Restoration of oxytocin responses and social behavior in a mouse model of autism

Hörnberg, H. and Perez-Garci, E. and Schreiner, D. and Hattstatt-Burklé, L. and Magara, F. and Baudouin, S. and Matter, A. and Nacro, K. and Pecho-Vrieseling, E. and Scheiffele, P.. (2020) Restoration of oxytocin responses and social behavior in a mouse model of autism. Nature. Online ahead of print.

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Official URL: https://edoc.unibas.ch/76752/

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One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases 1-3 . Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. To possibly circumvent this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin 4-6 which regulate aspects of social behavior in mammals 7 . However, whether genetic risk factors might predispose to autism due to modification of oxytocinergic signaling remains largely unknown. Here, we report that an autism-associated mutation in the synaptic adhesion molecule neuroligin-3 ( Nlgn3) results in impaired oxytocin signaling in dopaminergic neurons and in altered social novelty responses in mice. Surprisingly, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3 KO mice with a novel, highly specific, brain-penetrant inhibitor of MAP-kinase interacting kinases resets mRNA translation and restores oxytocin and social novelty responses. Thus, this work identifies an unexpected convergence between the genetic autism risk factor Nlgn3 , translational regulation, and oxytocinergic signaling. Focus on such common core plasticity elements might provide a pragmatic approach to reduce the heterogeneity of autism. Ultimately, this would allow for mechanism-based stratification of patient populations to increase the success of therapeutic interventions.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Cell Biology (Scheiffele)
UniBasel Contributors:Scheiffele, Peter
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 Nov 2021 16:09
Deposited On:24 Nov 2021 16:09

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