Format

Send to

Choose Destination
See comment in PubMed Commons below
Neurobiol Dis. 2015 May;77:141-54. doi: 10.1016/j.nbd.2015.02.016. Epub 2015 Mar 10.

Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome.

Author information

  • 1Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children Hospital Research Institute, Seattle, WA 98101, USA.
  • 2Department of Neurology, University of Washington, Seattle, WA 98195, USA.
  • 3Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
  • 4Department of Pharmacology, University of Washington, Seattle, WA 98195, USA; Department of Biology, University of Washington, Seattle, WA 98195, USA.
  • 5Department of Biology, University of Washington, Seattle, WA 98195, USA.
  • 6Department of Pharmacology, University of Washington, Seattle, WA 98195, USA. Electronic address: wcatt@u.washington.edu.

Abstract

Dravet Syndrome (DS) is caused by heterozygous loss-of-function mutations in voltage-gated sodium channel NaV1.1. Our mouse genetic model of DS recapitulates its severe seizures and premature death. Sleep disturbance is common in DS, but its mechanism is unknown. Electroencephalographic studies revealed abnormal sleep in DS mice, including reduced delta wave power, reduced sleep spindles, increased brief wakes, and numerous interictal spikes in Non-Rapid-Eye-Movement sleep. Theta power was reduced in Rapid-Eye-Movement sleep. Mice with NaV1.1 deleted specifically in forebrain interneurons exhibited similar sleep pathology to DS mice, but without changes in circadian rhythm. Sleep architecture depends on oscillatory activity in the thalamocortical network generated by excitatory neurons in the ventrobasal nucleus (VBN) of the thalamus and inhibitory GABAergic neurons in the reticular nucleus of the thalamus (RNT). Whole-cell NaV current was reduced in GABAergic RNT neurons but not in VBN neurons. Rebound firing of action potentials following hyperpolarization, the signature firing pattern of RNT neurons during sleep, was also reduced. These results demonstrate imbalance of excitatory vs. inhibitory neurons in this circuit. As predicted from this functional impairment, we found substantial deficit in homeostatic rebound of slow wave activity following sleep deprivation. Although sleep disorders in epilepsies have been attributed to anti-epileptic drugs, our results show that sleep disorder in DS mice arises from loss of NaV1.1 channels in forebrain GABAergic interneurons without drug treatment. Impairment of NaV currents and excitability of GABAergic RNT neurons are correlated with impaired sleep quality and homeostasis in these mice.

PMID:
25766678
PMCID:
PMC4402280
DOI:
10.1016/j.nbd.2015.02.016
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center