A Novel Human Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors.

Stephenson JR, Wang X, Perfitt TL, Parrish WP, Shonesy BC, Marks CR, Mortlock DP, Nakagawa T, Sutcliffe JS, Colbran RJ
J Neurosci. 2017 37 (8): 2216-2233

PMID: 28130356 · PMCID: PMC5338762 · DOI:10.1523/JNEUROSCI.2068-16.2017

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 Glu183 to Val (E183V) mutation in the CaMKIIα catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIα substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIα-WT autophosphorylation. The E183V mutation also reduces CaMKIIα binding to established ASD-linked proteins, such as Shank3 and subunits of l-type calcium channels and NMDA receptors, and increases CaMKIIα turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIα targeting to dendritic spines. Moreover, neuronal expression of CaMKIIα-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIα-E183V mutation have lower total forebrain CaMKIIα levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIα-E183V mice also display aberrant behavioral phenotypes, including hyperactivity, social interaction deficits, and increased repetitive behaviors. Together, these data suggest that CaMKIIα plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes. Many autism spectrum disorder (ASD)-linked mutations disrupt the function of synaptic proteins, but no single gene accounts for >1% of total ASD cases. The molecular networks and mechanisms that couple the primary deficits caused by these individual mutations to core behavioral symptoms of ASD remain poorly understood. Here, we provide the first characterization of a mutation in the gene encoding CaMKIIα linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked mutation disrupts multiple CaMKII functions, induces synaptic deficits, and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD.

Copyright © 2017 the authors 0270-6474/17/372217-18$15.00/0.

MeSH Terms (25)

Animals Autism Spectrum Disorder Brain Calcium-Calmodulin-Dependent Protein Kinase Type 2 Cells, Cultured Cycloheximide Dendrites Disease Models, Animal Embryo, Mammalian Excitatory Postsynaptic Potentials Exploratory Behavior Female Gene Expression Regulation Humans Male Mice Mice, Inbred C57BL Mice, Transgenic Mutation Rats Rats, Sprague-Dawley Receptors, AMPA Receptors, N-Methyl-D-Aspartate Sialoglycoproteins Synaptic Transmission

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