A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors
A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors
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DOI：
10.1523/jneurosci.2068-16.2017
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发表时间：
2017-02-22
影响因子：
5.3
通讯作者：
Colbran, Roger J.
中科院分区：
文献类型：
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作者：
Stephenson, Jason R.;Wang, Xiaohan;Colbran, Roger J.
表征与自闭症谱系障碍（ASD）相关的新突变的功能影响可以提供对潜在病理生理机制的更深入的理解。在这里，我们表明，在诊断为 ASD 的先证者中发现的 CaMKII α 催化结构域中的从头 Glu183 到 Val (E183V) 突变，降低了 CaMKII α 底物磷酸化和调节性自身磷酸化，并且突变激酶以显性失活方式发挥作用，减少 CaMKII α-WT 自身磷酸化。 E183V 突变还减少了 CaMKII α 与已建立的 ASD 相关蛋白（例如 Shank3 以及 L 型钙通道和 NMDA 受体的亚基）的结合，并增加了完整细胞中的 CaMKII α 周转。在培养的神经元中，E183V 突变减少了 CaMKII α 对树突棘的靶向。此外，CaMKII α-E183V 的神经元表达增加树突分枝，降低树突棘密度和兴奋性突触传递。具有敲入 CaMKII α-E183V 突变的小鼠的总前脑 CaMKII α 水平较低，对突触亚细胞部分的靶向性降低。 CaMKII α-E183V 小鼠还表现出异常的行为表型，包括多动、社交互动缺陷和重复行为增加。总之，这些数据表明 CaMKII α 在 ASD 相关突触和行为表型中发挥着以前未被认识到的作用。
Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a de novo Glu183 to Val (E183V) mutation in the CaMKII alpha catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKII alpha substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKII alpha-WT autophosphorylation. The E183V mutation also reduces CaMKII alpha binding to established ASD-linked proteins, such as Shank3 and subunits of L-type calcium channels and NMDA receptors, and increases CaMKII alpha turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKII alpha targeting to dendritic spines. Moreover, neuronal expression of CaMKII alpha-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKII alpha-E183V mutation have lower total forebrain CaMKII alpha levels, with reduced targeting to synaptic subcellular fractions. The CaMKII alpha-E183V mice also display aberrant behavioral phenotypes, including hyperactivity, social interaction deficits, and increased repetitive behaviors. Together, these data suggest that CaMKII alpha plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes.