Voltage-gated Na+ channel (VGSC) SCN1B is a multi-functional gene involved in modulation of VGSC transcription, cell surface expression and subcellular localization, regulation of Na+ current (INa), and cell adhesion. SCN1B is expressed as two splice variants in brain: 21 and 21B (initially called 21A). 21B is predominantly expressed in developing brain while 21 expression prevails after the first postnatal week. 21 and 21B share the N-terminal immunoglobulin domain in SCN1B that is required for cell adhesion. Mutations in SCN1B in humans are linked to Genetic Epilepsy with Febrile Seizures Plus (GEFS+)-spectrum disorders. A mutation causing complete functional loss of SCN1B results in Dravet Syndrome, a pediatric epileptic encephalopathy that is the most severe disorders of the GEFS+ spectrum. Scn1b null mice have severe, spontaneous epilepsy and early lethality, a phenotype similar to Dravet Syndrome. In addition, loss of Scn1b in mice results in neuronal migration and pathfinding abnormalities, disrupted axonal fasciculation, INa abnormalities, altered VGSC expression in the hippocampus, and mistargeting of Nav1.6 to the axon initial segment (AIS) in cerebellum. Thus, disruptions in SCN1B expression during development may lead to a spectrum of neurological diseases. The long-term goal of this work is to understand the physiological role of SCN1B in brain. The objective here is to determine the roles of 21 and 21B in neuronal excitability. The central hypothesis to be tested is that SCN1B is crucial for establishment of excitability in brain. It is proposed that 21B, which is expressed during late prenatal/early postnatal brain development, is essential to SCN1B function. Further, it is proposed that disruptions in SCN1B expression during this critical developmental period result in defects in brain circuitry, as well as aberrant VGSC subcellular localization in neurons, that lead to secondary changes in excitability. The rationale for this work is that understanding the role of SCN1B in brain development may lead to novel treatments targeting SCN1B for epilepsy.
Three specific aims will be pursued: 1: To test whether Scn1b expression during brain development is critical for establishment of excitability in vivo. 2: To determine whether Scn1b-mediated epilepsy is an interneuronopathy. 3: To use human induced pluripotent stem cell (iPSC) neurons to understand the role of Scn1b in human epilepsy. This work is expected to reveal the physiological roles of Scn1b (21 and 21B) in brain development and how defects in Scn1b expression contribute to epilepsy in mice and humans. These results will have positive impact because these identified roles will lead to greater understanding of the mechanisms of GEFS+-spectrum diseases and may lead to novel therapeutic agents for epilepsy.

Public Health Relevance

Na+ channel SCN1B is a multi-functional gene involved in modulation of channel transcription, cell surface expression and subcellular localization, regulation of Na+ current, and cell adhesion. SCN1B is expressed as two splice variants in brain: b1 and b1B. b1B is predominantly expressed in developing brain while b1 prevails after the first postnatal week. Mutations in SCN1B in humans are linked to Genetic Epilepsy with Febrile Seizures Plus (GEFS+)-spectrum disorders. Complete functional loss of SCN1B results in Dravet Syndrome, a severe pediatric epileptic encephalopathy on the GEFS+ spectrum. Scn1b null mice are models of Dravet Syndrome. We will test whether SCN1B is crucial for establishment of excitability in brain. We propose that b1B, which is expressed during brain development, is essential to SCN1B function. Further, that disruptions in SCN1B expression during development result in defects in brain circuitry and aberrant Na+ channel localization in neurons that lead to secondary changes in excitability. Understanding the role of SCN1B in brain development may lead to novel epilepsy treatments targeting SCN1B. This work is expected to reveal the physiological roles of Scn1b in brain development and how defects in Scn1b expression contribute to epilepsy in mice and humans. These results will have positive impact because these identified roles will lead to greater understanding of the mechanisms of GEFS+-spectrum diseases and may lead to novel therapeutic agents for epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS076752-02
Application #
8326655
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2011-09-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$405,887
Indirect Cost
$142,000
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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