Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors.
Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors.
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DOI：
10.1172/jci.insight.150698
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发表时间：
2021-08-09
期刊：
影响因子：
8
通讯作者：
Pitt GS
中科院分区：
文献类型：
--
作者：
Wang HG;Bavley CC;Li A;Jones RM;Hackett J;Bayleyen Y;Lee FS;Rajadhyaksha AM;Pitt GS
SCN2A编码神经元电压门控Na+通道NaV1.2，是与自闭症谱系障碍（asd）相关的最常见受影响的基因座之一。大多数SCN2A与ASD相关的突变是功能缺失突变，但关于这些突变如何影响神经元功能以及SCN2A突变小鼠是否表现出ASD内表型的研究一直不一致。我们通过CRISPR生成了一个蛋白质截断变体Scn2a小鼠模型（Scn2aΔ1898/+），该模型消除了NaV1.2通道的远端细胞内c端结构域，并在异种表达系统、神经元培养、脑切片和体内分析了该变体的分子和细胞后果。我们还分析了WT和Scn2aΔ1898/+小鼠的多种行为，并将行为与SCN2A变异体人类受试者的临床数据相关联。在异源表达系统中表达NaV1.2突变体显示NaV1.2通道功能降低，并且从Scn2aΔ1898/+前脑分离的培养锥体神经元显示相应的电压门控Na+通道电流降低，而不受其他CNS电压门控Na+通道的补偿。抑制神经元中的Na+电流不受影响。与电压门控Na+通道电流的丧失一致，Scn2aΔ1898/+锥体神经元在前脑神经元培养中表现出兴奋性降低，脑切片中锥体神经元的兴奋性突触输入减少。Scn2aΔ1898/+小鼠表现出几种行为异常，包括异常的社会互动，这反映了在ASD患者和携带功能丧失SCN2A变体的人类中观察到的行为。该模型及其细胞电生理特征为追踪SCN2A功能缺失变体如何导致导致asd相关行为的细胞缺陷提供了一个框架。
SCN2A, encoding the neuronal voltage-gated Na+ channel NaV1.2, is one of the most commonly affected loci linked to autism spectrum disorders (ASDs). Most ASD-associated mutations in SCN2A are loss-of-function mutations, but studies examining how such mutations affect neuronal function and whether Scn2a mutant mice display ASD endophenotypes have been inconsistent. We generated a protein truncation variant Scn2a mouse model (Scn2aΔ1898/+) by CRISPR that eliminates the NaV1.2 channel’s distal intracellular C-terminal domain, and we analyzed the molecular and cellular consequences of this variant in a heterologous expression system, in neuronal culture, in brain slices, and in vivo. We also analyzed multiple behaviors in WT and Scn2aΔ1898/+ mice and correlated behaviors with clinical data obtained in human subjects with SCN2A variants. Expression of the NaV1.2 mutant in a heterologous expression system revealed decreased NaV1.2 channel function, and cultured pyramidal neurons isolated from Scn2aΔ1898/+ forebrain showed correspondingly reduced voltage-gated Na+ channel currents without compensation from other CNS voltage-gated Na+ channels. Na+ currents in inhibitory neurons were unaffected. Consistent with loss of voltage-gated Na+ channel currents, Scn2aΔ1898/+ pyramidal neurons displayed reduced excitability in forebrain neuronal culture and reduced excitatory synaptic input onto the pyramidal neurons in brain slices. Scn2aΔ1898/+ mice displayed several behavioral abnormalities, including abnormal social interactions that reflect behavior observed in humans with ASD and with harboring loss-of-function SCN2A variants. This model and its cellular electrophysiological characterizations provide a framework for tracing how a SCN2A loss-of-function variant leads to cellular defects that result in ASD-associated behaviors.
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影响因子：
5.9
作者：
Deneault E;White SH;Rodrigues DC;Ross PJ;Faheem M;Zaslavsky K;Wang Z;Alexandrova R;Pellecchia G;Wei W;Piekna A;Kaur G;Howe JL;Kwan V;Thiruvahindrapuram B;Walker S;Lionel AC;Pasceri P;Merico D;Yuen RKC;Singh KK;Ellis J;Scherer SW
通讯作者：
Scherer SW
影响因子：
11
作者：
Bavley CC;Fetcho RN;Burgdorf CE;Walsh AP;Fischer DK;Hall BS;Sayles NM;Contoreggi NH;Hackett JE;Antigua SA;Babij R;De Marco García NV;Kash TL;Milner TA;Liston C;Rajadhyaksha AM
通讯作者：
Rajadhyaksha AM
影响因子：
46.9
作者：
Chen R;Gore F;Nguyen QA;Ramakrishnan C;Patel S;Kim SH;Raffiee M;Kim YS;Hsueh B;Krook-Magnusson E;Soltesz I;Deisseroth K
通讯作者：
Deisseroth K
影响因子：
5.9
作者：
Ogiwara I;Miyamoto H;Tatsukawa T;Yamagata T;Nakayama T;Atapour N;Miura E;Mazaki E;Ernst SJ;Cao D;Ohtani H;Itohara S;Yanagawa Y;Montal M;Yuzaki M;Inoue Y;Hensch TK;Noebels JL;Yamakawa K
通讯作者：
Yamakawa K
影响因子：
3.4
作者：
Luchkina NV;Bolshakov VY
通讯作者：
Bolshakov VY