy of the Scn1a gene. Mice with SMEI (mSMEI) have spontaneous seizures, ataxia, and premature deaths. Heterozygous loss of function in NaV1.1 results in reduced whole-cell sodium current in hippocampal GABAergic inhibitory interneurons but not excitatory pyramidal cells. A similar loss of sodium current is observed in cerebellar Purkinje cells, which are also GABAergic inhibitory neurons. The disinhibition caused by selective failure of excitability of GABAergic inhibitory neurons is likely the cause of hyperexcitability, epilepsy, and ataxia in mSMEI. mSMEI animal model substantially phenocopies the human SMEI condition and spontaneous, recurrent epileptic seizures is acquired in juvenile heterozygous mutant mice with varying degree of penetrance and severity depending on genetic background of strain. Because of the small number of patients and their variable clinical course, it has been difficult to precisely define the essential features of SMEI in humans. The NaV1.1 heterozygous mouse model offers an unique opportunity to probe the pathophysiology of SMEI experimentally and provides a platform to test efficacies of potential antiepileptic therapies. ------------------------------------------------------------------------------------------------------------------------------------------------------------- Person in charge : Jeong Min Lee Contact: yjm0329@dgist.ac.kr, 053)785-6101yjm0329@dgist.ac.kr