Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome.
Heterozygous loss-of-function mutations in the brain sodium channel Na(V)1.1 cause Dravet syndrome (DS), a pharmacoresistant infantile-onset epilepsy syndrome with comorbidities of cognitive impairment and premature death. Previous studies using a mouse model of DS revealed reduced sodium currents and impaired excitability in GABAergic interneurons in the hippocampus, leading to the hypothesis that impaired excitability of GABAergic inhibitory neurons is the cause of epilepsy and premature death in DS. However, other classes of GABAergic interneurons are less impaired, so the direct cause of hyperexcitability, epilepsy, and premature death has remained unresolved. We generated a floxed Scn1a mouse line and used the Cre-Lox method driven by an enhancer from the Dlx1,2 locus for conditional deletion of Scn1a in forebrain GABAergic neurons. Immunocytochemical studies demonstrated selective loss of Na(V)1.1 channels in GABAergic interneurons in cerebral cortex and hippocampus. Mice with this deletion died prematurely following generalized tonic-clonic seizures, and they were equally susceptible to thermal induction of seizures as mice with global deletion of Scn1a. Evidently, loss of Na(V)1.1 channels in forebrain GABAergic neurons is both necessary and sufficient to cause epilepsy and premature death in DS.
Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
Christine S
CS
Cheah
Frank H
FH
Yu
Ruth E
RE
Westenbroek
Franck K
FK
Kalume
John C
JC
Oakley
Gregory B
GB
Potter
John L
JL
Rubenstein
William A
WA
Catterall
D000818:Animals; D004562:Electrocardiography; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D007395:Interneurons / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000172:deficiency* / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D016548:Prosencephalon / Q000378:metabolism
D062550:NAV1.1 Voltage-Gated Sodium Channel; C568249:Scn1a protein, mouse