A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding
A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding
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DOI：
10.15252/embj.2019104136
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发表时间：
2020-05-25
期刊：
影响因子：
11.4
通讯作者：
Piao, Xianhua
中科院分区：
文献类型：
--
作者：
Li, Tao;Chiou, Brian;Piao, Xianhua
发育性突触重塑对于精确神经回路的形成很重要，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是难以捉摸的。粘附G蛋白偶联受体ADGRG 1/GPR 56以细胞类型特异性方式控制脑发育的多个方面：在神经祖细胞中，GPR 56调节皮质层压，而在少突胶质细胞祖细胞中，GPR 56控制发育髓鞘形成和髓鞘修复。在这里，我们表明，小胶质GPR 56保持适当的突触数量在几个大脑区域的时间和电路依赖的方式。突触前元件上的磷脂酰丝氨酸（PS）以结构域特异性的方式结合GPR 56，小胶质细胞特异性的GPR 56缺失导致突触增加，这是由于小胶质细胞对PS（+）突触前输入的吞噬减少。值得注意的是，一个特定的选择性剪接异构体的GPR 56是选择性需要小胶质细胞介导的突触修剪。我们目前的数据提供了一个配体和亚型特异性机制的基础小胶质细胞GPR 56介导的突触修剪的背景下，复杂的神经发育过程。
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.