Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Abstract

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 negativemasking 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. entrainment | neuronal oscillators | sodium channel T he mammalian suprachiasmatic nucleus (SCN) of the hypothalamus houses a master circadian clock that governs phase coordination between peripheral oscillators and overt circadian rhythms (1) as well as synchronization of these rhythms to the light-dark (LD) cycle through the retinohypothalamic tract (RHT) (2). Although SCN neurons are autonomous single-cell oscillators that rely on autoregulatory transcriptional/translational feedback loops of clock genes (3, 4), interneuronal synchronization is critical for the SCN to act as a tissue pacemaker with a coherent output (5, 6). Sodium-dependent action potentials are known to be essential for the synchronization between clock neurons in the SCN as well as necessary to maintain robust oscillations of clock gene expression (ref. 7 and reviewed in ref. 6), but the molecular identity of voltage-gated Na + channels contributing to the synchronization of the SCN neuronal network is currently unknown.Over 90% of SCN neurons contain GABA as a neurotransmitter and express GABA A and GABA B receptors (8-10), and electrophysiological and pharmacological studies in vitro have pointed to GABA as a key signal mediating SCN neuronal network properties (11,12). Studies of mutant mice show that voltage-gated sodium channel type 1 (Na V 1.1) encoded by the Scn1a gene is the primary voltage-gated Na + channel in...

Synergistic GABA-Enhancing Therapy against Seizures in a Mouse Model of Dravet Syndrome

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