Autism-related behavioral phenotypes of three Camk2a mutant mouse lines with reduced CaMKIIalpha expression and/or activity
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key modulator of excitatory synaptic transmission, gene expression, learning and memory. Mutations in the CAMK2A gene, which encodes CaMKII and is highly expressed in multiple regions in the forebrain, have been recently linked to neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Our lab generated and characterized a knock-in (KI) mutant mouse with a glutamate-183 to valine (E183V) CaMKII mutation detected in several children diagnosed with ASD or ID. The E183V mutation reduces CaMKII activity and expression levels but the contributions of these two changes to the ASD-related behavioral phenotypes of these mice are unclear. Therefore, we performed side-by-side comparisons of the behavioral phenotypes of CaMKII E183V-KI mice with two other mutant mouse lines with either a complete loss of CaMKII expression (CaMKII Null mice) or reduced kinase activity (due to a threonine-286 to alanine mutation that abrogates autophosphorylation at this site) with no significant change in expression levels (CaMKII T286A-KI mice). In all three lines, homozygous mutant mice displayed increased stereotypic jumping behavior and hyperactivity, without alterations in anxiety or social interactions. Interestingly, homozygous mutant mice in all three lines also displayed a substantial reduction in tactile sensitivity using the Von Frey filament test. Together, these data suggest that reductions of either CaMKII expression or activity in mice disrupted normal motor and sensory functions.