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Dysfunction of the Scn8a Voltage-gated Sodium Channel Alters Sleep Architecture,Reduces Diurnal Corticosterone Levels,and Enhances Spatial Memory
Authors:Ligia A. Papale  Ketema N. Paul  Nikki T. Sawyer  Joseph R. Manns  Sergio Tufik  Andrew Escayg
Affiliation:From the Department of Psychobiology, Universidade Federal de São Paulo, São Paulo 04024-002, Brazil.;the Departments of §Human Genetics and ;Psychology, Emory University, Atlanta, Georgia 30322, and ;the Department of Anatomy and Neurobiology, Morehouse School of Medicine, Atlanta, Georgia 30310
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.
Keywords:Ion Channels   Mouse Genetics   Neurobiology   Neurological Diseases   Sodium Channels   HPA Axis   SCN8A   Sleep   Behavior
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