RT Journal Article
SR Electronic
T1 Effects of gene by microbiome interactions on behavioral and neurobiological phenotypes in a mouse model for autism spectrum disorder
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.29.065821
DO 10.1101/2020.04.29.065821
A1 Aya Osman
A1 Nicholas L. Mervosh
A1 Ana N. Strat
A1 Katherine R. Meckel
A1 Tanner J. Euston
A1 Gillian D. Zipursky
A1 Elodie Drapeau
A1 Joseph. D. Buxbaum
A1 Michael S. Breen
A1 Drew D. Kiraly
YR 2020
UL http://biorxiv.org/content/early/2020/04/30/2020.04.29.065821.abstract
AB Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder with a very high prevalence rate and a chronic disease course beginning in early childhood. Despite the tremendous burden of ASD, there are currently no disease-modifying treatments. Like many neuropsychiatric illnesses ASD has a complex pathophysiology driven by genetic and environmental factors. There is interest in identifying modifiable environmental factors as potential translational research strategies for development of therapeutics for ASD. A rapidly growing body of research demonstrates that the resident bacteria of the gastrointestinal tract, collectively the gut microbiome, have profound influence on brain and behavior. This gut-brain signaling pathway is highly relevant to ASD as the microbiome begins to form at birth, is heavily influenced by environmental factors throughout early life, and begins to stabilize at the same stage of development that symptoms of ASD begin to develop. To investigate potential gene x microbiome interactions in a model of ASD, we utilized mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO), which clinically manifests as Phelan-McDermid syndrome, as a model for genetic risk of ASD. Analysis of the gut microbiome of Shank3KO mice demonstrated genotype effects on both microbiome composition and metabolite production. Behaviorally, Shank3KO mice demonstrate decreased social interactions and have altered anxiety and compulsive-like behaviors. Disruption of the microbiome with broad spectrum antibiotics lead to an exacerbation of all behavioral phenotypes in Shank3KO mice. Additionally, we found that Shank3KO mice had markedly increased changes in gene expression in the prefrontal cortex following microbiome depletion. Taken together, our results suggest a gene x microbiome interaction in this mouse model for ASD and raise the possibility that targeting the microbiome may be a valid translational research strategy in developing therapeutics for ASD.Competing Interest StatementThe authors have declared no competing interest.