Makinson Christopher D, Dutt Karoni, Lin Frank, Papale Ligia A, Shankar Anupama, Barela Arthur J, Liu Robert, Goldin Alan L, Escayg Andrew
Department of Human Genetics, Emory University, Atlanta, GA 30022, USA.
Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA 92697, USA.
Exp Neurol. 2016 Jan;275 Pt 1(0 1):46-58. doi: 10.1016/j.expneurol.2015.09.008. Epub 2015 Sep 26.
Understanding the role of SCN8A in epilepsy and behavior is critical in light of recently identified human SCN8A epilepsy mutations. We have previously demonstrated that Scn8a(med) and Scn8a(med-jo) mice carrying mutations in the Scn8a gene display increased resistance to flurothyl and kainic acid-induced seizures; however, they also exhibit spontaneous absence seizures. To further investigate the relationship between altered SCN8A function and epilepsy, we introduced the SCN1A-R1648H mutation, identified in a family with generalized epilepsy with febrile seizures plus (GEFS+), into the corresponding position (R1627H) of the mouse Scn8a gene. Heterozygous R1627H mice exhibited increased resistance to some forms of pharmacologically and electrically induced seizures and the mutant Scn8a allele ameliorated the phenotype of Scn1a-R1648H mutants. Hippocampal slices from heterozygous R1627H mice displayed decreased bursting behavior compared to wild-type littermates. Paradoxically, at the homozygous level, R1627H mice did not display increased seizure resistance and were susceptible to audiogenic seizures. We furthermore observed increased hippocampal pyramidal cell excitability in heterozygous and homozygous Scn8a-R1627H mutants, and decreased interneuron excitability in heterozygous Scn8a-R1627H mutants. These results expand the phenotypes associated with disruption of the Scn8a gene and demonstrate that an Scn8a mutation can both confer seizure protection and increase seizure susceptibility.
鉴于最近发现的人类SCN8A癫痫突变，了解SCN8A在癫痫和行为中的作用至关重要。我们之前已经证明，携带Scn8a基因突变的Scn8a(med)和Scn8a(med-jo)小鼠对氟烷和 kainic 酸诱导的癫痫发作具有更高的抵抗力；然而，它们也表现出自发性失神发作。为了进一步研究SCN8A功能改变与癫痫之间的关系，我们将在一个伴有热性惊厥附加症的全身性癫痫（GEFS+）家族中鉴定出的SCN1A-R1648H突变引入小鼠Scn8a基因的相应位置（R1627H）。杂合R1627H小鼠对某些形式的药理学和电诱导癫痫发作的抵抗力增强，并且突变的Scn8a等位基因改善了Scn1a-R1648H突变体的表型。与野生型同窝小鼠相比，杂合R1627H小鼠的海马切片显示出爆发性行为减少。矛盾的是，在纯合水平上，R1627H小鼠没有表现出癫痫发作抵抗力的增加，并且易患听源性癫痫发作。我们还观察到杂合和纯合Scn8a-R1627H突变体中海马锥体细胞兴奋性增加，而杂合Scn8a-R1627H突变体中中间神经元兴奋性降低。这些结果扩展了与Scn8a基因破坏相关的表型，并表明Scn8a突变既可以赋予癫痫发作保护作用，也可以增加癫痫发作易感性。
