Maintenance and plasticity of synaptic connections are fundamental to all higher cognitive processes. The proper trafficking of postsynaptic glutamate receptors (GluRs) is critical for this process. It is suggested that their misregulation can impair memory formation, as in Alzheimer patients, and can potentially contribute to other neurological disorders, such as epilepsy and schizophrenia. Our goal is to understand the mechanistic steps of receptor trafficking. This is critical for both understanding basic neuronal function and potentially for treatment of neurological disorders. By using a combination of EM and two-photon imaging techniques, along with electrophysiology, we will determine at high resolution the site of membrane and synapse insertion of specific receptor subunits in tissue. Post-embedding immunogold will be used to localize proteins under EM, and a pH-sensitive eGFP, super ecliptic pHluorin, will monitor surface delivery of receptors. Working in young rat hippocampal slices we will first study the trafficking of GluR4, a process critical for early synaptic strengthening. Next, we will track the coordinated syanptic insertion of GluR1 and replacement by GluR2 following the induction of long-term potentiation (LTP). These phenomena will be studied in preexisting and nascent synapses with the goal of understnading the role each plays in maintaining synaptic circuits.
