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.

中文翻译：

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GPR56 的剪接异构体通过磷脂酰丝氨酸结合介导小胶质细胞突触细化。

发育性突触重塑对于精确神经回路的形成非常重要，其破坏与自闭症和精神分裂症等神经发育障碍有关。小胶质细胞修剪突触，但这种突触修剪与重叠和并发的神经发育过程的整合仍然难以捉摸。粘附 G 蛋白偶联受体 ADGRG1/GPR56 以细胞类型特异性方式控制大脑发育的多个方面：在神经祖细胞中，GPR56 调节皮质分层，而在少突胶质细胞祖细胞中，GPR56 控制发育髓鞘形成和髓磷脂修复。在这里，我们证明小胶质细胞 GPR56 以时间和电路依赖的方式在多个大脑区域维持适当的突触数量。突触前元件上的磷脂酰丝氨酸 (PS) 以域特异性方式结合 GPR56，小胶质细胞特异性删除Gpr56会导致小胶质细胞吞噬 PS ⁺突触前输入的减少，从而导致突触增加。值得注意的是，小胶质细胞介导的突触修剪选择性地需要 GPR56 的特定选择性剪接亚型。我们目前的数据提供了复杂神经发育过程中小胶质细胞 GPR56 介导的突触修剪的配体和亚型特异性机制。