Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France.
Institut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, 75248 Paris Cedex 05, France.
Neuron. 2019 Dec 18;104(6):1081-1094.e7. doi: 10.1016/j.neuron.2019.09.027. Epub 2019 Nov 5.
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.
精细协调兴奋性和抑制性突触的发育是大脑正常功能所必需的，而其改变可能导致神经发育障碍。我们利用完整大脑回路中的稀疏分子操作，表明谷氨酸受体 delta-1（GluD1）是离子型谷氨酸受体（iGluRs）的成员，是皮质锥体神经元中抑制性突触的后突触组织者。GluD1 选择性地需要形成抑制性突触，并相应地调节 GABA 能突触传递。在抑制性突触中，GluD1 与小脑蛋白-4 相互作用，小脑蛋白-4 是由表达生长抑素的中间神经元分泌的细胞外支架蛋白，它桥接后突触 GluD1 和突触前神经连接蛋白。当与激动剂甘氨酸或 D-丝氨酸结合时，GluD1 会引发涉及鸟嘌呤核苷酸交换因子 ARHGEF12 和蛋白磷酸酶 1 的调节亚基 PPP1R12A 的非离子型突触后信号转导。因此，GluD1 定义了一种跨突触相互作用，调节皮质抑制性连接的正确建立的突触后信号通路，并挑战了 iGluRs 和抑制性突触分子之间的二分法。
