SNARE proteins are essential in the potentiation of NMDA receptors by group II metabotropic glutamate receptors

The group II metabotropic glutamate receptors (group II mGluRs) have emerged as the new drug targets for the treatment of mental disorders like schizophrenia. To understand the potential mechanisms underlying the antipsychotic effects of group II mGluRs, we examined their impact on NMDA receptors (NMDARs), since NMDAR hypofunction has been implicated in schizophrenia. The activation of group II mGluRs caused a significant enhancement of NMDAR currents in cortical pyramidal neurons, which was associated with increased NMDAR surface expression and synaptic localization. We further examined whether these effects of group II mGluRs are through the regulation of NMDAR exocytosis via SNARE proteins, a family of proteins involved in vesicle fusion. We found that the enhancing effect of APDC, a selective agonist of group II mGluRs, on NMDAR currents was abolished when botulinum toxin was delivered into the recorded neurons to disrupt the SNARE complex. Inhibiting the function of two key SNARE proteins, SNAP-25 and syntaxin 4, also eliminated the effect of APDC on NMDAR currents. Moreover, the application of APDC increased the activity of Rab4, a small Rab GTPase mediating fast recycling from early endosomes to the plasma membrane, and enhanced the interaction between syntaxin 4 and Rab4. Knockdown of Rab4 or expression of dominant-negative Rab4 attenuated the effect of APDC on NMDAR currents. Taken together, these results have identified key molecules involved in the group II mGluR-induced potentiation of NMDAR exocytosis and function.