Intracellular Trafficking of AMPA Receptors

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DESCRIPTION (provided by applicant): Neurotransmission requires a precise number and arrangement of receptors and ion channels in the neuronal plasma membrane. Alterations in the localization or levels of these proteins in the membrane regulates synapse function, thereby strengthening or weakening synaptic connections in the brain. In all eukaryotic cells, the internalization, recycling, and degradation of membrane proteins is controlled by regulated trafficking through the endocytic pathway. Although previous studies have helped define this pathway in many nonneuronal cell types, the mechanisms underlying endocytic trafficking of postsynaptic receptors and the role of dendritic endosomal transport in synaptic transmission and plasticity remain unknown. To address these important questions, my laboratory has initiated a program of biochemical and cell biological studies to analyze the endocytic trafficking of AMPA-type glutamate receptors. AMPA receptors are the major mediators of fast excitatory transmission in the brain, and alteration of the number and function of AMPA receptors is a critical feature of synaptic plasticity. We have recently found that AMPA receptors are differentially sorted between recycling and degradative pathways following endocytosis. This sorting decision is in turn controlled by the relative activation of AMPA and NMDA-type glutamate receptors in the postsynaptic membrane. Taking advantage of these preliminary data and our ability to monitor and manipulate AMPA receptor trafficking in neurons, we propose to define the underlying molecular and cellular mechanisms of AMPA receptor endocytic trafficking and determine the functional consequences for synapse maturation and maintenance. This work will provide insight into fundamental mechanisms that underlie synapse formation and synaptic plasticity. Moreover, given the importance of excitatory synaptic transmission and AMPA receptor activation in the pathogenesis of numerous psychiatric and neurologic diseases, these studies hold promise for the development of novel therapeutic strategies.