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

Item Type:Article
Title:Rescue of oxytocin response and social behaviour in a mouse model of autism
Creators Name:Hörnberg, H. and Pérez-Garci, E. and Schreiner, D. and Hatstatt-Burklé, L. and Magara, F. and Baudouin, S. and Matter, A. and Nacro, K. and Pecho-Vrieseling, E. and Scheiffele, P.
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 cases. 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 vasopressin, which regulate aspects of social behaviour in mammals. 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.
Keywords:Animal Disease Models, Autistic Disorder, Eukaryotic Initiation Factor-4E, Inbred C57BL Mice, Knockout Mice, Membrane Proteins, Messenger RNA, Mitogen-Activated Protein Kinases, Nerve Tissue Proteins, Neuronal Cell Adhesion Molecules, Neurons, Oxytocin, Phosphorylation, Protein Biosynthesis, Signal Transduction, Social Behavior, Ventral Tegmental Area, Animals, Mice
Source:Nature
ISSN:0028-0836
Publisher:Nature Publishing Group
Volume:584
Number:7820
Page Range:252-256
Date:13 August 2020
Official Publication:https://doi.org/10.1038/s41586-020-2563-7
PubMed:View item in PubMed

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