In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 6 ( 2012-02-07)
Abstract:
Together, our findings directly show a critical role of a specific voltage-gated Na + channel in SCN neuronal network communication. Scn1a +/− mice serve as a model of a devastating form of epilepsy. Humans carrying similar mutations suffer severe myoclonic epilepsy of infancy (SMEI) ( 5 ), which causes several symptoms of sleep disorder. Although the cause for this sleep disorder is unknown, the circadian disruptions that we showed in Scn1a +/− mice would contribute significantly to sleep disorder in SMEI if these disruptions also occur in patients. Furthermore, the rescue of these disruptions with GABA transmission-enhancing drugs points to a potential pharmacological treatment of sleep disorders in SMEI patients. A closer examination of the response of SCN neurons to the phase-shifting light stimulus revealed a difference in the way that neurons responded depending on their location in the SCN. Whereas ventral neurons, which are the first neurons to respond to light with increases in gene expression, presented a normal response in Scn1a +/− mice, the response was dramatically reduced in dorsal neurons ( Fig. P1 ). This result was confirmed in vitro after stimulation of the neural fibers from the retina that innervate the SCN and analysis of the intracellular Ca 2+ increases that result from this stimulation. Scn1a +/− mice showed reduced intracellular Ca 2+ increases and impaired ventro-dorsal communication in SCN neurons, and this communication was barely detectable in mice with the mutation in both copies of the gene in question ( Scn1a −/− ). The known critical role of the Na V 1.1 channels in maintaining GABAergic interneuron functions predicted that the impaired clock function should be rescued by enhancement of GABAergic transmission. We show that this rescue is the case with a combination of drugs that enhance normal GABAergic transmission. As predicted, this treatment substantially rescues all abnormal features of circadian rhythmicity in Scn1a +/− mice, including their circadian period and amplitude, and their ability to respond to light with a phase shift. Because virtually all SCN neurons are GABAergic, we hypothesized that the Na V 1.1 channel would be expressed in SCN neurons and would represent a key channel for SCN interneuronal communication. In the present study, we used a mouse carrying a mutation in the Scn1a gene, which encodes a crucial subunit of Na V 1.1. We show that, compared with unmutated WT mice, the mice with the mutation ( Scn1a +/− ) show circadian rhythms of wheel-running activity with longer period, lower amplitude, and delayed onset of activity under a 12:12 light–dark cycle ( Fig. P1 ). Furthermore, despite the fact that the locomotor activity of Scn1a +/− mice is more sensitive to inhibition by light and their retinal cells show normal responses to light, their biological clock is not reset by light as in WT animals. Scn1a +/− mice also show a substantially reduced resynchronization speed after abrupt advancing or delaying shifts of the light–dark cycle that mimic jet lag. Voltage-gated channels are involved in the generation of action potentials, which permit neurons to transmit messages. The necessity of Na + -mediated action potentials for proper SCN functioning has been shown previously. Nevertheless, the nature and mechanism of the channels remain unknown. The Na V 1.1 channel is the primary voltage-gated Na + channel in interneurons that communicate by the neurotransmitter GABA (i.e., GABAergic interneurons), and its reduced activity leads to decreased excitability of GABAergic cells ( 3 , 4 ), which would cause a concomitant reduction in GABA release. In mammals, a master biological clock governing 24-h rhythms is located in a brain region called the suprachiasmatic nucleus (SCN) of the hypothalamus. Because the period of the SCN is not exactly 24 h, it needs to be reset daily, which is achieved predominantly by the light–dark cycle ( 1 ). Research has long shown that interneuronal communication within the SCN is critical for this resetting and communicating timing ( 2 ), although the mechanisms are not completely understood. Here, we provide evidence that a specific voltage-gated Na + channel is critical for normal SCN function. Failure of this Na + channel is the main cause of a severe form of epilepsy. Our study provides putative mechanisms underlying sleep disruptions in patients with this disease and suggests a potential treatment for their sleep disorders.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1115729109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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