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

Kevin M. Woolfrey, Deepak P. Srivastava, Huzefa Photowala, Megumi Yamashita, Maria V. Barbolina, Michael E. Cahill, Zhong Xie, Kelly A. Jones, Lawrence A. Quilliam, Murali Prakriya, Peter Penzes

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1275-1284
Number of pages10
JournalNature Neuroscience
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2009

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Synapses
Spine
Depression
Guanine Nucleotide Exchange Factors
Dopamine D1 Receptors
AMPA Receptors
Missense Mutation
Autistic Disorder
Morphogenesis
Neurons
Membranes
Genes
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Woolfrey, K. M., Srivastava, D. P., Photowala, H., Yamashita, M., Barbolina, M. V., Cahill, M. E., ... Penzes, P. (2009). Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nature Neuroscience, 12(10), 1275-1284. https://doi.org/10.1038/nn.2386

Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. / Woolfrey, Kevin M.; Srivastava, Deepak P.; Photowala, Huzefa; Yamashita, Megumi; Barbolina, Maria V.; Cahill, Michael E.; Xie, Zhong; Jones, Kelly A.; Quilliam, Lawrence A.; Prakriya, Murali; Penzes, Peter.

In: Nature Neuroscience, Vol. 12, No. 10, 01.10.2009, p. 1275-1284.

Research output: Contribution to journalArticle

Woolfrey, KM, Srivastava, DP, Photowala, H, Yamashita, M, Barbolina, MV, Cahill, ME, Xie, Z, Jones, KA, Quilliam, LA, Prakriya, M & Penzes, P 2009, 'Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines', Nature Neuroscience, vol. 12, no. 10, pp. 1275-1284. https://doi.org/10.1038/nn.2386
Woolfrey KM, Srivastava DP, Photowala H, Yamashita M, Barbolina MV, Cahill ME et al. Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nature Neuroscience. 2009 Oct 1;12(10):1275-1284. https://doi.org/10.1038/nn.2386
Woolfrey, Kevin M. ; Srivastava, Deepak P. ; Photowala, Huzefa ; Yamashita, Megumi ; Barbolina, Maria V. ; Cahill, Michael E. ; Xie, Zhong ; Jones, Kelly A. ; Quilliam, Lawrence A. ; Prakriya, Murali ; Penzes, Peter. / Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. In: Nature Neuroscience. 2009 ; Vol. 12, No. 10. pp. 1275-1284.
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