Our research focuses on molecular mechanisms that underlie protein synthesis-dependent synaptic plasticity. In particular, we are examining an immediate early gene (IEG) termed Narp that was identified based on its rapid up-regulation in response to synaptic activity (Tsui et al., 1996). Narp (Neuronal activity-regulated Pentraxin) is a secreted, self-multimerizing protein that is expressed by neurons. In recent studies, we find that Narp is selectively enriched at axo-dendritic excitatory synapses. Moreover, Narp induces clusters of AMPA-type glutamate receptors on the surface of heterologous cells, and selectively co-immunoprecipitates with AMPA receptors from brain. Narp shows extensive co-localization with AMPA receptors, both before and after synaptogenesis, and transient up-regulation of Narp results in an increased number of excitatory synapses. Based on these observations, we hypothesize that Narp modulates synaptic clustering of AMPA receptors and plays a role in excitatory synaptogenesis. Studies described in Aims 1-3 will define the structure-function relationships for Narp membrane surface self-clustering and for its association with AMPA receptors. Conventional mutation analyses and genetic approaches will be used to define the critical sites of interaction for these molecules. Based on this information, peptide and antibody antagonists will be developed to perturb the clustering activity of Narp and test its role in natural synaptogenesis.
Aims 4 -5 will examine the cell biological properties of Narp in brain neurons. Studies will test the hypotheses that Narp is targeted to specific excitatory synapses and that it can modify their morphological and functional properties of excitatory synapses. Since Narp is an IEG, our research will provide new insights into the molecular and cellular mechanisms of activity dependent synaptic plasticity.
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