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Rescue of oxytocin response and social behaviour in a mouse model of autism

Hörnberg, Hanna, Pérez-Garci, Enrique, Schreiner, Dietmar, Hatstatt-Burklé, Laetitia, Magara, Fulvio, Baudouin, Stephane, Matter, Alex, Nacro, Kassoum, Pecho-Vrieseling, Eline and Scheiffele, Peter 2020. Rescue of oxytocin response and social behaviour in a mouse model of autism. Nature 584 , pp. 252-256. 10.1038/s41586-020-2563-7

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Abstract

A fundamental challenge 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 cases1,2,3. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin4,5,6, which regulate aspects of social behaviour in mammals7. However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3-knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor Nlgn3, regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Nature Research
ISSN: 0028-0836
Date of First Compliant Deposit: 2 November 2020
Date of Acceptance: 25 May 2020
Last Modified: 05 Feb 2021 05:51
URI: http://orca.cf.ac.uk/id/eprint/134594

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