Dysfunction of the Scn8a Voltage-gated Sodium Channel Alters Sleep Architecture, Reduces Diurnal Corticosterone Levels, and Enhances Spatial Memory

• Type of Material: Article
• Authors: Ligia A. Papale, Emory University; Ketema N. Paul, Morehouse; Nikki T. Sawyer, Emory University; Joseph Manns, Emory University; Sergio Tufik, Universidade Federal de São Paulo; Andrew Escayg, Emory University
• Language: English
• Date: 2010-05-28
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://www.jbc.org/content/285/22/16553
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 285
• Issue: 22
• Start Page: 16553
• End Page: 16561
• Grant/Funding Information: This work was supported, in whole or in part, by National Institutes of Health Grants NS046484 and NS065187 (to A. E.) and NS060659 (to K. N. P.).
• Keywords: Neurological Diseases; Sleep; Mouse Genetics; SCN8A; HPA Axis; Behavior; Neurobiology; Ion Channels; Sodium Channels
• Research Categories: Chemistry, Biochemistry; Biology, Neuroscience; Biology, Genetics

Abstract

Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of transient depolarizing currents and play a critical role in the electrical signaling between neurons. A null mutation in the VGSC gene SCN8A, which encodes the transmembrane protein Nav1.6, was identified previously in a human family. Heterozygous mutation carriers displayed a range of phenotypes, including ataxia, cognitive deficits, and emotional instability. A possible role for SCN8A was also proposed in studies examining the genetic basis of attempted suicide and bipolar disorder. In addition, mice with a Scn8a loss-of-function mutation (Scn8amed-Tg/+) show altered anxiety and depression-like phenotypes. Because psychiatric abnormalities are often associated with altered sleep and hormonal patterns, we evaluated heterozygous Scn8amed-jo/+ mutants for alterations in sleep-wake architecture, diurnal corticosterone levels, and behavior. Compared with their wild-type littermates, Scn8amed-jo/+ mutants experience more non-rapid eye movement (non-REM) sleep, a chronic impairment of REM sleep generation and quantity, and a lowered and flattened diurnal rhythm of corticosterone levels. No robust differences were observed between mutants and wild-type littermates in locomotor activity or in behavioral paradigms that evaluate anxiety or depression-like phenotypes; however, Scn8amed-jo/+ mutants did show enhanced spatial memory. This study extends the spectrum of phenotypes associated with mutations in Scn8a and suggests a novel role for altered sodium channel function in human sleep disorders.