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.
VAcUL-1 and Dsc, two different E3 ubiquitin ligase complexes coexist on the vacuole membrane to regulate different subsets of membrane proteins via the vReD pathway in response to different environmental cues.
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 proteincoupled receptor ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-5 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 pre-synaptic elements binds GPR56 in a domain-specific manner, and microglia-specific deletion of Gpr56 10 leads to increased synapses as a result of reduced microglial engulfment of PS + pre-synaptic 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. 15 Keywords: GPR56; ADGRG1; adhesion GPCR; synaptic pruning; microglia; phosphatidylserine 15 and is dramatically decreased at P10 (Schafer et al., 2012). To investigate whether there are more PS + synapses during the time point of peak synaptic pruning, we performed dual labeling of PSVue and CTB at P6 and P13. Indeed, we observed that nearly 10% of RGC inputs were PSVue-positive at P6, but only 3% were PSVue-positive at P13 (Fig. 1C and D), coinciding with the rise and fall of microglia-mediated synaptic pruning from P5 to P10. To further confirm PS 20 reside with synaptic structures, we performed immunohistochemistry (IHC) on P6 brain for vesicular glutamate transporter 2 (vGlut2), a presynaptic marker specific to RGC inputs in the
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