Transmission at excitatory synapses in mammalian brain is mediated primarily by glutamate acting on AMPA receptors and NMDA receptors, two classes of ligand gated ion channels. Whereas NMDA receptors are stable components of the postsynaptic density (PSD), AMPA receptors cycle on and off the synaptic membrane in a manner that is tightly controlled by neuronal activity. This regulated insertion and removal of AMPA receptors at the synapse provides a mechanism for altering synaptic efficacy and for storing information in brain. Our preliminary data show that functional expression of AMPA receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins. And, we have defined a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma3., gamma-4 and gamma-8 - but not related proteins - that mediate surface expression of AMPA receptors. TARPs mediate synaptic trafficking of AMPA receptors by interacting with the postsynaptic density protein, PSD-95. Whether stargazin-like proteins control AMPA receptor turnover and synaptic plasticity in forebrain regions such as hippocampus remains uncertain. However, we found that one of the TARPs, gamma-8, is uniquely enriched in hippocampus, where it interacts with AMPA receptors. We now propose to determine whether gamma-8 regulates the activity-dependent AMPA receptor trafficking that underlies aspects of synaptic plasticity. Because phosphorylation plays a major role in activity-dependent AMPA receptor trafficking, we will assess functional roles for phosphorylation of gamma-8 in hippocampus. We will also characterize functional domains and protein interactions with the unique C-terminal tail of gamma-8. We will also take genetic approaches and determine how overexpression or targeted disruption of gamma-8 modulates AMPA receptor targeting and turnover at synapses. These studies will provide fundamental insight into mechanisms for postsynaptic development and function. Understanding mechanisms that control synaptic targeting of glutamate receptors will help clarify the role that this plasticity plays in learning and memory.
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