Dataset Information

Rescue of oxytocin response and social behavior in a rodent model of autism

ABSTRACT: 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. 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 which regulate aspects of social behavior in mammals. 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 Nlgn3KO 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 phenotypes. Ultimately, this would allow for mechanism-based stratification of patient populations to increase the success of therapeutic interventions.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Alexander Schmidt

LAB HEAD: Alexander Schmidt

PROVIDER: PXD018808 | Pride | 2020-04-27

REPOSITORIES: Pride

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Publications

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

Hörnberg Hanna H Pérez-Garci Enrique E Schreiner Dietmar D Hatstatt-Burklé Laetitia L Magara Fulvio F Baudouin Stephane S Matter Alex A Nacro Kassoum K Pecho-Vrieseling Eline E Scheiffele Peter P

Nature 20200805 7820

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<sup>1-3</sup>. 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 comple ...[more]

PMID: 32760004

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Project description:Maintaining skeletal muscle mass is of high importance as muscle atrophy like during sarcopenia or cachexia lead to a decrease in independence and a higher risk of morbidity and mortality. A leading compound in the treatment against ageing and cancer is rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1). Whether the treatment with mTORC1 inhibitors would work at a cost of losing muscle mass is unclear, as most studies have been focusing on the role of mTORC1 specifically during hypertrophy. In order to answer this question we developed an inducible muscle specific knockout mouse model in which raptor can be ablated during adulthood to eliminate mTORC1 activity. We analysed the muscles after different time points and found that after 3 months the mice showed a fiber shift towards slower fiber types, a loss in oxidative capacity but only very few myopathic features. After 5 months the myopathic features became more apparent, however it did not largely affect the ex vivo muscle force. Surprisingly despite the myopathy we did not see a significant loss of muscle mass even after 5 months, that we hypothesised based on mTORC1s central role in protein synthesis. We assume that the myopathy after long-term mTORC1 inactivation is mostly a result of secondary effects through the loss of mitochondria, alterations in metabolism and in cytoskeletal components. In conclusion, during skeletal muscle maintenance mTORC1 is more essential for metabolic processes than it is for maintaining basal muscle mass.Maintaining skeletal muscle mass is of high importance as muscle atrophy like during sarcopenia or cachexia lead to a decrease in independence and a higher risk of morbidity and mortality. A leading compound in the treatment against ageing and cancer is rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1). Whether the treatment with mTORC1 inhibitors would work at a cost of losing muscle mass is unclear, as most studies have been focusing on the role of mTORC1 specifically during hypertrophy. In order to answer this question we developed an inducible muscle specific knockout mouse model in which raptor can be ablated during adulthood to eliminate mTORC1 activity. We analysed the muscles after different time points and found that after 3 months the mice showed a fiber shift towards slower fiber types, a loss in oxidative capacity but only very few myopathic features. After 5 months the myopathic features became more apparent, however it did not largely affect the ex vivo muscle force. Surprisingly despite the myopathy we did not see a significant loss of muscle mass even after 5 months, that we hypothesised based on mTORC1s central role in protein synthesis. We assume that the myopathy after long-term mTORC1 inactivation is mostly a result of secondary effects through the loss of mitochondria, alterations in metabolism and in cytoskeletal components. In conclusion, during skeletal muscle maintenance mTORC1 is more essential for metabolic processes than it is for maintaining basal muscle mass.

Dataset Information

Rescue of oxytocin response and social behavior in a rodent model of autism

Publications

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

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