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 <i>CAMK4</i> (calcium/calmodulin-dependent protein kinase 4). However, the molecular mechanisms linking <i>CAMK4</i> dysregulation and ASD-associated phenotypes remain poorly understood. Here, we used <i>Drosophila melanogaster</i> as a model system to investigate ASD-associated phenotypes in flies with dysregulated <i>CaMKI</i>, the fly homolog of mammalian <i>CAMK4</i>. We show that <i>CaMKI</i> 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 <i>CaMKI</i> 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 <i>CaMKI</i> 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 <i>CaMKI</i> 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.