Dysregulation of Protein Kinase CaMKI Leads to Autism-Related Phenotypes in Synaptic Connectivity, Sleep, Sociality, and Aging-Dependent Degeneration in Drosophila.

Autism spectrum disorder (ASD) encompasses a range of conditions, primarily marked by deficits in social behaviors, along with several comorbidities such as sleep abnormalities and motor dysfunction. Recent studies have identified genetic risk factors associated with ASD, including the CAMK4 (calcium/calmodulin-dependent protein kinase 4). However, the molecular mechanisms linking CAMK4 dysregulation and ASD-associated phenotypes remain poorly understood. Here, we used Drosophila melanogaster as a model system to investigate ASD-associated phenotypes in flies with dysregulated CaMKI, the fly homolog of mammalian CAMK4. We show that CaMKI manipulations affect sleep, circadian rhythmicity, and social behavior. Consistent with the higher prevalence of dementia observed in autistic patients, we also observed a significantly enhanced behavioral decline in motor performance and dendritic degeneration in flies expressing RNAi-based CaMKI knockdown in flight motoneurons, suggesting a link between developmental and degenerative processes. As aberrant synaptic pruning is hypothesized to underlie the synaptic phenotypes observed in brains of autistic patients, we examined synaptic phenotypes following CaMKI manipulations using the larval neuromuscular junction (NMJ) and observed miswiring phenotypes suggesting aberrant synaptic refinement. We performed shotgun mass-spectrometry proteomics and identified various molecular candidates, particularly molecules involved in cytoskeleton regulation and chemorepulsion, likely to regulate the phenotypes described here. Thus, our results suggest that CaMKI plays a role in developmental processes and influences aging-dependent degenerative processes, possibly providing mechanistic insight into the genetic basis of ASD etiology and the development of effective treatments.