Cited by 155Neuroendocrine regulation and behaviorAutism Spectrum Disorder ResearchGenetics and Neurodevelopmental Disorders

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

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Hörnberg, Hanna, Pérez-Garci, Enrique, Schreiner, Dietmar, Hatstatt-Burklé, Laetitia, Magara, Fulvio, Baudouin, Stephane, Matter, Alex, Nacro, Kassoum, Pecho-Vrieseling, Eline, Scheiffele, Peter·2020·Nature

DOI 10.1038/s41586-020-2563-7PMC PMC7116741

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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 cases 1-3. 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 vasopressin 4-6, which regulate aspects of social behaviour in mammals 7. 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.

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Authors: Hörnberg, H., Pérez-Garci, E., Schreiner, D., Hatstatt-Burklé, L., Magara, F., Baudouin, S., Matter, A., Nacro, K., Pecho-Vrieseling, E., & Scheiffele, P.
Affiliations: University of Basel (CH)
Centre Hospitalier Universitaire Vaudois (CH)
Experimental Drug Development Centre (SG)
Corresponding author: Scheiffele, Peter
ORCID: Hörnberg, Hanna
Magara, Fulvio
Nacro, Kassoum
Scheiffele, Peter
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2020-08-05
Volume: 584
Issue: 7820
Pages: 252-256
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-020-2563-7
PMC: PMC7116741
OpenAlex: W3047544314
Cited by: 154
References: 64
Citations by year: 2026: 13 · 2025: 25 · 2024: 28 · 2023: 24 · 2022: 28 · 2021: 31 · 2020: 5
FWCI: 24.31
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
PubMed Central (acceptedVersion)
SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
IRIS (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
edoc (University of Basel) (submittedVersion)
Funders: National Science Foundation
Autism Speaks
European Federation of Pharmaceutical Industries and Associations (777394, AIMS-2-TRIALS)
Simons Foundation Autism Research Initiative
European Commission (HORIZON2020, 777394)
Agency for Science, Technology and Research (11 03 FG 07 05)
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (140944, 160319)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: autism spectrum disorder, neuroligin-3, dopaminergic neurons, ventral tegmental area, social behavior, synaptic adhesion molecules, translational regulation, autism heterogeneity
MeSH terms: Animals, Autistic Disorder, Disease Models, Animal, Male, Membrane Proteins, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Oxytocin, Phosphorylation, RNA, Messenger, Social Behavior, Protein Biosynthesis, Signal Transduction, Cell Adhesion Molecules, Neuronal, Ventral Tegmental Area, Mice, Knockout, Mitogen-Activated Protein Kinases, Eukaryotic Initiation Factor-4E, Mice

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

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