Dissertation Details

Dissertation Code :  IDpq 3402731

Dissertation Title   :  The role of Epac2 in the structure and function of cortical spiny synapses and its contribution to the pathophysiology of autism


About This Dissertation

256 pages
Ph.D. dissertation
2010.

Abstract
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 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 receptordependent 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.

Dendritic structure is critical for neuronal computation and neural circuit organization. Mechanisms that support dendritic maintenance are poorly understood. We have identified a role for Epac2 in the selective maintenance of basal dendrites in cortical pyramidal neurons. Autism-associated mutations in the EPAC2 gene cause dendritic deficits consistent with Epac2 and Rap hypofunction. We present evidence that the deficits in dendrite maintenance exhibited by these mutants result from deficient Ras interaction.

Finally we provide initial characterization of an Epac2 knockout mouse. These animals demonstrate selective impairment in sociability, communication and emotional learning. The data support the utility of this mouse not only as a tool for probing mechanisms of learning and memory, but also as an animal model for autism.


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