Kv1.1 deficiency alters repetitive and social behaviors in mice and rescues autistic-like behaviors due to Scn2a haploinsufficiency.
Kv1.1 deficiency alters repetitive and social behaviors in mice and rescues autistic-like behaviors due to Scn2a haploinsufficiency.
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DOI：
10.1002/brb3.2041
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发表时间：
2021-04
影响因子：
3.1
通讯作者：
Glasscock E
中科院分区：
文献类型：
--
作者：
Indumathy J;Pruitt A;Gautier NM;Crane K;Glasscock E
自闭症谱系障碍（ASD）和癫痫是高度共病，这表明在遗传病因学，病理生理学和神经发育异常的潜在重叠，然而，这种关系的性质仍然不清楚。这项工作研究了两种离子通道突变，一种与自闭症（Scn 2a-null）相关，一种与癫痫（Kcna 1-null）相关，如何相互作用以改变自闭症背景下的基因型-表型关系。先前的研究表明，Scn 2a +/-改善Kcna 1-/-小鼠的癫痫，改善生存率，癫痫发作特征和脑心动力学。在这里，我们测试了匡威的情况，Kcna 1缺失是否会改变Scn 2a +/-小鼠中的ASD样重复和社会行为。用Kcna 1和Scn 2a敲除等位基因的各种组合繁殖小鼠。使用大理石掩埋、梳理和雏鸟切碎测试评估动物的重复行为，并使用社交性和社交新奇偏好测试评估动物的社交行为。行为测试显示，癫痫Kcna 1-/-小鼠的所有重复行为急剧减少，但相对正常的社会互动。相比之下，部分Kcna 1缺失（Kcna 1 +/-）的小鼠表现出自我梳理增加和社交能力降低，提示ASD样特征与Scn 2a +/-小鼠中观察到的相似。在双突变Scn 2a +/-; Kcna 1 +/-小鼠中，两种突变相互作用，使与每种突变相关的ASD样行为独立地部分正常化。综上所述，这些发现表明Kv1.1亚基在ASD相关的通路和神经网络中很重要，Kcna 1可能是治疗Scn 2a相关ASD的治疗靶点。这项工作调查了两个离子通道突变，一个与自闭症（Scn 2a-null）相关，一个与癫痫（Kcna 1-null）相关，如何在自闭症的背景下相互作用以改变基因型-表型关系。行为测试显示，小鼠的重复行为和社会行为的改变取决于Kcna 1基因是否被部分或完全敲除。在双突变Scn 2a +/-; Kcna 1 +/-小鼠中，两种突变相互作用，部分挽救了与每个突变独立相关的ASD样行为，表明Kv1.1亚基在ASD相关的通路和神经网络中很重要，Kcna 1可能是治疗Scn 2a相关ASD的治疗靶点。
Autism spectrum disorder (ASD) and epilepsy are highly comorbid, suggesting potential overlap in genetic etiology, pathophysiology, and neurodevelopmental abnormalities; however, the nature of this relationship remains unclear. This work investigated how two ion channel mutations, one associated with autism (Scn2a‐null) and one with epilepsy (Kcna1‐null), interact to modify genotype–phenotype relationships in the context of autism. Previous studies have shown that Scn2a +/– ameliorates epilepsy in Kcna1 –/– mice, improving survival, seizure characteristics, and brain–heart dynamics. Here, we tested the converse, whether Kcna1 deletion modifies ASD‐like repetitive and social behaviors in Scn2a+/– mice. Mice were bred with various combinations of Kcna1 and Scn2a knockout alleles. Animals were assessed for repetitive behaviors using marble burying, grooming, and nestlet shredding tests and for social behaviors using sociability and social novelty preference tests. Behavioral testing revealed drastic reductions in all repetitive behaviors in epileptic Kcna1 –/– mice, but relatively normal social interactions. In contrast, mice with partial Kcna1 deletion (Kcna1 +/–) exhibited increased self‐grooming and decreased sociability suggestive of ASD‐like features similar to those observed in Scn2a +/– mice. In double‐mutant Scn2a +/–; Kcna1 +/– mice, the two mutations interacted to partially normalize ASD‐like behaviors associated with each mutation independently. Taken together, these findings suggest that Kv1.1 subunits are important in pathways and neural networks underlying ASD and that Kcna1 may be a therapeutic target for treatment of Scn2a‐associated ASD. This work investigates how two ion channel mutations, one associated with autism (Scn2a‐null) and one with epilepsy (Kcna1‐null), interact to modify genotype–phenotype relationships in the context of autism. Behavioral testing revealed altered repetitive and social behaviors in mice dependent on whether the Kcna1 gene was partially or completely knocked out. In double‐mutant Scn2a +/–; Kcna1 +/– mice, the two mutations interacted to partially rescue ASD‐like behaviors associated with each mutation independently, suggesting that Kv1.1 subunits are important in pathways and neural networks underlying ASD and that Kcna1 may be a therapeutic target for treatment of Scn2a‐associated ASD.
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影响因子：
30.8
作者：
Krumm, Niklas;Turner, Tychele N.;Baker, Carl;Vives, Laura;Mohajeri, Kiana;Witherspoon, Kali;Raja, Archana;Coe, Bradley P.;Stessman, Holly A.;He, Zong-Xiao;Leal, Suzanne M.;Bernier, Raphael;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
DOI：
10.1523/jneurosci.3191-12.2013
发表时间：
2013-01-23
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Holth JK;Bomben VC;Reed JG;Inoue T;Younkin L;Younkin SG;Pautler RG;Botas J;Noebels JL
通讯作者：
Noebels JL
影响因子：
1.9
作者：
Jeste SS;Tuchman R
通讯作者：
Tuchman R
影响因子：
64.5
作者：
Klassen T;Davis C;Goldman A;Burgess D;Chen T;Wheeler D;McPherson J;Bourquin T;Lewis L;Villasana D;Morgan M;Muzny D;Gibbs R;Noebels J
通讯作者：
Noebels J
DOI：
10.1016/j.yebeh.2015.01.006
发表时间：
2015-03
期刊：
Epilepsy & behavior : E&B
影响因子：
--
作者：
Bernard PB;Castano AM;Beitzel CS;Carlson VB;Benke TA
通讯作者：
Benke TA