Role of GluR2-N-Cadherin Interaction in the Regulation of Hippocampal Metabotropic Glutamate Receptor-dependent Long-term Depression

Excitatory synaptic transmission and plasticity mediated by glutamate receptors are important for many brain functions, including learning and memory. Various molecular and cellular models have been established to study multiple forms of synaptic plasticity that coexist in the hippocampal CA1 region. Metabotropic glutamate receptor-dependent long-term depression (mGluR-dependent LTD) is a form of long lasting synaptic plasticity thought to play critical roles in diverse physiological and pathological processes. The GluR2 subunit of AMPA receptors has been a focus of neuroscience research over the last decade due to its important roles in endocytic trafficking and Ca2+ permeation in many forms of activity-dependent synaptic plasticity and homeostatic plasticity. However, the underlying mechanisms of mGluR-dependent LTD and the possible involvement of GluR2 in this form of plasticity remain unknown. In this project, I utilized GluR2 knockout (KO) mice and tested the requirement of GluR2 in multiple forms of hippocampal synaptic plasticity at different developmental stages. The results showed that although GluR2 is dispensable for long lasting synaptic plasticity in juvenile mice, it is essential for the expression of mGluR-dependent LTD in adult animals. Next, I examined the involvement of a number of GluR2-specific functions in mGluR-dependent LTD and found that GluR2 N-terminal interaction with the cell adhesion molecule N-cadherin is a key process required for GluR2 to regulate the expression of mGluR-dependent LTD. Furthermore, using a combination of approaches including electrophysiology, biochemical assays, and virus-mediated expression of several mutant GluR2 constructs, I identified a signaling cascade involving N-cadherin/β-catenin complex, Rac1 Rho GTPase, LIM-kinase 1 and cofilin, through which GluR2 exerts its effect on actin regulation and mGluR-dependent LTD. Importantly, the impaired LTD in GluR2 KO mice can be fully rescued by manipulating GluR2-N-cadherin N-terminus interaction or cofilin-mediated actin reorganization. Lastly, I showed that this signaling cascade also plays a critical role in the regulation of dendritic spine plasticity during mGluR-dependent LTD. Together, these results reveal a novel signaling process by which GluR2 regulates long lasting synaptic plasticity and provide insights into how functional and structural plasticity are coordinated in the mammalian central nervous system.Ph