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

• Published in: Brain, behavior, and immunity behavior, and immunity, 2023-11, Vol.114, p.311-324
• Main Authors: Osman, Aya, Mervosh, Nicholas L., Strat, Ana N., Euston, Tanner J., Zipursky, Gillian, Pollak, Rebecca M., Meckel, Katherine R., Tyler, Scott R., Chan, Kenny L., Buxbaum Grice, Ariela, Drapeau, Elodie, Litichevskiy, Lev, Gill, Jasleen, Zeldin, Sharon M., Thaiss, Christoph A., Buxbaum, Joseph.D., Breen, Michael S., Kiraly, Drew D.
• Format: Article
• Language: English
• Subjects: Acetates - pharmacology; Animals; Autism Spectrum Disorder - genetics; Dietary Supplements; Female; Humans; Male; Mice; Microfilament Proteins; Nerve Tissue Proteins - genetics; Prefrontal Cortex
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2023.08.020

•Shank3KO mice have decreased microbiome diversity and decreased social preference. Depletion of the microbiome further decreases social preference.•Levels of the microbiome derived metabolite acetate are decreased in Shank3KO mice and are further decreased by antibiotic depletion of the microbiome.•Supplementation of acetate via the drinking water reverses social deficits in Shank3KO mice, both in those with an intact microbiome and those with a depleted microbiome.•Acetate induces unique transcriptional patterns in the medial prefrontal cortex affecting gene expression related to synaptic plasticity and immune function.•Patients with Phelan McDermid Syndrome, who carry mutations to the Shank3 gene, exhibit correlations of acetate with clinical hyperactivity scores. 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. 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. 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. These results suggest a key role for th