Postsynaptic RIM1α Coordinates Surface Expression Of Recycling NMDA Receptor

N-methyl-D-aspartate receptors (NMDARs) are a subtype of glutamate-gated ion channels in the central nerve system, and play crucial roles in excitatory synaptic transmission and plasticity, learning and memory, and various nervous and mental diseases. The number and subunit composition of synaptic NMDARs are strictly regulated through delicate mechanisms of membrane trafficking processes in neurons. In synaptic sites, NMDARs undergo endocytosis, vesicle sorting, degradation, recycling and reinsertion to membrane. NMDAR endocytosis is mainly clathrin complex-dependent, while its reinsertion relys on exocytosis complex, e.g SNARE complex. However, until now, the mechanism underlying NMDAR trafficking including its reinsertion to membrane from recycling vesicles yet remains unclear.The active zone protein RIMla was identified by Thomas C.Sudhof research group in 1997 using photoreceptor synapses and spinal-cord motor neurons as a putative effector for Rab3 and thought of exsiting only at presynapses. Nowadays we have already known that RIMla interacts with other presynaptic proteins and is required for maintainence of a normal probability of neurotransmitter release and long-term presynaptic potentiation.In our study, we found that RIMla is not only located at presynaptic sites but also located at postsynaptic in cortical neurons by using electron microscopic, biochemical and immunocytochemical analysis. Interestingly, the postsynaptic RIMla is associated with NMDARs, but not AMPA receptors. Furthermore, RIM1αa mediates interaction of NMDAR recycling vesicles and SNAP25 complexes through its direct interaction with Rabll at postsynaptic sites. Knockdown of RIMla in cortical neurons decreases the surface expression of GluN2B subunits, and impairs NMDAR-mediated synaptic transmission and plasiticity. In addition, blockade of the interaction between RIMla and Rab11 significantly decreases the surface expression of the GluN2B, as well as its colocalization with SNAP25. It suggests that RIMla mediates exocytosis of NMDAR recycling vesicles through RIMla’s binding to Rab11.Taken together, we have revealed for the first time in this study that RIM1α is also located at the postsynaptic sites and functions as Rabll effector. These findings provide new insights into reinsertion mechanism of NMDAR recycling vesicles, a key step of trafficking processes, and potentiate to explore the relevance of NMDAR trafficking to nervous and mental disorders.