| First Author | Stephenson JR | Year | 2017 |
| Journal | J Neurosci | Volume | 37 |
| Issue | 8 | Pages | 2216-2233 |
| PubMed ID | 28130356 | Mgi Jnum | J:239596 |
| Mgi Id | MGI:5829293 | Doi | 10.1523/JNEUROSCI.2068-16.2017 |
| Citation | Stephenson JR, et al. (2017) A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors. J Neurosci 37(8):2216-2233 |
| abstractText | 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 CaMKIIalpha catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIalpha substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIalpha-WT autophosphorylation. The E183V mutation also reduces CaMKIIalpha binding to established ASD-linked proteins, such as Shank3 and subunits of l-type calcium channels and NMDA receptors, and increases CaMKIIalpha turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIalpha targeting to dendritic spines. Moreover, neuronal expression of CaMKIIalpha-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIalpha-E183V mutation have lower total forebrain CaMKIIalpha levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIalpha-E183V mice also display aberrant behavioral phenotypes, including hyperactivity, social interaction deficits, and increased repetitive behaviors. Together, these data suggest that CaMKIIalpha plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes.SIGNIFICANCE STATEMENT 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 CaMKIIalpha linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked de novo CAMK2A mutation disrupts multiple CaMKII functions, induces synaptic deficits, and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD. |
