Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition
Open accessAbstract
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.
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β-catenin links loss of Shank3 in synapse to upregulation of HDAC2 and EHMT1/2 transcription in nucleus.
“The nucleocytoplasmic shuttle protein involved in both cell adhesion and transcriptional regulation, β-catenin, is found to link the loss of Shank3 in the synapse to the upregulation of HDAC2 and EHMT1/2 transcription in the nucleus 145,146 (Fig. 3).”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [145]
In PFC of Shank3-deficient mice, loss of histone acetylation and upregulation of HDAC2 have been identified.
“In PFC of Shank3-deficient mice, the loss of histone acetylation and upregulation of HDAC2 have been identified 145.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [145]
Systemic administration of class I HDAC inhibitor romidepsin or MS-275 leads to robust and persistent alleviation of social deficits and restoration of actin regulators and NMDAR function in PFC.
“Systemic administration of the class I HDAC inhibitor romidepsin or MS-275 leads to the robust and persistent alleviation of social deficits, as well as the restoration of actin regulators and NMDAR function in PFC 144,145.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [145]
Targeting epigenetic enzymes to adjust gene expression and ameliorate synaptic defects in PFC is a potential strategy to normalize behavioral phenotypes associated with autism.
“A recent series of studies have shown that targeting epigenetic enzymes to adjust gene expression and ameliorate synaptic defects in PFC is a potential strategy to normalize behavioral phenotypes associated with autism 144–147.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [145]
NMDARs are substantially involved in autism spectrum disorder.
“consistent with the significant involvement of NMDARs in ASD [101–103].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [102]
NMDAR hypofunction in the prefrontal cortex is a core mechanism underlying phenotypes linked to 16p11.2 deletion.
“This study suggests NMDAR hypofunction in PFC as a core mechanism in 16p11.2 deletion-linked phenotypes, consistent with the significant involvement of NMDARs in ASD [101–103].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [102]
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- Authors
- Qin, L., Ma, K., Wang, Z.-J., Hu, Z., Matas, E., Wei, J., & Yan, Z.
- Affiliations
- University at Buffalo, State University of New York (US)
- Corresponding author
- Yan, Zhen
- Venue
- Nature Neuroscience
- Published
- 2018-03-12
- Volume
- 21
- Issue
- 4
- Pages
- 564-575
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC5876144
- OpenAlex
- W2790053528
- Cited by
- 240
- References
- 48
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 33 · 2023: 30 · 2022: 35 · 2021: 35 · 2020: 21 · 2019: 28 · 2018: 10 · 2014: 1
- FWCI
- 14.41
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-06-05)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Nancy Lurie Marks Family Foundation
- National Institutes of Health
- National Institute of Mental Health (R41MH112237, R01MH108842)
- National Institute on Drug Abuse (R01DA037618)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- SHANK3, autism spectrum disorder, social dysfunction, HDAC2, histone deacetylase inhibition, romidepsin, β-catenin, epigenetic regulation, NMDA receptor, GRIN2A, actin cytoskeleton, prefrontal cortex, chromatin remodeling
- MeSH terms
- Animals, Autistic Disorder, Disease Models, Animal, Exploratory Behavior, Gene Expression Regulation, Grooming, Histone Deacetylases, Locomotion, Male, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Nerve Tissue Proteins, Psychomotor Performance, Social Behavior Disorders, Prefrontal Cortex, Depsipeptides, Mice, Synaptic Potentials, Histone Deacetylase Inhibitors
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