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.
| Baker, Erin M; Thompson, Christopher H; Hawkins, Nicole A et al. (2018) The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy. Epilepsia 59:1166-1176 |
| Wagnon, Jacy L; Mencacci, Niccolò E; Barker, Bryan S et al. (2018) Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus. Hum Mutat 39:965-969 |
| Chen, Chunling; Holth, Jerrah K; Bunton-Stasyshyn, Rosie et al. (2018) Mapt deletion fails to rescue premature lethality in two models of sodium channel epilepsy. Ann Clin Transl Neurol 5:982-987 |
| 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 |
| 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 |
| 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 |
| Sprissler, Ryan S; Wagnon, Jacy L; Bunton-Stasyshyn, Rosie K et al. (2017) Altered gene expression profile in a mouse model of SCN8A encephalopathy. Exp Neurol 288:134-141 |
| 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 |
| Malcolmson, Janet; Kleyner, Robert; Tegay, David et al. (2016) SCN8A mutation in a child presenting with seizures and developmental delays. Cold Spring Harb Mol Case Stud 2:a001073 |
| 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 |
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