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

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

Ligia A Papale et al. J Biol Chem. 2010.

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.

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Figures

FIGURE 1.

FIGURE 1.

The Scn8a med-jo/+ mutation reduces wakefulness, enhances NREM sleep, and reduces REM sleep amounts. Percentage of time spent in wakefulness (A and B), NREM sleep (C and D), and REM sleep (E and F) during the base-line recording period. Data were averaged over light and dark phases (A, C, and E). The circadian variation of the sleep-wake cycle was obtained by dividing the light and dark periods into 2-h intervals (B, D, and F). Black bars and squares, Scn8a med-jo/+; white bars and squares, WT. Values are presented as mean ± S.E. *, p < 0.05; **, p < 0.01; ***, p < 0.0001; rANOVA followed by Tukey's post hoc test.

FIGURE 2.

FIGURE 2.

Effect of 6 h of total SD in Scn8a med-jo/+ and WT littermates. Comparison of the amount of time spent in NREM sleep (A and B) and REM sleep (C and D), during 18 h of the recovery period with the equivalent time period during base-line recording. The recovery period comprised 6 h of the light period (1 p.m. to 7 p.m.) (A and C) and 12 h of the dark period (B and D). White bars, base-line period; black bars, recovery period. Values are presented as mean ± S.E. *, p < 0.05; **, p < 0.001; rANOVA followed by Tukey's post hoc test.

FIGURE 3.

FIGURE 3.

Altered diurnal CORT rhythm in Scn8a med-jo/+ mutants. CORT levels are shown at the beginning of the light phase (7 a.m.) and at the beginning of the dark phase (7 p.m.). The difference in the magnitude of CORT levels between the 7 a.m. and 7 p.m. samples is also shown. White bars, WT; black bars, Scn8a med-jo/+. Error bars, mean ± S.E. *, p < 0.01, rANOVA followed by Tukey's post hoc test, for 7 p.m. CORT levels. *, p < 0.01, t test, for difference between 7 p.m. and 7 a.m. CORT levels.

FIGURE 4.

FIGURE 4.

Scn8a_med-jo_/+ mutants show modest enhancement in spatial memory. Shown is a comparison of the percentage of time spent exploring the novel and relocated objects. A value of 50% represents chance performance. White bars, WT; black bars, Scn8a med-jo/+. Error bars, mean ± S.E. *, p < 0.05, one-tailed t test.

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