Dysfunction of the Scn8a voltage-gated sodium channel alters sleep architecture, reduces diurnal corticosterone levels, and enhances spatial memory.
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.
Papale
Ligia A
LA
Department of Psychobiology, Universidade Federal de São Paulo, São Paulo 04024-002, Brazil.
Paul
Ketema N
KN
Sawyer
Nikki T
NT
Manns
Joseph R
JR
Tufik
Sergio
S
Escayg
Andrew
A
D000818:Animals; D001522:Behavior, Animal; D002940:Circadian Rhythm; D003345:Corticosterone / Q000097:blood*; D004562:Electrocardiography / Q000379:methods; D005838:Genotype; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009422:Nervous System Diseases / Q000235:genetics / Q000473:pathology; D012890:Sleep / Q000502:physiology*; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D013037:Spatial Behavior / Q000502:physiology*
D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C491046:Scn8a protein, mouse; D015222:Sodium Channels; D003345:Corticosterone