Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities.
Voltage-gated sodium channels are required for the initiation and propagation of action potentials. Mutations in the neuronal voltage-gated sodium channel SCN1A are associated with a growing number of disorders including generalized epilepsy with febrile seizures plus (GEFS+),(7) severe myoclonic epilepsy of infancy, and familial hemiplegic migraine. To gain insight into the effect of SCN1A mutations on neuronal excitability, we introduced the human GEFS+ mutation SCN1A-R1648H into the orthologous mouse gene. Scn1a(RH/RH) mice homozygous for the R1648H mutation exhibit spontaneous generalized seizures and premature death between P16 and P26, whereas Scn1a(RH/+) heterozygous mice exhibit infrequent spontaneous generalized seizures, reduced threshold and accelerated propagation of febrile seizures, and decreased threshold to flurothyl-induced seizures. Inhibitory cortical interneurons from P5-P15 Scn1a(RH/+) and Scn1a(RH/RH) mice demonstrated slower recovery from inactivation, greater use-dependent inactivation, and reduced action potential firing compared with wild-type cells. Excitatory cortical pyramidal neurons were mostly unaffected. These results suggest that this SCN1A mutation predominantly impairs sodium channel activity in interneurons, leading to decreased inhibition. Decreased inhibition may be a common mechanism underlying clinically distinct SCN1A-derived disorders.
Martin
Melinda S
MS
Department of Human Genetics, Emory University, Atlanta, Georgia 30322.
Dutt
Karoni
K
Departments of Microbiology and Molecular Genetics, Irvine, California 92697.
Papale
Ligia A
LA
Department of Human Genetics, Emory University, Atlanta, Georgia 30322; Department of Psychobiology, Universidade Federal de São Paulo, São Paulo 04024-000, Brazil.
Dubé
Céline M
CM
Anatomy and Neurobiology, Irvine, California 92697; Pediatrics, University of California, Irvine, California 92697.
Dutton
Stacey B
SB
Department of Human Genetics, Emory University, Atlanta, Georgia 30322.
de Haan
Georgius
G
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109.
Shankar
Anupama
A
Department of Human Genetics, Emory University, Atlanta, Georgia 30322.
Tufik
Sergio
S
Department of Psychobiology, Universidade Federal de São Paulo, São Paulo 04024-000, Brazil.
Meisler
Miriam H
MH
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109.
Baram
Tallie Z
TZ
Anatomy and Neurobiology, Irvine, California 92697; Pediatrics, University of California, Irvine, California 92697.
Goldin
Alan L
AL
Departments of Microbiology and Molecular Genetics, Irvine, California 92697; Anatomy and Neurobiology, Irvine, California 92697. Electronic address: agoldin@uci.edu.
Escayg
Andrew
A
Department of Human Genetics, Emory University, Atlanta, Georgia 30322. Electronic address: aescayg@emory.edu.
D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D006720:Homozygote; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D012640:Seizures / Q000235:genetics; D015222:Sodium Channels / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; D015222:Sodium Channels; D005680:gamma-Aminobutyric Acid