Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice.
Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2aK1422E mice.
复制标题
DOI：
10.1093/hmg/ddac087
复制
发表时间：
2022-08-25
影响因子：
3.5
通讯作者：
中科院分区：
文献类型：
--
作者：
Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to developmental and epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to intellectual disability and/or autism spectrum disorder (ASD) with or without co-morbid seizures. One unique case less easily classified using this framework is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms and features of ASD. Prior structure–function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model incorporating variant channels that predicted reductions in peak action potential (AP) speed. We generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous Scn2aK1422E/+ mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from Scn2aK1442E/+ cortical slices demonstrated impaired AP initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the AP, suggesting complex effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal electroencephalogram abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from other Scn2a models, consistent with complex effects of K1422E on NaV1.2 channel function.
登录
查看更多内容
影响因子：
3.4
作者：
Favre, I;Moczydlowski, E;Schild, L
通讯作者：
Schild, L
影响因子：
2.5
作者：
Connor, JX;McCormack, K;Messing, A
通讯作者：
Messing, A
DOI：
10.1038/s41436-021-01120-1
发表时间：
2021-07
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Crawford K;Xian J;Helbig KL;Galer PD;Parthasarathy S;Lewis-Smith D;Kaufman MC;Fitch E;Ganesan S;O'Brien M;Codoni V;Ellis CA;Conway LJ;Taylor D;Krause R;Helbig I
通讯作者：
Helbig I
影响因子：
2.5
作者：
Eaton, Muriel;Zhang, Jingliang;Yang, Yang
通讯作者：
Yang, Yang
影响因子：
25
作者：
Barak B;Feng G
通讯作者：
Feng G