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Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD

Abstract

Autism spectrum disorder (ASD) is a common set of heterogeneous neurodevelopmental disorders resulting from a variety of genetic and environmental risk factors. A core feature of ASD is impairment in prosocial interactions. Current treatment options for individuals diagnosed with ASD are limited, with no current FDA-approved medications that effectively treat its core symptoms. We recently demonstrated that enhanced serotonin (5-HT) activity in the nucleus accumbens (NAc), via optogenetic activation of 5-HTergic inputs or direct infusion of a specific 5-HT1b receptor agonist, reverses social deficits in a genetic mouse model for ASD based on 16p11.2 copy number variation. Furthermore, the recreational drug MDMA, which is currently being evaluated in clinical trials, promotes sociability in mice due to its 5-HT releasing properties in the NAc. Here, we systematically evaluated the ability of MDMA and a selective 5-HT1b receptor agonist to rescue sociability deficits in multiple different mouse models for ASD. We find that MDMA administration enhances sociability in control mice and reverses sociability deficits in all four ASD mouse models examined, whereas administration of a 5-HT1b receptor agonist selectively rescued the sociability deficits in all six mouse models for ASD. These preclinical findings suggest that pharmacological enhancement of 5-HT release or direct 5-HT1b receptor activation may be therapeutically efficacious in ameliorating some of the core sociability deficits present across etiologically distinct presentations of ASD.

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Fig. 1: Behavior deficits present in four mouse models for ASD.
Fig. 2: Systemic administration of MDMA reverses social deficits in four mouse models for ASD.
Fig. 3: Systemic administration of CP-94,253 reverses social deficits in four mouse models for ASD.
Fig. 4: Systemic administration of CP-94,253 reverses social deficits in Actl6b−/− and Sert-Cre+/–:Arid1bflx/+ mice.
Fig. 5: Systemic administration of CP-94,253 normalizes the global behavioral profile of all ASD models.

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Acknowledgements

We thank the members of the Malenka and Heifets labs for helpful comments on the project. We thank Claire Ellis for her help with breeding, maintaining, and delivering many of the mouse lines. We also thank Jason M. Tucciarone for his expertise in timed pregnancies for the generation of the valproic acid mice. MDMA was a gift from R. Doblin, Multidisciplinary Association for Psychedelic Studies (MAPS).

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JJW performed and analyzed the majority of the experiments with assistance of PL. DFCP designed the PCA code and with DJC performed the PCA analysis. DJC assisted in behavioral analysis and design. WW and GRC helped select the mouse lines to study and bred, maintained, and delivered a significant proportion of the cohorts used in the studies. BDH and JS assisted in the design of the MDMA studies. JJW and RCM developed the project, designed the experiments, interpreted results, and wrote the paper, which was edited by all authors.

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Correspondence to Robert C. Malenka.

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Walsh, J.J., Llorach, P., Cardozo Pinto, D.F. et al. Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD. Neuropsychopharmacol. 46, 2000–2010 (2021). https://doi.org/10.1038/s41386-021-01091-6

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