HDAC2 negatively regulates memory formation and synaptic plasticity

By J. Guan, S. Haggarty, Emanuela Giacometti, J. Dannenberg, Nadine F. Joseph, Jun Gao, T. J. Nieland, Ying Zhou, Xinyu Wang, Ralph Mazitschek and 4 more. Nature, 2009

1,612 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e8a7c1579447ef65146d958231bdb3e42382e35b

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Citations in the corpus

Dnmt1 and Dnmt3a are required for the maintenance of DNA methylation and synaptic function in adult forebrain neurons (2010, background): “; moreover, increasing histone acetylation by treatment with histone deacetylase inhibitors promotes recovery of learning and memory in a mouse model of neurodegeneratio”
Multiple roles of HDAC inhibition in neurodegenerative conditions (2009, background): “convincingly demonstrated that mice overexpressing HDAC2, but not HDAC1, exhibit decreased dendritic spine density, synaptic number and synaptic plasticity, and show impaired memory formation [100].”
Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes (2015, positive): “We previously showed that HDAC2 binds to the promoters of several early-response genes and negatively modulates their expression (Guan et al., 2009).”
Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate (2016, background): “Because DBHB is a potent inhibitor of HDAC3 (Shimazu et al., 2013) and HDAC2 has been previously shown to repress BDNF gene expression (Guan et al., 2009), we focused our attention on HDAC3.”
Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy (2012, background): “HDAC2 inhibitors could therefore enhance these pro-cognitive processes and also promote fear-extinction learning, suggesting utility in PTS”
β-Hydroxybutyrate (2017, positive): “Conversely, Hdac2 knockout mice show improved memory formation, which is not further improved by HDAC inhibitors (42).”
An epigenetic blockade of cognitive functions in the neurodegenerating brain (2012, background): “One likely candidate is HDAC2, a class I HDAC that negatively regulates memory and synaptic plasticity in the healthy mouse brai”
The world of protein acetylation. (2016, background): “Thus, a dissociation of HDAC2 from chromosomes leads to hyperacetylation of histones and subsequent neurotrophin-dependent gene expression [278].”
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “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,”