How Do NMDA and AMPA Receptors Share a Common Regulatory Mechanism That Underlies the NMDAR-dependent LTP and LTD?

NMDA receptor (NMDAR)-dependent AMPA receptor (AMPAR)-mediated synaptic plasticity, encompassing long-term potentiation (LTP) and depression (LTD), is considered a cellular mechanism for learning and memory. However, the intertwined regulatory mechanisms of NMDAR and AMPAR-mediated synaptic plasticity are not yet fully understood. Here, we discovered that activating either NMDAR, AMPAR, or both leads to an activity-dependent synaptic depression, which is independent of Ca 2+ . Interestingly, even stimulating NMDAR at a test frequency of 0.1 Hz was able to induce LTP. Yet, this induction was impeded by antagonists of ryanodine receptors or CaMKII. We also observed that the activity-dependent synaptic depression is developmentally regulated and could be reversed by NMDAR-induced Ca 2+ -dependent upregulation. Furthermore, postsynaptic responses driven by both NMDAR and AMPAR displayed additive effects and synchronously shifted throughout the synaptic plasticity processes. This synchronous evolution indicates a shared regulatory mechanism. Based on previous studies and our current findings, it is suggested that a dynamic balance between activity-dependent dephosphorylation and CaMKII-dependent rephosphorylation of postsynaptic glutamate receptor functional sites guides the direction of NMDAR-dependent, AMPAR-mediated synaptic plasticity.