The astrocyte-specific proteome in inhibitory tripartite synapse formation and function in the context of Autism Spectrum Disorder

The neurobiology underlying Autism Spectrum Disorder (ASD) remains elusive. Results from largescale genetic studies strongly implicate abnormal synaptic organization and inhibitory signaling in the pathophysiology of ASD. To date, the research on ASD has been neuron-centric. However, astrocytes, a type of glial cell, closely interact with neurons and play a critical role in the formation and function of synapses. Recent work suggests that excitatory and inhibitory synapse formation and function are differentially regulated by astrocytes. My goal is to gain fundamental knowledge on the composition and function of the inhibitory synapse and the role this may play in ASD. For this, I will use a novel proximity biotinylation-based approach to identify astrocyte proteins, previously linked with ASD, which are present at the inhibitory synapse. I will then assess the role of these proteins using a loss-of-function approach combined with testing for structural and functional effects on synapse formation, and by performing extensive in vivo behavioral phenotyping for ASD. Establishing a key role for astrocytes in controlling synapse-specific wiring and function would constitute a novel important finding that would spark intensive research in the ASD field, with important consequences for human disease research.