VIB Center for Brain & Disease Research, Herestraat 49, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Herestraat 49, 3000 Leuven, Belgium.
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
Neuron. 2018 Oct 10;100(1):201-215.e9. doi: 10.1016/j.neuron.2018.08.038. Epub 2018 Oct 2.
Pyramidal neuron dendrites integrate synaptic input from multiple partners. Different inputs converging on the same dendrite have distinct structural and functional features, but the molecular mechanisms organizing input-specific properties are poorly understood. We identify the orphan receptor GPR158 as a binding partner for the heparan sulfate proteoglycan (HSPG) glypican 4 (GPC4). GPC4 is enriched on hippocampal granule cell axons (mossy fibers), whereas postsynaptic GPR158 is restricted to the proximal segment of CA3 apical dendrites receiving mossy fiber input. GPR158-induced presynaptic differentiation in contacting axons requires cell-surface GPC4 and the co-receptor LAR. Loss of GPR158 increases mossy fiber synapse density but disrupts bouton morphology, impairs ultrastructural organization of active zone and postsynaptic density, and reduces synaptic strength of this connection, while adjacent inputs on the same dendrite are unaffected. Our work identifies an input-specific HSPG-GPR158 interaction that selectively organizes synaptic architecture and function of developing mossy fiber-CA3 synapses in the hippocampus.
锥体神经元树突整合来自多个合作伙伴的突触输入。在同一树突上汇聚的不同输入具有不同的结构和功能特征，但组织输入特异性特性的分子机制尚不清楚。我们发现孤儿受体 GPR158 是硫酸乙酰肝素蛋白聚糖 (HSPG) 聚糖 4 (GPC4) 的结合伴侣。GPC4 在海马颗粒细胞轴突（苔藓纤维）上丰富，而突触后 GPR158 仅限于接收苔藓纤维输入的 CA3 顶树突的近端段。与接触轴突的 GPR158 诱导的突触前分化需要细胞表面 GPC4 和共受体 LAR。GPR158 的缺失增加了苔藓纤维突触的密度，但破坏了末梢形态，损害了活性区和突触后密度的超微结构组织，并降低了该连接的突触强度，而同一树突上的相邻输入则不受影响。我们的工作确定了一种输入特异性的 HSPG-GPR158 相互作用，该相互作用选择性地组织了海马体中发育中的苔藓纤维-CA3 突触的突触结构和功能。
