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The Journal of Neuroscience, May 30, 2007, 27(22):5903-5914; doi:10.1523/JNEUROSCI.5270-06.2007
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Neurobiology of Disease
Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying an Scn1a Gene Mutation
Ikuo Ogiwara,1 Hiroyuki Miyamoto,2 Noriyuki Morita,3 Nafiseh Atapour,2 Emi Mazaki,1 Ikuyo Inoue,1 Tamaki Takeuchi,1 Shigeyoshi Itohara,4 Yuchio Yanagawa,6 Kunihiko Obata,5 Teiichi Furuichi,3 Takao K. Hensch,2 andKazuhiro Yamakawa1 Laboratories for 1Neurogenetics, 2Neuronal Circuit Development, 3Molecular Neurogenesis, and 4Behavior Genetics and 5Neuronal Circuit Mechanisms Research Group, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, and 6Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine and Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, Maebashi 371-8511, Japan
Correspondence should be addressed to Dr. Kazuhiro Yamakawa, Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: yamakawa{at}brain.riken.jp
Loss-of-function mutations in human SCN1A gene encoding Nav1.1 are associated with a severe epileptic disorder known as severe myoclonic epilepsy in infancy. Here, we generated and characterized a knock-in mouse line with a loss-of-function nonsense mutation in the Scn1a gene. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. Immunohistochemical analyses revealed that, in the developing neocortex, Nav1.1 was clustered predominantly at the axon initial segments of parvalbumin-positive (PV) interneurons. In heterozygous knock-in mice, trains of evoked action potentials in these fast-spiking, inhibitory cells exhibited pronounced spike amplitude decrement late in the burst. Our data indicate that Nav1.1 plays critical roles in the spike output from PV interneurons and, furthermore, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice.
Key words: SCN1A; Nav1.1; severe myoclonic epilepsy in infancy; parvalbumin-positive; fast spiking; interneurons
Received Dec. 6, 2006; revised April 17, 2007; accepted April 18, 2007.
Correspondence should be addressed to Dr. Kazuhiro Yamakawa, Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: yamakawa{at}brain.riken.jp
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