dc.contributor.author | Krishnan, Vaishnav | en_US |
dc.contributor.author | Stoppel, David C. | en_US |
dc.contributor.author | Nong, Yi | en_US |
dc.contributor.author | Johnson, Mark A. | en_US |
dc.contributor.author | Nadler, Monica J.S. | en_US |
dc.contributor.author | Ozkaynak, Ekim | en_US |
dc.contributor.author | Teng, Brian L. | en_US |
dc.contributor.author | Nagakura, Ikue | en_US |
dc.contributor.author | Mohammad, Fahim | en_US |
dc.contributor.author | Silva, Michael A. | en_US |
dc.contributor.author | Peterson, Sally | en_US |
dc.contributor.author | Cruz, Tristan J. | en_US |
dc.contributor.author | Kasper, Ekkehard M. | en_US |
dc.contributor.author | Arnaout, Ramy | en_US |
dc.contributor.author | Anderson, Matthew P. | en_US |
dc.date.accessioned | 2017-12-05T23:46:40Z | |
dc.date.issued | 2017 | en_US |
dc.identifier.citation | Krishnan, V., D. C. Stoppel, Y. Nong, M. A. Johnson, M. J. Nadler, E. Ozkaynak, B. L. Teng, et al. 2017. “Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.” Nature 543 (7646): 507-512. doi:10.1038/nature21678. http://dx.doi.org/10.1038/nature21678. | en |
dc.identifier.issn | | en |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:34491817 | |
dc.description.abstract | Summary Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant autism linked to increased gene dosages of UBE3A, which both possesses ubiquitin-ligase and transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus down-regulates glutamatergic synapse organizer cerebellin-1 (Cbln1) that is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases of UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA) where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activations of, or Cbln1 restorations in VTA glutamatergic neurons rescues sociability deficits induced by Ube3a and/or seizures. Our results suggest a gene × seizure interaction in VTA glutamatergic neurons that impairs sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes. | en |
dc.language.iso | en_US | en |
dc.relation.isversionof | doi:10.1038/nature21678 | en |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364052/pdf/ | en |
dash.license | LAA | en_US |
dc.title | Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1 | en |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en |
dc.relation.journal | Nature | en |
dash.depositing.author | Nong, Yi | en_US |
dc.date.available | 2017-12-05T23:46:40Z | |
dc.identifier.doi | 10.1038/nature21678 | * |
dash.authorsordered | false | |
dash.contributor.affiliated | Nadler, Monica | |
dash.contributor.affiliated | Kasper, Ekkehard | |
dash.contributor.affiliated | Johnson, Mark | |
dash.contributor.affiliated | Arnaout, Ramy | |
dash.contributor.affiliated | Nong, Yi | |
dash.contributor.affiliated | Silva, Michael | |
dash.contributor.affiliated | Anderson, Matthew | |