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Nat Commun. 2019 Apr 23;10(1):1917. doi: 10.1038/s41467-019-09954-9.

Impaired cortico-striatal excitatory transmission triggers epilepsy.

Author information

1
Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.
2
PRESTO, Japan Science and Technology Agency, Saitama, 332-0012, Japan.
3
International Research Center for Neurointelligence (IRCN), The University of Tokyo Institutes for Advanced Study, Tokyo, 113-0033, Japan.
4
Department of Physiology, Nippon Medical School, Tokyo, 113-8602, Japan.
5
Laboratory for Behavioral Genetics, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.
6
FIRST, Japan Science and Technology Agency, Saitama, 332-0012, Japan.
7
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan.
8
Section of Viral Vector Development, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan.
9
Graduate University for Advanced Studies (SOKENDAI), Hayama, 240-0193, Japan.
10
Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.
11
Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan. kazuhiro.yamakawa@riken.jp.

Abstract

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice.

PMID:
31015467
PMCID:
PMC6478892
DOI:
10.1038/s41467-019-09954-9
[Indexed for MEDLINE]
Free PMC Article

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