UCLA

Astrocytes are morphologically complex and bushy cells that tile the entire central nervous system and contribute, along with neurons, to the formation of a complex network with dense physical, chemical, and electrical connectivity. In the striatum, astrocyte fine processes contact about eleven neuronal somata and their synapses where they mediate homeostatic and supportive roles. Because there is a clear spatial and functional relationship between astrocytes and neurons, we used cell- and subcompartment-specific proximity dependent biotinylation to explore the proteomes of striatal astrocytes and neurons in vivo. We studied cytosolic and plasma membrane compartments of astrocytes and neurons to assess how these cells differ at the protein level. Furthermore, we assessed functional subcellular compartments of astrocytes, including the end feet and fine processes, to understand the molecular basis of essential astrocytic functions. Surprisingly, SAPAP3 protein (gene: Dlgap3) associated with obsessive-compulsive disorder (OCD) was detected at equivalent levels in both cell types and in select astrocyte subcompartments including the plasma membrane and fine processes. Validation with transcriptomics, in situ hybridization, and protein labeling revealed that SAPAP3 RNA and protein are highly expressed in astrocytes. Furthermore, causal genetic experiments in the SAPAP3 knockout mouse model of OCD revealed cell-specific contributions of astrocytes and neurons to repetitive and anxiety-related behaviors. Thus, our data define the molecular basis of astrocyte and neuronal signaling in the striatum and how astrocyte and neuronal SAPAP3 mechanisms contribute to OCD phenotypes in mice. Taken together, our findings suggest that targeting both astrocytes and neurons could likely be effective in OCD and potentially other neuropsychiatric disorders.