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

This study in mice finds that MDMA (and a selective 5-HT1b receptor agonist) reverse social deficits through increased activity in the nucleus accumbens (NAc). The authors argue that enhancement of 5-HT release or direct 5-HT1b receptor activation may help with treating sociability deficits commonly found in those with autism spectrum disorder (ASD).


“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.”

Authors: Jessica J. Walsh, Pierre Llorach, Daniel F. Cardozo Pinto, Wendy Wenderski, Daniel J. Christoffel, Juliana S. Salgado, Boris D. Heifets, Gerald R. Crabtree & Robert C. Malenka

Study details

Compounds studied

Topics studied
Neuroscience Autism

Study characteristics
Animal Study