A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding

Developmental synaptic remodeling is important for the formation of precise neural circuitry, and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes, remains elusive. Adhesion G protein-coupled receptorADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: In neural progenitor cells,GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells,GPR56 controls developmental myelination and myelin repair. Here, we show that microglialGPR56 maintains appropriate synaptic numbers in several brain regions in a time- and circuit-dependent fashion. Phosphatidylserine (PS) on presynaptic elements bindsGPR56 in a domain-specific manner, and microglia-specific deletion ofGpr56leads to increased synapses as a result of reduced microglial engulfment ofPS(+)presynaptic inputs. Remarkably, a particular alternatively spliced isoform ofGPR56 is selectively required for microglia-mediated synaptic pruning. Our present data provide a ligand- and isoform-specific mechanism underlying microglialGPR56-mediated synapse pruning in the context of complex neurodevelopmental processes.