Dynamic remodeling of spiny synapses is crucial for cortical circuit development, refinement and plasticity, whereas abnormal morphogenesis is associated with neuropsychiatric disorders. We found that activation of Epac2, a PKA-independent cAMP target and Rap guanine-nucleotide exchange factor (GEF), in cultured rat cortical neurons induced spine shrinkage, increased spine motility, removed synaptic GluR2/3-containing AMPA receptors and depressed excitatory transmission, whereas its inhibition promoted spine enlargement and stabilization. Epac2 was required for dopamine D1-like receptor–dependent spine shrinkage and GluR2 removal from spines. Epac2 interaction with neuroligin promoted its membrane recruitment and enhanced its GEF activity. Rare missense mutations in the EPAC2 (also known as RAPGEF4) gene, previously found in individuals with autism, affected basal and neuroligin-stimulated GEF activity, dendritic Rap signaling, synaptic protein distribution and spine morphology. Thus, we identify a previously unknown mechanism that promotes dynamic remodeling and depression of spiny synapses, disruption of which may contribute to some aspects of disease.
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We thank R.L. Huganir (Johns Hopkins University) for antibodies to AMPAR and NMDAR subunits, J. Bos (Utrecht University) and P. Stork (Vollum Institute) for plasmids, A. El-Husseini (University of British Columbia) and P. Scheiffele (University of Basel) for antibodies to neuroligin and plasmid constructs, and G. Borisy and S.-I. Kojima (Northwestern University) for the pGSuper plasmid. We thank A.K. Srivastava (J.C. Self Research Institute of Human Genetics) and G. Swanson (Northwestern University) for thoughtful discussion. This work was supported by the National Alliance for Autism Research, the National Alliance for Research on Schizophrenia and Depression, the Alzheimer's Association, grants from the US National Institutes of Health (MH 071316 to P.P., NS057499 to M.P. and CA108647 to L.A.Q.), a pre-doctoral American Heart Association fellowship to K.M.W. and a post-doctoral American Heart Association fellowship to D.P.S.
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Woolfrey, K., Srivastava, D., Photowala, H. et al. Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nat Neurosci 12, 1275–1284 (2009). https://doi.org/10.1038/nn.2386
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