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

Autor: Osman A; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Mervosh NL; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Strat AN; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Euston TJ; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Zipursky G; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Pollak RM; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Meckel KR; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Tyler SR; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Chan KL; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Buxbaum Grice A; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Drapeau E; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Litichevskiy L; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Gill J; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Zeldin SM; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Thaiss CA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Institute of Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Institute for Obesity, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Buxbaum JD; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Breen MS; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States., Kiraly DD; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC 27101, United States; Department of Psychiatry, Wake Forest University School of Medicine, Atrium Wake Forest Baptist Health, Winston-Salem, NC 27101, United States. Electronic address: dkiraly@wakehealth.edu.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2023 Nov; Vol. 114, pp. 311-324. Date of Electronic Publication: 2023 Aug 30.
DOI: 10.1016/j.bbi.2023.08.020
Abstrakt: 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 (Shank3 KO ) 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: Shank3 KO 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: Shank3 KO 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 Shank3 KO 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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