Epigenetic Rescue of Autism-like Social Deficits in Shank3-Deficient Mouse Models
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA430439 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6501080.fastq.gz | Fastqsanger.gz | |||
| SRR6501081.fastq.gz | Fastqsanger.gz | |||
| SRR6501074.fastq.gz | Fastqsanger.gz | |||
| SRR6501075.fastq.gz | Fastqsanger.gz | |||
| SRR6501076.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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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.
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Project description:Despite the growing prevalence of autism, no pharmacological interventions have been approved for core symptoms. The endocannabinoid system (ECS) has recently gained interest as a potential target for treating autism. Cannabidiol (CBD), a compound found in the Cannabis plant (C. Sativa), is a potential autism treatment due to its tolerability and promising early results in fragile X syndrome patients. Here, we aimed to evaluate the efficacy of CBD in treating social deficits and restrictive/repetitive behaviours in two monogenetic models of autism, Shank3 and Fmr1 knock-out (KO) mice. Male and female mice were tested in the 3-chamber social apparatus or for self-grooming and open field test (baseline or pre-treatment), followed by 5 daily treatments of vehicle or CBD (s.c., 5mg/kg for males, 50mg/kg for females) and tested again after the last injection (post-treatment). At baseline and following vehicle treatment, male and female Shank3 and Fmr1 KO mice exhibited deficits in social novelty, which were restored to control levels following CBD administration. Meanwhile, self-grooming (increased in male and female Shank3 KO mice) and open-field exploration (decreased locomotion in Shank3 KO mice) were not affected by CBD. Females had hippocampal CBD levels ~11.6 times higher than males (concordant with the dosing) and presented elevated levels of anandamide (AEA) in the CBD-treated groups. Transcriptomic analysis of the hippocampus revealed a lack of overlap in the CBD differentially expressed genes (DEGs) among the different strains and between sexes. These results suggest sex- and strain-specific mechanisms for CBD and support its therapeutic effects for syndromic autism.
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Project description:Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice
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Project description:One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases. Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. To possibly circumvent this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin which regulate aspects of social behavior in mammals. However, whether genetic risk factors might predispose to autism due to modification of oxytocinergic signaling remains largely unknown. Here, we report that an autism-associated mutation in the synaptic adhesion molecule neuroligin-3 (Nlgn3) results in impaired oxytocin signaling in dopaminergic neurons and in altered social novelty responses in mice. Surprisingly, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3KO mice with a novel, highly specific, brain-penetrant inhibitor of MAP-kinase interacting kinases resets mRNA translation and restores oxytocin and social novelty responses. Thus, this work identifies an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, and oxytocinergic signaling. Focus on such common core plasticity elements might provide a pragmatic approach to reduce the heterogeneity of autism phenotypes. Ultimately, this would allow for mechanism-based stratification of patient populations to increase the success of therapeutic interventions.
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Project description:In humans, mutations in the transcription factor encoding gene, FOXP2, are associated with language and Autism Spectrum (ASD) Disorders, the latter characterized by deficits in social interactions. However, little is known regarding the function of Foxp2 in male or female social behavior. Our previous studies in mice revealed high expression of Foxp2 within the medial subnucleus of the amygdala (MeA), a limbic brain region highly implicated in innate social behaviors such as mating, aggression, and parental care. Here, using a comprehensive panel of behavioral tests in male and female Foxp2+/- heterozygous mice, we investigated the role Foxp2 plays in MeA-linked innate social behaviors. We reveal significant deficits in olfactory processing, social interaction, mating, aggressive and parental behaviors. Interestingly, some of these deficits displayed in a sex-specific manner. To examine the consequences of Foxp2 loss of function specifically in the MeA, we conducted a proteomic analysis of microdissected MeA tissue and found sex differences in a host of proteins implicated in neuronal communication, connectivity and dopamine signaling. Consistent with this, we discovered that MeA Foxp2-lineage cells were responsive to dopamine with differences between males and females. Thus, our findings reveal a central and sex-specific role for Foxp2 in social behavior and MeA function.
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Project description:Inhibition of TRPV4 rescues impaired excitability and social deficits in NAc-specific Shank3-deficient mice.
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Project description:Autism spectrum disorder (ASD) is a neurodevelopmental condition caused by a combination of genetic and environmental factors. The blood-brain barrier (BBB) plays a key role in regulating environmental influences on the brain, yet its contributions to ASD remain unclear. We report that endothelium-specific SHANK3 (eSHANK3) is expressed in brain endothelial cells (BECs) that form the BBB. Our analysis of eSHANK3 interactions in BECs shows significant enrichment of proteins involved in membrane and cell junction functions. We found that eSHANK3 maintains tight junction (TJ) integrity, which is essential for BBB function. Loss of Shank3 disrupts TJs, increasing paracellular passage through the endothelium. In vivo, eShank3 knockout (KO) mice show BBB hyperpermeability, reduced neuronal excitability, and impaired ultrasonic communication. Although BBB permeability is restored in adulthood, the mutant mice continue to have reduced neuronal excitability and impaired sociability. Further analysis reveals that neonatal BBB hyperpermeability is due to β-Catenin imbalance caused by eShank3-KO. Restoring β-Catenin signaling rescues neuronal and social behavior deficits. These findings uncover a new pathogenic mechanism linked to Shank3 in ASD and suggest that neonatal BECs in the BBB could be a potential therapeutic target for ASD.
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