Cerebellar Synaptic Dysfunction in Autism Spectrum Disorder - Project Summary Autism spectrum disorders (ASD) are a highly complex and multi-faceted group of related neurodevelopmental disorders with numerous genetic, epigenetic, and environmental etiologies. Despite such complex underlying causes, one common theme among ASD variants is that it is a disorder of synaptic development. This observation strongly motivates testing whether experimental models of ASD disrupt the normal synaptic and biophysical development of neural circuits, with the goal of understanding whether and how such perturbations alter circuit function into adulthood. One particularly compelling circuit, which has recently become a major focus in the field of ASD research, is the cerebellum. Although traditionally viewed as a motor structure, emerging clinical and preclinical data suggest that the cerebellum plays an important role in cognitive and emotional processing. Disruptions in cerebellar activity during development may also centrally contribute to ASD – as the developing cerebellum is a common locus the expression of ASD risk factor genes. Furthermore, ASD results in decreased numbers and synaptic complexity of Purkinje cells as well as their postsynaptic targets, cerebellar nuclear cells, the two cell populations that form the cerebellar cortico-nuclear circuit, a disruption which persists into adulthood. These observations have resulted in the cerebellar diaschisis model of ASD, which posits that disruptions in cerebellar circuit function, particularly during early critical periods of synaptic development, may causally contribute to ASD. If the cerebellar diaschisis model is correct, then perinatal circuit function in the developing cerebellar cortico-nuclear circuit is likely perturbed. Therefore, the goal of the proposed research is to explicitly test whether ASD results in aberrant cortico- nuclear circuit formation and electrophysiological maturation during early developmental critical periods, and test whether these changes persist into adulthood. More specifically, the proposal will test the hypothesis that ASD is associated with aberrant developmental glutamate release during early sensitive periods of circuit formation. In other inhibitory circuits, developmental glutamate release is critical for proper circuit maturation, however, this hypothesis has not been tested during cerebellar development or in the context of ASD. Together, the proposed experiments have the potential to provide a biophysical and mechanistic grounding for the cerebellar diaschisis model of ASD, which may provide novel therapeutic targets for the treatment of ASD.
