Molecular mechanisms of NMDAR- and mGluR-mediated synaptic depression

Abstract

Models of synaptic plasticity in the central nervous system (CNS) such as long-term potentiation (LTP) and long-term depression (LTD) are considered the cellular correlates of learning and memory. Understanding the mechanisms that underlie these long-lasting changes in synaptic efficacy may provide insight into biological functions such as development and experience-dependent plasticity. Intense investigation has focused on postsynaptic mechanisms for receptor-induced forms of synaptic plasticity. Research in the field has uncovered AMPA receptor (AMPAR) trafficking as the likely mechanism for NMDA receptor (NMDAR)- and metabotropic glutamate receptor (mGluR)-dependent forms of LTD at CA1 hippocampal neurons. Further work revealed the importance of protein-protein interactions in mediating changes in surface AMPAR content. PICK1, an AMPAR-interacting protein, is important for the regulated internalization of AMPARs; however, PICK1's role under different signaling conditions that elicit AMPAR endocytosis is still unclear. I begin by investigating the function of dendritic PICK1 in NMDAR-induced changes in surface AMPAR expression. Bidirectional NMDAR-mediated changes in PICK1 serves to regulate a population of cycling receptors, either maintaining them away from the membrane surface or releasing them for surface expression. While NMDAR-mediated PICK1 clustering required LTD-associated phosphatases, the NMDAR-driven unclustering of PICK1 was attributed to NO acting on NSF. AMPAR trafficking is responsible not only for NMDAR-induced LTD but also underlies mGluR-mediated synaptic depression. As these two forms of depression are non-occlusive, we tested how dendritic PICK1 clustering impacts AMPAR internalization during these models of synaptic depression. We find that these receptor-induced forms of synaptic depression are mediated by the endocytosis of different populations of AMPARs based on the differential distribution of PICK1 to synapses or endosomes and their association with another AMPAR- and PICK1-interacting protein GRIP. While PICK1 facilitates endocytosis, GRIP anchors receptors at the surface. Our results suggest the existence of two different types of PICK1-regulated populations of receptors or even synapses, where GRIP determines the stability of surface AMPARs and their susceptibility to mGluR or NMDAR-mediated LTD. We propose a novel mechanism by which multiple signaling pathways can bidirectionally control the number and strength of synaptic inputs, a process likely crucial for sculpting functional circuits and generating behavioral flexibility.