An Autism-Associated Variant of Epac2 Reveals a Role for Ras/Epac2 Signaling in Controlling Basal Dendrite Maintenance in Mice

• Published in: PLoS biology Vol. 10; no. 6; p. e1001350
• Main Authors: Srivastava, Deepak P., Woolfrey, Kevin M., Jones, Kelly A., Anderson, Charles T., Smith, Katharine R., Russell, Theron A., Lee, Hyerin, Yasvoina, Marina V., Wokosin, David L., Ozdinler, P. Hande, Shepherd, Gordon M. G., Penzes, Peter
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2012; Public Library of Science (PLoS)
• Subjects: Alliances; Animals; Autism; Autistic Disorder - genetics; Autistic Disorder - metabolism; Biology; Brain research; Cell Communication; Dendrites; Dendrites - metabolism; Development and progression; Experiments; Female; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Health aspects; HEK293 Cells; Humans; Mental disorders; Mice; Mice, Inbred C57BL; Mutation; Neural circuitry; Neurons; Neurons - metabolism; Physiological aspects; Proteins; ras Proteins; Rats; Rats, Sprague-Dawley; Schizophrenia; Signal Transduction; United States; ras Proteins; Signal Transduction; Autistic Disorder; Neurons; Humans; Mice, Inbred C57BL; Cell Communication; Rats; Rats, Sprague-Dawley; Guanine Nucleotide Exchange Factors; Animals; HEK293 Cells; Female; Dendrites; Mice
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1001350

The architecture of dendritic arbors determines circuit connectivity, receptive fields, and computational properties of neurons, and dendritic structure is impaired in several psychiatric disorders. While apical and basal dendritic compartments of pyramidal neurons are functionally specialized and differentially regulated, little is known about mechanisms that selectively maintain basal dendrites. Here we identified a role for the Ras/Epac2 pathway in maintaining basal dendrite complexity of cortical neurons. Epac2 is a guanine nucleotide exchange factor (GEF) for the Ras-like small GTPase Rap, and it is highly enriched in the adult mouse brain. We found that in vivo Epac2 knockdown in layer 2/3 cortical neurons via in utero electroporation reduced basal dendritic architecture, and that Epac2 knockdown in mature cortical neurons in vitro mimicked this effect. Overexpression of an Epac2 rare coding variant, found in human subjects diagnosed with autism, also impaired basal dendritic morphology. This mutation disrupted Epac2's interaction with Ras, and inhibition of Ras selectively interfered with basal dendrite maintenance. Finally, we observed that components of the Ras/Epac2/Rap pathway exhibited differential abundance in the basal versus apical dendritic compartments. These findings define a role for Epac2 in enabling crosstalk between Ras and Rap signaling in maintaining basal dendrite complexity, and exemplify how rare coding variants, in addition to their disease relevance, can provide insight into cellular mechanisms relevant for brain connectivity.