Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy.
Voltage-gated sodium channels (Na(V)) are critical for initiation of action potentials. Heterozygous loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy in infancy (SMEI). Homozygous null Scn1a-/- mice developed ataxia and died on postnatal day (P) 15 but could be sustained to P17.5 with manual feeding. Heterozygous Scn1a+/- mice had spontaneous seizures and sporadic deaths beginning after P21, with a notable dependence on genetic background. Loss of Na(V)1.1 did not change voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. The sodium current density was, however, substantially reduced in inhibitory interneurons of Scn1a+/- and Scn1a-/- mice but not in their excitatory pyramidal neurons. An immunocytochemical survey also showed a specific upregulation of Na(V)1.3 channels in a subset of hippocampal interneurons. Our results indicate that reduced sodium currents in GABAergic inhibitory interneurons in Scn1a+/- heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.
Yu
Frank H
FH
Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.
Mantegazza
Massimo
M
Westenbroek
Ruth E
RE
Robbins
Carol A
CA
Kalume
Franck
F
Burton
Kimberly A
KA
Spain
William J
WJ
McKnight
G Stanley
GS
Scheuer
Todd
T
Catterall
William A
WA
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000503:physiopathology*; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D007223:Infant; D007395:Interneurons / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D012640:Seizures / Q000235:genetics / Q000401:mortality / Q000503:physiopathology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015996:Survival Rate; 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