title: A Novel HumanCAMK2AMutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors.
abstract: 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 ade novoGlu183 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.SIGNIFICANCE STATEMENTMany 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-linkedde novo CAMK2Amutation disrupts multiple CaMKII functions, induces synaptic deficits, and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD.
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Jason R
authors.identifier: 0000-0002-7926-8055
authors.initials: JR
authors.lastname: Stephenson
authors.affiliation: Vanderbilt Brain Institute.|Vanderbilt International Scholar Program.
authors.forename: Xiaohan
authors.identifier: 0000-0001-7895-2333
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Tyler L
authors.identifier: 0000-0002-2381-3341
authors.initials: TL
authors.lastname: Perfitt
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Walker P
authors.initials: WP
authors.lastname: Parrish
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Shonesy
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marks
authors.affiliation: Department of Molecular Physiology and Biophysics.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Mortlock
authors.affiliation: Department of Molecular Physiology and Biophysics.|Center for Structural Biology.
authors.forename: Terunaga
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Molecular Physiology and Biophysics.|Department of Psychiatry, and.
authors.forename: James S
authors.identifier: 0000-0001-5200-6007
authors.initials: JS
authors.lastname: Sutcliffe
authors.affiliation: Department of Molecular Physiology and Biophysics, roger.colbran@vanderbilt.edu.|Vanderbilt Brain Institute.|Vanderbilt-Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: Roger J
authors.identifier: 0000-0001-7401-8244
authors.initials: RJ
authors.lastname: Colbran
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003712:Dendrites / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics*
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003513:Cycloheximide; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012795:Sialoglycoproteins; C517657:CAMK2A protein, human
keywords: CaMKII; autism; behavior; synaptic transmission