Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

Aya Osman, Nicholas L. Mervosh, Ana N. Strat, Tanner J. Euston, Gillian Zipursky, Rebecca M. Pollak, Katherine R. Meckel, Scott R. Tyler, Kenny L. Chan, Ariela Buxbaum Grice, Elodie Drapeau, Lev Litichevskiy, Jasleen Gill, Sharon M. Zeldin, Christoph A. Thaiss, Joseph D. Buxbaum, Michael S. Breen, Drew D. Kiraly

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: The pathophysiology of autism spectrum disorder (ASD) involves genetic and environmental factors. Mounting evidence demonstrates a role for the gut microbiome in ASD, with signaling via short-chain fatty acids (SCFA) as one mechanism. Here, we utilize mice carrying deletion to exons 4–22 of Shank3 (Shank3KO) to model gene by microbiome interactions in ASD. We identify SCFA acetate as a mediator of gut-brain interactions and show acetate supplementation reverses social deficits concomitant with alterations to medial prefrontal cortex (mPFC) transcriptional regulation independent of microbiome status. Methods: Shank3KO and wild-type (Wt) littermates were divided into control, Antibiotic (Abx), Acetate and Abx + Acetate groups upon weaning. After six weeks, animals underwent behavioral testing. Molecular analysis including 16S and metagenomic sequencing, metabolomic and transcriptional profiling were conducted. Additionally, targeted serum metabolomic data from Phelan McDermid Syndrome (PMS) patients (who are heterozygous for the Shank3 gene) were leveraged to assess levels of SCFA's relative to ASD clinical measures. Results: Shank3KO mice were found to display social deficits, dysregulated gut microbiome and decreased cecal levels of acetate – effects exacerbated by Abx treatment. RNA-sequencing of mPFC showed unique gene expression signature induced by microbiome depletion in the Shank3KO mice. Oral treatment with acetate reverses social deficits and results in marked changes in gene expression enriched for synaptic signaling, pathways among others, even in Abx treated mice. Clinical data showed sex specific correlations between levels of acetate and hyperactivity scores. Conclusion: These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.

Original languageEnglish
Pages (from-to)311-324
Number of pages14
JournalBrain, Behavior, and Immunity
Volume114
DOIs
StatePublished - Nov 2023

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