Commentary Cell Science Reviews Vol 6 No 3 ISSN 1742-8130

Autism-associated protein Epac2 promotes Rap-dependent excitatory synapse remodeling and depression

Synaptic remodeling is critical for neural circuit development and experience-dependent refinement and plasticity, whereas abnormal synapse morphogenesis is associated with neurodevelopmental and neurodegenerative disorders. While changes in synapse structure are highly correlated with alterations in synaptic function, the mechanisms that coordinately regulate these processes are not well understood. In a recent report in Nature Neuroscience Epac2, a cAMP-regulated Rap guanine nucleotide exchange factor (GEF), is identified as a mediator of both Rap-dependent synapse remodeling and synaptic depression. Activation of Epac2 promotes dendritic spine shrinkage, spine motility, synaptic AMPA receptor removal, and depressed excitatory synaptic transmission, whereas Epac2 inhibition induces spine enlargement and stabilization. Examination of upstream mechanisms regulating Epac2 function indicated that Epac2 is required for dopamine D1-like receptor-dependent synaptic remodeling. Furthermore, Epac2 interacts with neuroligin synaptic adhesion molecules, resulting in its membrane recruitment and activation. In addition to investigating Epac2’s normal function, the authors also examined the effects of rare EPAC2 missense mutations, previously identified in individuals with autism. Two of these disease-associated mutations were found to affect Epac2 Rap-GEF activity, PSD-95 clustering and spine morphology. Taken together, these data suggest that Epac2 plays an important role in Rap-dependent dynamic remodeling and depression of spiny synapses, and that disruption of this pathway may contribute to synaptic dysfunction associated with autism.

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