Dysfunction of the Scn8a voltage-gated sodium channel alters sleep architecture, reduces diurnal corticosterone levels, and enhances spatial memory

J Biol Chem. 2010 May 28;285(22):16553-61. doi: 10.1074/jbc.M109.090084. Epub 2010 Mar 30.

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 Na(v)1.6, 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 (Scn8a(med-Tg/+)) show altered anxiety and depression-like phenotypes. Because psychiatric abnormalities are often associated with altered sleep and hormonal patterns, we evaluated heterozygous Scn8a(med-jo/+) mutants for alterations in sleep-wake architecture, diurnal corticosterone levels, and behavior. Compared with their wild-type littermates, Scn8a(med-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, Scn8a(med-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Circadian Rhythm
  • Corticosterone / blood*
  • Electrocardiography / methods
  • Genotype
  • Heterozygote
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • NAV1.6 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Nervous System Diseases / genetics
  • Nervous System Diseases / pathology
  • Sleep / physiology*
  • Sodium Channels / genetics*
  • Sodium Channels / metabolism*
  • Spatial Behavior / physiology*

Substances

  • NAV1.6 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • Scn8a protein, mouse
  • Sodium Channels
  • Corticosterone