Effects of gene by microbiome interactions on behavioral and neurobiological phenotypes in a mouse model for autism spectrum disorder

Osman, A.; Mervosh, N. L.; Strat, A. N.; Meckel, K. R.; Euston, T. J.; Zipursky, G. D.; Drapeau, E.; Buxbaum, J.; Breen, M. S.; Kiraly, D. D.

doi:10.1101/2020.04.29.065821

bioRxiv · 10.1101/2020.04.29.065821

Effects of gene by microbiome interactions on behavioral and neurobiological phenotypes in a mouse model for autism spectrum disorder

Osman, A.·Mervosh, N. L.·Strat, A. N.·Meckel, K. R.·Euston, T. J.·Zipursky, G. D.·Drapeau, E.·Buxbaum, J.·Breen, M. S.·Kiraly, D. D.

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Abstract

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder with complex pathophysiology including both genetic and environmental factors. Recent evidence demonstrates the gut microbiome and its resultant metabolome can influence brain and behavior and have been implicated in ASD. To investigate gene by microbiome interactions in a model for genetic risk of ASD, we utilize mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO). Shank3KO have altered microbiome composition and function at baseline in addition to social deficits. Further depletion of the microbiome with antibiotics exacerbates social deficits in Shank3KO, and results in transcriptional changes in the frontal cortex. Supplementation with the microbial metabolite acetate leads to reversal of social behavioral phenotypes even in mice with a depleted microbiome, and significantly alters transcriptional regulation in the prefrontal cortex. These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.

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Osman, A., Mervosh, N. L., Strat, A. N., Meckel, K. R., Euston, T. J., Zipursky, G. D., Drapeau, E., Buxbaum, J., Breen, M. S., Kiraly, D. D.. 2020-04-30. Effects of gene by microbiome interactions on behavioral and neurobiological phenotypes in a mouse model for autism spectrum disorder. https://doi.org/10.1101/2020.04.29.065821

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