Synaptic connections in the brain are continuously remodeled in response to neuronal activity. This process, known as synaptic plasticity, is widely accepted as the cellular basis for learning and memory, and it is thought to be altered in several cognitive disorders. An important aspect of synaptic plasticity is the regulated movement of neurotransmitter receptors in and out of synapses. However, the mechanisms by which this regulation takes place are largely unknown. The general goal of this project is to elucidate the mechanisms controlling the trafficking and synaptic targeting of the AMPA-type glutamate receptors, which are the major mediators of fast excitatory transmission in the brain. To address this important question, our laboratory has initiated a series of studies combining molecular biology, electrophysiology and imaging techniques on organotypic hippocampal slice cultures. Our hypothesis is that key mediators of intracellular membrane sorting and protein transport, such as the Rab family of small GTPases and the exocyst, regulate the synaptic delivery and removal of AMPA receptors. We are testing this hypothesis by investigating the role of Rab8a, Rab5a and several exocyst subunits in AMPA receptor synaptic trafficking. Our preliminary studies suggest that Rab8a and Rab5a mediate the regulated delivery and removal, respectively, of AMPA receptors, whereas the exocyst may act in combination with Rab8a and synaptic scaffolding molecules to target the receptors specifically into synapses. We are proposing a combination of functional and anatomical studies to elucidate the contribution of these molecules to AMPA receptor trafficking and synaptic plasticity. This proposal constitutes a new approach in the study of neurotransmitter receptor trafficking, by integrating the local mechanisms and regulation of receptor transport at the synapse with the machinery that controls subcellular membrane sorting. We believe that these basic studies on the molecular and cellular mechanisms of synaptic plasticity will contribute to further our understanding of the physiological processes and pathological alterations affecting cognitive function.
