| Full text | |
| Author(s): Show less - |
Martin, Melinda S.
[1]
;
Dutt, Karoni
[2]
;
Papale, Ligia A.
[1, 3]
;
Dube, Celine M.
[4, 5]
;
Dutton, Stacey B.
[1]
;
de Haan, Georgius
[6]
;
Shankar, Anupama
[1]
;
Tufik, Sergio
[3]
;
Meisler, Miriam H.
[6]
;
Baram, Tallie Z.
[4, 5]
;
Goldin, Alan L.
[2, 4]
;
Escayg, Andrew
[1]
Total Authors: 12
|
| Affiliation: | [1] Emory Univ, Dept Human Genet, Atlanta, GA 30322 - USA
[2] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 - USA
[3] Univ Fed Sao Paulo, Dept Psychobiol, BR-04024000 Sao Paulo - Brazil
[4] Univ Calif Irvine, Dept Anat & Neurobiol, Irvine, CA 92697 - USA
[5] Univ Calif Irvine, Dept Pediat, Irvine, CA 92697 - USA
[6] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 - USA
Total Affiliations: 6
|
| Document type: | Journal article |
| Source: | Journal of Biological Chemistry; v. 285, n. 13, p. 9823-9834, MAR 26 2010. |
| Web of Science Citations: | 125 |
| Abstract | |
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. (AU) | |