Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome.
Dravet syndrome is a severe epileptic encephalopathy mainly caused by heterozygous mutations in the SCN1A gene encoding a voltage-gated sodium channel Nav1.1. We previously reported dense localization of Nav1.1 in parvalbumin (PV)-positive inhibitory interneurons in mice and abnormal firing of those neurons in Nav1.1-deficient mice. In the present study, we investigated the physiologic consequence of selective Nav1.1 deletion in mouse global inhibitory neurons, forebrain excitatory neurons or PV cells, using vesicular GABA transporter (VGAT)-Cre, empty spiracles homolog 1 (Emx1)-Cre or PV-Cre recombinase drivers. We show that selective Nav1.1 deletion using VGAT-Cre causes epileptic seizures and premature death that are unexpectedly more severe than those observed in constitutive Nav1.1-deficient mice. Nav1.1 deletion using Emx1-Cre does not cause any noticeable abnormalities in mice; however, the severe lethality observed with VGAT-Cre-driven Nav1.1 deletion is rescued by additional Nav1.1 deletion using Emx1-Cre. In addition to predominant expression in PV interneurons, we detected Nav1.1 in subpopulations of excitatory neurons, including entorhino-hippocampal projection neurons, a subpopulation of neocortical layer V excitatory neurons, and thalamo-cortical projection neurons. We further show that even minimal selective Nav1.1 deletion, using PV-Cre, is sufficient to cause spontaneous epileptic seizures and ataxia in mice. Overall, our results indicate that functional impairment of PV inhibitory neurons with Nav1.1 haploinsufficiency contributes to the epileptic pathology of Dravet syndrome, and show for the first time that Nav1.1 haploinsufficiency in excitatory neurons has an ameliorating effect on the pathology.
Laboratory for NeurogeneticsRIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Ikuo
I
Ogiwara
Takuji
T
Iwasato
Hiroyuki
H
Miyamoto
Ryohei
R
Iwata
Tetsushi
T
Yamagata
Emi
E
Mazaki
Yuchio
Y
Yanagawa
Nobuaki
N
Tamamaki
Takao K
TK
Hensch
Shigeyoshi
S
Itohara
Kazuhiro
K
Yamakawa
D000818:Animals; D003645:Death, Sudden; D004195:Disease Models, Animal; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000503:physiopathology*; D057895:Haploinsufficiency; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010320:Parvalbumins / Q000378:metabolism
D062550:NAV1.1 Voltage-Gated Sodium Channel; D010320:Parvalbumins; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse