AMPA Receptor Cycling in the Retina

DESCRIPTION (provided by applicant): The rapid cycling of AMPA receptors (AMPARs) into and out of the membrane maintains neurotransmission at a number of CNS synapses. The cycling of AMPARs in the hippocampus and cortex is dynamically regulated by changes in levels of basal synaptic transmission and has been proposed to play a role in certain forms of synaptic plasticity. It remains unclear, however, whether the cycling of AMPARs also occurs at synapses not believed to exhibit postsynaptic forms of activity dependent plasticity. Additionally the question remains as to whether there are differences in the regulation of receptor trafficking at synapses that are subject to very different patterns of synaptic activation. For example, while many CNS synapses function primarily through intermittent, activity driven neurotransmitter release, synapses in the retina are subject to tonic glutamate release and stimulus dependent cessation of synaptic transmission. We are investigating the trafficking of AMPARs in retinal neurons and its regulation by activity. Our preliminary data demonstrates that, GluR2-containing AMPARs, can be rapidly cycled at the extrasynaptic membrane in the retina. However, contrary to in hippocampal synapses, activity in the retina stabilizes AMPARs in a non-cycling mode. This reversible process is modulated by physiological light stimuli. Experiments in this proposal, will seek to test the hypothesis, that normal light/dark cycles drive changes in the cycling of GluR2-containihg AMPARs thereby impacting functional signaling in the retina. Experiments in Aim 1 will establish the physiological conditions that mediate changes in the cycling of AMPARs in the retina. In Aim 2 we will seek to determine the molecular mechanisms by which activity links to changes in the cycling of AMPARs. Finally, in Aim 3 we will characterize the physiological significance of altered AMPAR cycling on the function of synaptic transmission in the retina. Results from these experiments will greatly enhance our understanding of the function and regulation .of signaling in the retina potentially identifying the existence a previously unknown form activity dependent of retinal plasticity. This should provide valuable insight into possible therapeutic treatments relevant to diseases of retinal development and degeneration.