CaMKI dysregulation leads to autism-related phenotypes in precise synaptic connectivity, sleep, social behavior, and aging-dependent degeneration in Drosophila

Postmortem studies reveal increased density of synapses in brains of individuals with autism spectrum disorder (ASD. These observations have led to the hypothesis that defects in synaptic pruning may contribute to ASD pathology. Synaptic pruning, also called synaptic elimination or refinement, is a neuroplastic process involving the removal of ectopic synapses formed in the initial stages of neuronal development. Studies in vertebrates and invertebrates indicate that a crucial factor regulating synaptic pruning is neuronal activity, which was first hypothesized by Nobel laureates Hubel and Wiesel in the 1960s. Studies at the vertebrate retina as well as the mammalian and Drosophila neuromuscular junction (NMJ) indicate that waves of prenatal electrical activity and calcium (Ca2+) oscillations regulate the withdrawal of off-target synaptic contacts. Ca2+ oscillations regulate Ca2+-dependent molecular factors such as kinases (e.g. CaMKII), phosphatases (Calcineurin), and Ca2+-dependent adenylyl cyclases, which in turn regulate intracellular cyclic AMP (cAMP) levels for synaptic pruning in mammalian visual neurons and at the Drosophila NMJ21. Whereas a model to explain the refinement of synaptic connections often involves mechanisms based on Hebbian-like, spike-timing correlation between synaptic partners, where asynchronous inputs are removed, alternative non-Hebbian mechanisms have also been proposed that rely on activity-dependent modulation of chemorepulsion. Although some molecular aspects underlying activity-dependent synaptic refinement have recently been elucidated what molecules link dynamic levels of neuronal activity and the refinement of synaptic contacts during development remain to be elucidated. Consistent with its contributions to advance our understanding of synaptic development, Drosophila melanogaster has emerged as a suitable genetic model system for investigating fundamental mechanisms associated with ASD.