The assembly and plasticity of CNS synapses is intimately linked to the dynamic recruitment and turnover of its individual components. Of particular importance is the insertion and removal of synaptic -a-amino-5- hydroxy-3methyl-4-isoxacole propionate (AMPA) receptors. This has been shown to be critically important for the establishment of recurrent signaling at excitatory synapses as well as in setting the dynamic range of synapses as occurs during the establishment of certain forms of long term depression (LTD) or potentiation (LTP). Adapter proteins such SAP97, Grip and Pick1, known to interact with the cytoplasmic domains of AMPA receptors are thought to be important for receptor trafficking as well as synaptic localization and function. Of these SAP97 is emerging as one of the most important for trafficking and synaptic localization of AMPA receptors containing GluR1 subunits. In particular, this multidomain scaffold protein has been found to associate with GluR1 subunits in the endoplasmic reticulum (ER), Golgi and synapses. Excitingly, in our recent preliminary data, we have found that synaptic isoforms of SAP97 functionally affect the synaptic recruitment of AMPA receptors contain GluR1 subunits. As such, we hypothesize that SAP97 isoforms play a direct and integral role in the trafficking and dynamic insertion of synaptic GluR1 subunits of the AMPA receptor. In this application, we propose to test these and other hypotheses regarding the role that specific SAP97 isoforms play in the trafficking of GluR1 receptors as well as the assembly of multi-component protein complexes around GluRI. These issues are critical for understanding the cellular and molecular mechanisms underlying the dynamic properties of synaptic AMPA receptors and are relevant to issues of learning and memory and how drugs of abuse dramatically influence the behavior of these receptors and the activity of neural circuits.
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