Epac2 induces synapse remodeling and depression and its disease-associated forms alter spine morphology

Dynamic remodeling of spiny synapses is crucial for cortical circuit development, refinement, and plasticity, while abnormal morphogenesis is associated with neuropsychiatric disorders. Here we show in cultured rat cortical neurons that activation of Epac2, a PKA-independent cAMP target and Rap guanine-nucleotide exchange factor (GEF), induces spine shrinkage, increases spine motility, removes synaptic GluR2/3-containing AMPA receptors, and depresses excitatory transmission, while its inhibition promotes spine enlargement and stabilization. Epac2 is required for dopamine D1-like receptor-dependent spine shrinkage and GluR2 removal from spines. Epac2 interaction with neuroligin promotes its membrane recruitment and enhances its GEF activity. Rare missense mutations in the EPAC2 gene, previously found in individuals with autism, affect basal and neuroligin-stimulated GEF activity, dendritic Rap signaling, synaptic protein distribution, and spine morphology. Thus, we identify a novel mechanism that promotes dynamic remodeling and depression of spiny synapses, whose mutations may contribute to some aspects of disease.