Hebbian plasticity is a key mechanism for higher brain functions, such as learning and memory. This form of synaptic plasticity primarily involves the regulation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) abundance and properties, whereby AMPARs are inserted into synapses during long-term potentiation (LTP) or removed during long-term depression (LTD). The molecular mechanisms underlying AMPAR trafficking remain elusive, however. Here we show that glutamate receptor interacting protein 1 (GRIP1), an AMPAR-binding protein shown to regulate the trafficking and synaptic targeting of AMPARs, is required for LTP and learning and memory. GRIP1 is recruited into synapses during LTP, and deletion of Grip1 in neurons blocks synaptic AMPAR accumulation induced by glycine-mediated depolarization. In addition, Grip1 knockout mice exhibit impaired hippocampal LTP, as well as deficits in learning and memory. Mechanistically, we find that phosphorylation of serine-880 of the GluA2 AMPAR subunit (GluA2-S880) is decreased while phosphorylation of tyrosine-876 on GluA2 (GluA2-Y876) is elevated during chemically induced LTP. This enhances the strength of the GRIP1–AMPAR association and, subsequently, the insertion of AMPARs into the postsynaptic membrane. Together, these results demonstrate an essential role of GRIP1 in regulating AMPAR trafficking during synaptic plasticity and learning and memory.

赫布可塑性是高级大脑功能（例如学习和记忆）的关键机制。这种形式的突触可塑性主要涉及突触 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) 丰度和特性的调节，由此 AMPAR 在长时程增强 (LTP) 或在长期抑郁症 (LTD) 期间移除。然而，AMPAR 贩运的分子机制仍然难以捉摸。在这里，我们表明谷氨酸受体相互作用蛋白 1 (GRIP1) 是一种 AMPAR 结合蛋白，可调节 AMPAR 的运输和突触靶向，是 LTP 以及学习和记忆所必需的。GRIP1 在 LTP 期间被募集到突触中，并删除Grip1在神经元中阻断由甘氨酸介导的去极化诱导的突触 AMPAR 积累。此外，Grip1敲除小鼠表现出海马 LTP 受损以及学习和记忆缺陷。从机制上讲，我们发现在化学诱导的 LTP 过程中，GluA2 AMPAR 亚基 (GluA2-S880) 的丝氨酸 880 磷酸化降低，而 GluA2 (GluA2-Y876) 上酪氨酸 876 的磷酸化升高。这增强了 GRIP1-AMPAR 关联的强度，并随后将 AMPAR 插入突触后膜。总之，这些结果证明了 GRIP1 在突触可塑性和学习记忆过程中调节 AMPAR 运输的重要作用。