Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany; Focus Program Translational Neurosciences (FTN), University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Cell Rep. 2017 Oct 3;21(1):84-96. doi: 10.1016/j.celrep.2017.09.019.
Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking in response to neuronal activity is critical for synaptic function and plasticity. Here, we show that neuronal activity induces the binding of ephrinB2 and ApoER2 receptors at the postsynapse to regulate de novo insertion of AMPA receptors. Mechanistically, the multi-PDZ adaptor glutamate-receptor-interacting protein 1 (GRIP1) binds ApoER2 and bridges a complex including ApoER2, ephrinB2, and AMPA receptors. Phosphorylation of ephrinB2 in a serine residue (Ser-9) is essential for the stability of such a complex. In vivo, a mutation on ephrinB2 Ser-9 in mice results in a complete disruption of the complex, absence of ApoER2 downstream signaling, and impaired activity-induced and ApoER2-mediated AMPA receptor insertion. Using compound genetics, we show the requirement of this complex for long-term potentiation (LTP). Together, our findings uncover a cooperative ephrinB2 and ApoER2 signaling at the synapse, which serves to modulate activity-dependent AMPA receptor dynamic changes during synaptic plasticity.
神经元活动调控α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体转运对于突触功能和可塑性至关重要。在这里，我们表明神经元活动诱导突触后膜上的 EphrinB2 和 ApoER2 受体结合，从而调节 AMPA 受体的从头插入。在机制上，多 PDZ 衔接蛋白谷氨酸受体相互作用蛋白 1（GRIP1）与 ApoER2 结合，并桥接包括 ApoER2、EphrinB2 和 AMPA 受体在内的复合物。EphrinB2 丝氨酸残基（Ser-9）的磷酸化对于这种复合物的稳定性至关重要。在体内，小鼠 EphrinB2 Ser-9 上的突变导致复合物完全破坏，ApoER2 下游信号缺失，以及活动诱导和 ApoER2 介导的 AMPA 受体插入受损。通过复合遗传学，我们表明该复合物对于长时程增强（LTP）是必需的。总之，我们的研究结果揭示了突触处 EphrinB2 和 ApoER2 信号的协同作用，这种作用调节了突触可塑性过程中活动依赖性 AMPA 受体动态变化。
