Na(V)1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms.
Na(V)1.1 is the primary voltage-gated Na(+) channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that Na(V)1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a(+/-)), which encodes the pore-forming α-subunit of the Na(V)1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a(+/-) mice have exaggerated light-induced negative-masking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a(+/-) mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a(+/-) mice, and this communication is barely detectable in the homozygous gene KO (Scn1a(-/-)). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of Na(V)1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na(+) channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of Na(V)1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients.
Program in Neurobiology and Behavior, University of Washington, Seattle, WA 98195, USA.
Sung
S
Han
Frank H
FH
Yu
Michael D
MD
Schwartz
Jonathan D
JD
Linton
Martha M
MM
Bosma
James B
JB
Hurley
William A
WA
Catterall
Horacio O
HO
de la Iglesia
D000818:Animals; D001522:Behavior, Animal / Q000528:radiation effects; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication / Q000235:genetics / Q000528:radiation effects; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D004596:Electroretinography; D005110:Extracellular Space / Q000378:metabolism* / Q000528:radiation effects; D005260:Female; D059330:GABAergic Neurons / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000528:radiation effects; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010641:Phenotype; D010775:Photic Stimulation; D015398:Signal Transduction / Q000235:genetics; D015222:Sodium Channels / Q000378:metabolism*; D013493:Suprachiasmatic Nucleus / Q000166:cytology* / Q000378:metabolism* / Q000528:radiation effects; D009435:Synaptic Transmission / Q000235:genetics / Q000528:radiation effects
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568249:Scn1a protein, mouse; D015222:Sodium Channels; D056926:CLOCK Proteins