HDAC2 negatively regulates memory formation and synaptic plasticity
Open accessAbstract
Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.
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Prolonged administration of HDAC inhibitors improved synapse number and learning impairment.
“However, prolonged administration of HDAC inhibitors improved synapse number and learning impairment.134”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [134]
Overexpression of HDAC2 specifically in neurons resulted in decreased dendritic spine density, synapse number, synaptic plasticity, and memory formation in mice.
“The overexpression of HDAC2 specifically in neurons resulted in a decrease in dendritic spine density, synapse number, synaptic plasticity, and memory formation in mice.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [134]
Promoter occupancy analysis revealed a link between HDAC2 and promoters of genes involved in synaptic plasticity and memory formation.
“a promoter occupancy analysis has revealed a link between HDAC2 and the promoters of genes that play a role in synaptic plasticity and memory formation.134”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [134]
HDAC2 overexpression reduces dendritic spine density and impairs synaptic plasticity and memory by blocking expression of genes related to neuroplasticity, whereas downregulation or inhibition of HDACs restores synaptic and cognitive function in AD animal models.
“HDAC2 overexpression reduces dendritic spine density, and impairs synaptic plasticity and memory by blocking expression of genes related to neuroplasticity, whereas downregulation or inhibition of HDACs has been proven successful in restoring synaptic and cognitive function in AD animal models [508, 509].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [509]
HDAC2 overexpression reduced synapse number, decreased synaptic plasticity, and impaired memory.
“Conversely, Guan et al. 52 found that HDAC2 overexpression reduced synapse number, decreased synaptic plasticity, and impaired memory.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [52]
HDAC2 binds to the promoters of several genes involved in synaptic plasticity or whose expression is activity dependent.
“This group also demonstrated that HDAC2 bound to the promoters of several genes involved in synaptic plasticity or whose expression was activity dependent.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [52]
The detrimental effects of HDAC2 overexpression on plasticity and memory are reversed by the HDAC inhibitor suberoylanilide hydroxamic acid, whereas suberoylanilide hydroxamic acid was unable to further enhance memory in HDAC2 knockout mice.
“Importantly, the detrimental effects of HDAC2 overexpression on plasticity and memory are reversed by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), whereas SAHA was unable to further enhance memory in HDAC2 knockout mice.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [52]
HDACs have been implicated in metabolism, inflammation, circadian rhythm, neurological development, and brain function.
“HDACs have been implicated in diverse biology including metabolism, inflammation, circadian rhythm, as well as neurological development and brain function (Guan et al., 2009; Villagra et al., 2009; Gräff et al., 2012; Jakovcevski and Akbarian, 2012; Falkenberg and Johnstone, 2014; Tough et al., 2016).”
From Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase (2018) · cites this paper as Guan et al., 2009
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- Authors
- Guan, J.-S., Haggarty, S. J., Giacometti, E., Dannenberg, J.-H., Joseph, N., Gao, J., Nieland, T. J. F., Zhou, Y., Wang, X., Mazitschek, R., Bradner, J. E., DePinho, R. A., Jaenisch, R., & Tsai, L.-H.
- Affiliations
- Broad Institute (US)
- Whitehead Institute for Biomedical Research (US)
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Nature
- Published
- 2009-05
- Volume
- 459
- Issue
- 7243
- Pages
- 55-60
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3498958
- OpenAlex
- W2090760765
- Cited by
- 1,644
- References
- 33
- Citations by year
- 2026: 60 · 2025: 63 · 2024: 82 · 2023: 70 · 2022: 69 · 2021: 87 · 2020: 104 · 2019: 84 · 2018: 99 · 2017: 91 · 2016: 113 · 2015: 110 · 2014: 149 · 2013: 140 · 2012: 105
- FWCI
- 43.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (n01co12400-79-0-22)
- National Institute on Drug Abuse (R01DA028301)
- National Cancer Institute (N01-CO-012400, R01CA087869, R37CA084198)
- National Institute of Neurological Disorders and Stroke (R01NS051874)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- HDAC2, HDAC1, histone deacetylase inhibitors, histone acetylation, chromatin modification, memory formation, synaptic plasticity, dendritic spine density, synapse number, learning disabilities, promoter binding, memory impairment
- MeSH terms
- Vorinostat, Animals, Butyrates, Female, Gene Expression Regulation, Hippocampus, Histone Deacetylases, Hydroxamic Acids, Learning, Male, Memory, Mice, Inbred C57BL, Neurons, Promoter Regions, Genetic, Repressor Proteins, Sodium, Mice, Knockout, Dendritic Spines, Mice, Electrical Synapses, Histone Deacetylase 1, Histone Deacetylase 2, Histone Deacetylase Inhibitors
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