Department of Neurobiology, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.
Department of Anatomy, Histology and Embryology, Fourth Military Medical University, 710032, Xi'an, China.
Nat Commun. 2018 Jun 11;9(1):2267. doi: 10.1038/s41467-018-04672-0.
NMDA receptors (NMDARs) are crucial for excitatory synaptic transmission and synaptic plasticity. The number and subunit composition of synaptic NMDARs are tightly controlled by neuronal activity and sensory experience, but the molecular mechanism mediating NMDAR trafficking remains poorly understood. Here, we report that RIM1, with a well-established role in presynaptic vesicle release, also localizes postsynaptically in the mouse hippocampus. Postsynaptic RIM1 in hippocampal CA1 region is required for basal NMDAR-, but not AMPA receptor (AMPAR)-, mediated synaptic responses, and contributes to synaptic plasticity and hippocampus-dependent memory. Moreover, RIM1 levels in hippocampal neurons influence both the constitutive and regulated NMDAR trafficking, without affecting constitutive AMPAR trafficking. We further demonstrate that RIM1 binds to Rab11 via its N terminus, and knockdown of RIM1 impairs membrane insertion of Rab11-positive recycling endosomes containing NMDARs. Together, these results identify a RIM1-dependent mechanism critical for modulating synaptic function by facilitating membrane delivery of recycling NMDARs.
N-甲基-D-天冬氨酸受体（NMDARs）对于兴奋性突触传递和突触可塑性至关重要。突触 NMDAR 的数量和亚基组成受神经元活动和感觉经验的严格控制，但介导 NMDAR 运输的分子机制仍知之甚少。在这里，我们报告说，RIM1 在突触前囊泡释放中具有既定的作用，也在小鼠海马体中突触后定位。海马 CA1 区的突触后 RIM1 对于基础 NMDAR-介导但不是 AMPA 受体（AMPAR）介导的突触反应是必需的，并有助于突触可塑性和海马体依赖性记忆。此外，海马神经元中的 RIM1 水平既影响组成型又影响调节型 NMDAR 运输，而不影响组成型 AMPAR 运输。我们进一步证明 RIM1 通过其 N 端与 Rab11 结合，并且 RIM1 的敲低会损害含有 NMDAR 的 Rab11 阳性再循环内体的膜插入。总之，这些结果确定了一种 RIM1 依赖性机制，通过促进再循环 NMDAR 的膜递送来调节突触功能。
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