During development, activity refines neural connections by modulating the number and relative strength of synaptic inputs onto neurons. Long-term depression (LTD) is a form of synaptic plasticity believed to play a critical role in neural circuit formation, perhaps as an initial step in synapse elimination. Multiple signaling pathways can trigger LTD in a single neuron, however, the relative functional impact of these different pathways on mediating synaptic input is unclear. Two forms of LTD have been identified in hippocampal CA1 pyramidal neurons, metabotropic glutamate receptor (mGluR) - and NMDA- type glutamate receptor (NMDAR)-mediated, which have been proposed to share regulated endocytosis of synaptic AMPA-type glutamate receptors as an expression mechanism. However, differences in downstream signaling pathways and the absence of functional interaction between synaptic depressions activated by these receptors imply that they trigger the internalization of AMPARs through distinct, as yet undefined, mechanisms. We have found that activation of the NMDAR- or mGluR- coupled signaling pathways in pyramidal neurons actually causes the internalization of different populations of AMPARs. Furthermore, our preliminary studies suggest that the colocalization of the AMPAR- interacting proteins receptors GRIP with receptors at a subset of surface sites likely plays a role in mediating this signaling pathway selective AMPAR endocytosis. In this proposal, we will test the hypothesis that NMDARs and mGluRs target AMPARs for internalization from completely distinct synaptic sites mediated by the localized expression of GRIP. Furthermore, we will test whether GRIP promotes selective AMPAR endocytosis by establishing a stabilized synaptic population of AMPARs specifically targeted for internalization by mGluR activation but resistant to the actions of NMDARs. Results from these studies should provide important insight into mechanisms of AMPAR trafficking. In addition they should provide novel evidence that two forms of depression can differentially shape the connectivity of developing neuronal circuitry by acting at distinct synaptic sites on a single neuron. ? ?
