Rescue of oxytocin response and social behaviour in a mouse model of autism
| Autor: | Kassoum Nacro, Enrique Pérez-Garci, Stéphane J. Baudouin, Dietmar Schreiner, Laetitia Hatstatt-Burklé, Peter Scheiffele, Eline Pecho-Vrieseling, Hanna Hörnberg, Alex Matter, Fulvio Magara |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cell Adhesion Molecules Neuronal Nerve Tissue Proteins Biology Oxytocin medicine.disease_cause Article Mice 03 medical and health sciences 0302 clinical medicine Translational regulation medicine Animals RNA Messenger Autistic Disorder Phosphorylation Social Behavior Mice Knockout Neurons Mutation Multidisciplinary Mechanism (biology) Ventral Tegmental Area Dopaminergic Novelty Membrane Proteins Translation (biology) medicine.disease Mice Inbred C57BL Ventral tegmental area Disease Models Animal Eukaryotic Initiation Factor-4E 030104 developmental biology medicine.anatomical_structure Protein Biosynthesis Autism Mitogen-Activated Protein Kinases Neuroscience 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Nature Nature, vol. 584, no. 7820, pp. 252-256 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-020-2563-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink