Event Details:
Gut Derived Metabolites as Targets for Social Deficits in Rodent Models of ASD
Abstract
Aya Osman, Mount Sinai NY
Mounting evidence demonstrates a role for the gut microbiome in Autism Spectrum Disorder (ASD), with signaling via microbially produced metabolites as a potential mechanism. The microbiome-produced short chain fatty acids (SCFA) including acetate have received attention for their ability to influence brain and behavior. In order to investigate microbiome and metabolite effects in a model for ASD we utalized a gene x microbiome paradigm in which we combined antibiotic (Abx) depletion of the microbiome with acetate replenishment in the Shank3 deletion (Shank3KO) model for ASD. In addition, to assess the clinical relevance of findings from the mouse model, targeted serum SCFA metabolomic analysis in Phelan McDermid (PMS) patients, who are hemizygous for the Shank3 gene, was conducted. Shank3KO mice and wild-type (Wt) littermates were divided into control, Abx depletion, acetate replenishment and acetate + Abx groups at weaning. On postnatal day 60, animals were subjected to behavioral testing using three-chambered social interaction. Caecal content was collected for 16S sequencing, metagenomic analysis and metabolomic profiling. Medial prefrontal cortex (mPFC) taken for gene expression profiling and western blot analysis. Serum from male and female PMS patients and their control counterparts was collected for targeted SCFA analysis.
Analysis of mouse microbiome contents revealed a Shank3KO gene effect leading to decreased microbiome diversity, altered Bacteroidetes to Firmicutes ratios, and reduced levels of Lactobacillus genus bacteria. Metagenomic profiling revealed altered microbial functional output including fatty acid metabolism, this was confirmed by metabolomic analysis as reduced levels of SCFAs including acetate, effects that were exacerbated by Abx treatment. Behaviorally, control KO mice demonstrated decreased social interaction, a deficit exacerbated by microbiome depletion. RNA-sequencing showed marked changes in gene expression related to epigenetic regulation and synaptic plasticity in Abx+KO mice compared to Wt. Treatment of KO animals with acetate or Abx + acetate reversed the social deficits reported accompanied by changes to acetylation of specific histone marks. Human PMS patients were found to have sex-specific alterations in SCFA levels including acetate, which correlated with clinical behavioral measures. Our rodent data identified an altered gut microbiome and acetate levels in the Shank3KO model which can be targeted to reverse core social deficits possibly via epigenetic mechanisms. Clinical data corroborate findings of altered gut derived metabolites in PMS and add sex differences as a variable for further investigation.
Hosted by - Mari Sosa
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The BELONG seminar series features scientific talks from exceptional postdocs in the neurosciences who identify as Black, Indigenous, Latinx, and/or Person of Color. Sponsored by the Wu Tsai Neurosciences Institute Committee for Diversity, Inclusion, Belonging, Equity and Justice.
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