Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation.
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.
Ogiwara
Ikuo
I
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
Miyamoto
Hiroyuki
H
Morita
Noriyuki
N
Atapour
Nafiseh
N
Mazaki
Emi
E
Inoue
Ikuyo
I
Takeuchi
Tamaki
T
Itohara
Shigeyoshi
S
Yanagawa
Yuchio
Y
Obata
Kunihiko
K
Furuichi
Teiichi
T
Hensch
Takao K
TK
Yamakawa
Kazuhiro
K
D000200:Action Potentials / Q000235:genetics; D000818:Animals; D001369:Axons / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007395:Interneurons / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009415:Nerve Net / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D009433:Neural Inhibition / Q000235:genetics; D010320:Parvalbumins / Q000096:biosynthesis*; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; D015222:Sodium Channels