The voltage-gated sodium channel SCN8A is expressed in neurons throughout the CMS and PNS, with subcellular localization in axonal initial segments, dendrites, and nodes of Ranvier. The widespread expression pattern suggests that mutations of SCN8A could affect many aspects of brain and peripheral nerve function. During the previous funding period, we generated a 'floxed'mouse allele for CRE/loxP targeted conditional inactivation in vivo. We also found the first reported mutation of human SCN8A in a family with cognitive deficits. We will use the floxed mouse model to investigate the effects of Scnda deficiency on cognition in the mouse. We have characterized the 5'noncoding exons and promoter of SCN8A which are located 70 kb upstream of the first coding exon. The 5'noncoding exon of SCN8A contains three noncoding elements that are evolutionary conserved in fish, chicken and mammals. We will identify transcriptional regulatory proteins with affinity for these sites. We will extend our analysis of human mutations of SCN8A and their role in movement disorders and cognitive dysfunction. We will investigate the molecular mechanism of a novel missense mutation in the N-terminal domain of SCN8A that we identified in a novel ENU induced mouse mutant. The effect of this mutation on trafficking, protein interaction, and channel activity will be investigated, in order to elucidate the role of the N-terminus. Overall, this proposal will continue a long-term, productive program directed towards understanding the roles of the essential sodium channel SCN8A in normal function and disease. Public health relevance: There is a biological continuum between neurological disease and the psychiatric disorders. Mutations in channels involved in neuronal signalling can affect both types of functions. This project will characterize the neurological and behavioral effects of specific changes in sodium channel genes, using mouse models of human mutations.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Silberberg, Shai D
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Wagnon, Jacy L; Barker, Bryan S; Ottolini, Matteo et al. (2017) Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol Genet 3:e170
Ottolini, Matteo; Barker, Bryan S; Gaykema, Ronald P et al. (2017) Aberrant Sodium Channel Currents and Hyperexcitability of Medial Entorhinal Cortex Neurons in a Mouse Model of SCN8A Encephalopathy. J Neurosci 37:7643-7655
Lopez-Santiago, Luis F; Yuan, Yukun; Wagnon, Jacy L et al. (2017) Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy. Proc Natl Acad Sci U S A 114:2383-2388
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Barker, Bryan S; Ottolini, Matteo; Wagnon, Jacy L et al. (2016) The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin. Epilepsia 57:1458-66
Wagnon, Jacy L; Barker, Bryan S; Hounshell, James A et al. (2016) Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy. Ann Clin Transl Neurol 3:114-23
Meisler, Miriam H; Helman, Guy; Hammer, Michael F et al. (2016) SCN8A encephalopathy: Research progress and prospects. Epilepsia 57:1027-35
Frasier, Chad R; Wagnon, Jacy L; Bao, Yangyang Oliver et al. (2016) Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy. Proc Natl Acad Sci U S A :
Jones, Julie M; Dionne, Louise; Dell'Orco, James et al. (2016) Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder. Neurobiol Dis 89:36-45
He, Fang; Jones, Julie M; Figueroa-Romero, Claudia et al. (2016) Screening for novel hexanucleotide repeat expansions at ALS- and FTD-associated loci. Neurol Genet 2:e71

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