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

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

PROVIDER: PRJNA938142 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23603318_1.fastq.gz	Fastqsanger.gz
	SRR23603318_2.fastq.gz	Fastqsanger.gz
	SRR23603319_1.fastq.gz	Fastqsanger.gz
	SRR23603319_2.fastq.gz	Fastqsanger.gz
	SRR23603320_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

2023-03-02 | GSE225983 | GEO

Inhibition of TRPV4 rescues impaired excitability and social deficits in NAc-specific Shank3-deficient mice.

Project description:We used AAV transfection of Shank3 shRNA to study the effect of Shank3 knock down in Nucleus Accumbens neurons. We find that Shank3 knock down leads to social deficits and hyperexcitability of Nucleus Accumbens D1-MSN. Bulk RNA sequencing shows that D1-MSN with Shank3 knock down upregulate TRPV4 and its subsequent antagonist driven inhibition leads to both a rescue of D1-MSN hyperexcitability and social deficit.

2022-10-01 | GSE139683 | GEO

Inhibition of TRPV4 rescues impaired excitability and social deficits in NAc-specific Shank3-deficient mice.

Project description:Inhibition of TRPV4 rescues impaired excitability and social deficits in NAc-specific Shank3-deficient mice.

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

Project description:BackgroundThe 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.MethodsShank3KO 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.ResultsShank3KO 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.ConclusionThese results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.

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Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice

Project description:Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activityregulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.

2020-07-29 | GSE155291 | GEO

Epigenetic Rescue of Autism-like Social Deficits in Shank3-Deficient Mouse Models

Project description:To determine whether histone deacetylase (HDAC) inhibition has genome-wide effects on gene expression, we used RNA sequencing to analyze the mRNA profile in prefrontal cortex (PFC) of wild-type (WT) and Shank3-deficient (Shank3+/ΔC) mice treated with romidespin or saline control. We mapped the sequences to 24,420 mouse genes. Compared to WT, 365 genes in saline-treated Shank3+/ΔC mice showed a change in expression values of at least 1.2 fold and p ≤ 0.01 (213 downregulated, 152 upregulated). In romidepsin-treated Shank3+/ΔC mice, ~88% of the downregulated genes (n=187 genes) were normalized to control values. Further analysis of the romidepsin-restored genes revealed enrichment in actin cytoskeleton-mediated transport, signal transduction pathways, and developmental processes.

2018-03-12 | GSE109328 | GEO

Epicatechin rescues memory deficits by inducing autophagy in tauopathy

Project description:Proteomics raw data for “Epicatechin rescues memory deficits by inducing autophagy in tauopathy”

2021-10-11 | PXD029068 |

Epigenetic Rescue of Autism-like Social Deficits in Shank3-Deficient Mouse Models

Project description:Epigenetic Rescue of Autism-like Social Deficits in Shank3-Deficient Mouse Models

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Retinoic acid supplementation rescues the social deficits in Fmr1 knockout mice

Project description:Retinoic acid supplementation rescues the social deficits in Fmr1 knockout mice

| PRJNA832607 | ENA

Medial prefrontal cortex (mPFC) transcriptome analysis of Shank3-overexpressing mice

Project description:Shank3 is a core excitatory postsynaptic protein expressed in multiple brain regions including the medial prefrontal cortex, striatum, and hippocampus. We have previously generated and characterized Shank3-overexpressing transgenic mice, and found that these mice exhibited manic-like behavioral phenotypes. To understand molecular mechanisms underlying the behavioral changes, we performed transcriptome (RNA-sequencing) analysis of the mPFC tissues from 10 to 12-week-old wild-type and Shank3 transgenic mice.

2018-12-25 | GSE113368 | GEO

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