A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding. (25th May 2020) - Li, Tao
Abstract: 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 receptor ADGRG1/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 microglial GPR56 maintains appropriate synaptic numbers in several brain regions in a time‐ and circuit‐dependent fashion. Phosphatidylserine (PS) on presynaptic elements binds GPR56 in a domain‐specific manner, and microglia‐specific deletion of Gpr56 leads to increased synapses as a result of reduced microglial engulfment of PS + presynaptic inputs. Remarkably, a particular alternatively spliced isoform of GPR56 is selectively required for microglia‐mediated synaptic pruning. Our present data provide a ligand‐ and isoform‐specific mechanism underlying microglial GPR56‐mediated synapse pruning in the context of complex neurodevelopmental processes. Synopsis: Phosphatidylserine serves an "eat‐me" signal for apoptotic cells to be phagocytosed by macrophages. Here we reveal phosphatidylserine also flags synapses to be removed by microglia during early brain development. ADGRG1/GPR56 S4 isoform in microglia regulates circuit‐specific synapse refinement by binding to phosphatidylserine on pre‐synaptic elements. Synapses destined to be removed externalize phosphatidylserine to serve as an "eat‐me" signal. Microglia prune phosphatidylserine‐positive synapses. A splicing isoform of GPR56, the S4 variant, regulates microglia‐mediated synaptic pruning by binding to phosphatidylserine. Deleting microglial Gpr56 results in excess synapses. Abstract : Phosphatidylserine on presynaptic elements marks synapses for removal via microglia during early brain development, through direct binding to the microglia‐expressed S4 isoform of adhesion G protein‐coupled receptor GPR56.