Trans-Synaptic Signaling through the Glutamate Receptor Delta-1 Mediates Inhibitory Synapse Formation in Cortical Pyramidal Neurons
Trans-Synaptic Signaling through the Glutamate Receptor Delta-1 Mediates Inhibitory Synapse Formation in Cortical Pyramidal Neurons
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DOI：
10.1016/j.neuron.2019.09.027
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发表时间：
2019-12-18
期刊：
影响因子：
16.2
通讯作者：
Charrier, Cecile
中科院分区：
文献类型：
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作者：
Fossati, Matteo;Assendorp, Nora;Charrier, Cecile
兴奋性和抑制性突触发育的精细协调是正常脑功能所必需的，并且改变可能导致神经发育障碍。在完整的脑回路中使用稀疏的分子操作，我们表明，谷氨酸受体δ-1（GluD 1），离子型谷氨酸受体（iGluRs）的成员，是皮层锥体神经元抑制性突触的突触后组织者。GluD 1是形成抑制性突触所选择性需要的，并相应地调节GABA能突触传递。在抑制性突触中，GluD 1与小脑蛋白-4相互作用，小脑蛋白-4是一种由表达生长抑素的中间神经元分泌的细胞外支架蛋白，其桥接突触后GluD 1和突触前神经毒素。当结合其激动剂甘氨酸或D-丝氨酸时，GluD 1 eliminates涉及鸟嘌呤核苷酸交换因子ARHGEF 12和蛋白磷酸酶1 PPP 1 R12 A的调节亚基的非离子型突触后信号传导。因此，GluD 1定义了一种跨突触相互作用，调节突触后信号通路，以正确建立皮质抑制性连接，并挑战iGluRs和抑制性突触分子之间的二分法。
Fine orchestration of excitatory and inhibitory synaptic development is required for normal brain function, and alterations may cause neurodevelopmental disorders. Using sparse molecular manipulations in intact brain circuits, we show that the glutamate receptor delta-1 (GluD1), a member of ionotropic glutamate receptors (iGluRs), is a postsynaptic organizer of inhibitory synapses in cortical pyramidal neurons. GluD1 is selectively required for the formation of inhibitory synapses and regulates GABAergic synaptic transmission accordingly. At inhibitory synapses, GluD1 interacts with cerebellin-4, an extracellular scaffolding protein secreted by somatostatin-expressing interneurons, which bridges postsynaptic GluD1 and presynaptic neurexins. When binding to its agonist glycine or D-serine, GluD1 elicits non-ionotropic postsynaptic signaling involving the guanine nucleotide exchange factor ARHGEF12 and the regulatory subunit of protein phosphatase 1 PPP1R12A. Thus, GluD1 defines a trans-synaptic interaction regulating postsynaptic signaling pathways for the proper establishment of cortical inhibitory connectivity and challenges the dichotomy between iGluRs and inhibitory synaptic molecules.