Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition

Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase... Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA-receptor function and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism underlying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing SHANK3 mutations. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Neuroscience Springer Journals

Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition

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Publisher
Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Neurosciences; Behavioral Sciences; Biological Techniques; Neurobiology; Animal Genetics and Genomics
ISSN
1097-6256
eISSN
1546-1726
DOI
10.1038/s41593-018-0110-8
Publisher site
See Article on Publisher Site

Abstract

Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA-receptor function and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism underlying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing SHANK3 mutations.

Journal

Nature Neuroscience – Springer Journals

Published: Mar 12, 2018

References

  • Behavioural phenotyping assays for mouse models of autism
    Silverman, JL; Yang, M; Lord, C; Crawley, JN
  • Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin
    Naisbitt, S
  • Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome
    Bonaglia, MC
  • Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders
    Durand, CM
  • SHANK3 haploinsufficiency: a “common” but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders
    Betancur, C; Buxbaum, JD
  • Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments
    Leblond, CS
  • Modeling autism by SHANK gene mutations in mice
    Jiang, YH; Ehlers, MD
  • Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication
    Bozdagi, O
  • Shank3 mutant mice display autistic-like behaviours and striatal dysfunction
    Peça, J
  • Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3
    Wang, X
  • Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission
    Kouser, M
  • Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators
    Duffney, LJ
  • Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism
    Wang, X
  • CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency
    Bidinosti, M
  • Autism-associated insertion mutation (InsG) of SHANK3 exon 21 causes impaired synaptic transmission and behavioral deficits
    Speed, HE
  • Altered striatal synaptic function and abnormal behaviour in Shank3 Exon4-9 deletion mouse model of autism
    Jaramillo, TC
  • Meeting of minds: the medial frontal cortex and social cognition
    Amodio, DM; Frith, CD
  • Progress toward treatments for synaptic defects in autism
    Delorme, R
  • Synaptic, transcriptional and chromatin genes disrupted in autism
    Rubeis, S
  • The emerging picture of autism spectrum disorder: genetics and pathology
    Chen, JA; Peñagarikano, O; Belgard, TG; Swarup, V; Geschwind, DH
  • Autism and cancer share risk genes, pathways, and drug targets
    Crawley, JN; Heyer, WD; LaSalle, JM
  • HDAC2 negatively regulates memory formation and synaptic plasticity
    Guan, JS
  • Targeting the correct HDAC(s) to treat cognitive disorders
    Fischer, A; Sananbenesi, F; Mungenast, A; Tsai, LH
  • Epigenetic regulation in psychiatric disorders
    Tsankova, N; Renthal, W; Kumar, A; Nestler, EJ
  • Is there a future for histone deacetylase inhibitors in the pharmacotherapy of psychiatric disorders?
    Grayson, DR; Kundakovic, M; Sharma, RP
  • Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes
    Klimek, VM
  • Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma
    Piekarz, RL
  • Toxicological and metabolic considerations for histone deacetylase inhibitors
    Fraczek, J; Vanhaecke, T; Rogiers, V
  • A systematic review of medical treatments for children with autism spectrum disorders
    McPheeters, ML
  • The many faces and functions of β-catenin
    Valenta, T; Hausmann, G; Basler, K
  • Depolarization drives beta-Catenin into neuronal spines promoting changes in synaptic structure and function
    Murase, S; Mosser, E; Schuman, EM
  • Beta-catenin is critical for dendritic morphogenesis
    Yu, X; Malenka, RC
  • Patches of disorganization in the neocortex of children with autism
    Stoner, R
  • SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties
    Han, K
  • Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses
    Gilman, SR
  • The Shank family of postsynaptic density proteins interacts with and promotes synaptic accumulation of the beta PIX guanine nucleotide exchange factor for Rac1 and Cdc42
    Park, E
  • SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients
    Shcheglovitov, A
  • Autism and the synapse: emerging mechanisms and mechanism-based therapies
    Ebrahimi-Fakhari, D; Sahin, M
  • Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders
    Carlson, GC
  • Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function
    Won, H
  • Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression
    Chung, W
  • Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism
    Duffney, LJ
  • Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex
    Yuen, EY
  • Histone modification of Nedd4 ubiquitin ligase controls the loss of AMPA receptors and cognitive impairment induced by repeated stress
    Wei, J
  • Cutadapt removes adapter sequences from high-throughput sequencing reads
    Marcel, M
  • TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions
    Kim, D
  • HTSeq–a Python framework to work with high-throughput sequencing data
    Anders, S; Pyl, PT; Huber, W
  • edgeR: a Bioconductor package for differential expression analysis of digital gene expression data
    Robinson, MD; McCarthy, DJ; Smyth, GK

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