Guan, J.-S. et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459, 55-60

Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences.
Nature (Impact Factor: 41.46). 05/2009; 459(7243):55-60. DOI: 10.1038/nature07925


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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    • "Further, HDAC inhibitor reduces the threshold of training for LTM formation in novel object recognition task (Stefanko et al. 2009), and facilitates spatial memory in water maze task (Dagnas et al. 2015). Several other studies have also shown that acetylation is an important modification in synaptic plasticity and memory (e.g., Guan et al. 2009; Bousiges et al. 2010; Dagnas and Mons 2013). However, the role of acetylation in massed pattern-induced synaptic plasticity or memory is not well understood. "
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    ABSTRACT: Massed training is less effective for long-term memory formation than the spaced training. The role of acetylation in synaptic plasticity and memory is now well established. However, the role of this important protein modification in synaptic plasticity induced by massed pattern of stimulation or memory induced by massed training is not well understood. Here we show that increasing the level of acetylation enhances long-term potentiation induced by massed pattern of high frequency stimulation. Furthermore, enhancing acetylation level facilitates long-term memory by massed training. Thus, increasing acetylation level facilitates synaptic plasticity and memory by massed patterns.
    Learning & memory (Cold Spring Harbor, N.Y.) 09/2015; 22(10-10):514-8. DOI:10.1101/lm.039289.115 · 3.66 Impact Factor
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    • "shown to bind BDNF promoters I, II and IV (Gräff et al., 2012; Guan et al., 2009), the role of individual class I HDAC isoforms, in relation to BDNF, is still unknown. "
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    ABSTRACT: Background: Alterations of brain-derived neurotrophic factor (BDNF) have been associated with the development of addiction to different drugs of abuse, including ethanol (EtOH). EtOH exposure activates the BDNF-signaling cascade in dorsal striatum, which in turn affects further EtOH intake. Different alcohol exposures have been widely demonstrated to modulate chromatin remodeling, affecting histone acetylation/deacetylation balance. Recently, class I histone deacetylases (HDACs) inhibition has been reported to modulate BDNF mRNA expression and to attenuate morphological and behavioral phenomena related to EtOH exposure. However, the role played by different HDAC isoforms in EtOH-induced plasticity is still unclear. Methods: We investigated the effects induced by acute EtOH exposure on the protein levels of class I HDAC 1-3 isoforms of wild-type (WT) and BDNF heterozygous mice (BDNF(+/-)), in nuclear and cytoplasmic extracts of specific brain regions associated with EtOH addiction. Results: Nuclear HDAC 1-3 levels were markedly reduced after acute EtOH treatment in the caudate putamen (CPu) of WT mice only. Furthermore, CPu basal levels of nuclear HDAC isoforms were significantly lower in BDNF(+/-) mice compared to WT. With the exception of nuclear HDAC 3, no significant changes were observed after acute EtOH treatment in the prefrontal cortex (PFCx) of BDNF(+/-) and WT mice. In this area, the nuclear HDAC basal levels were significantly different between the two experimental groups. Conclusions: These results provide details about EtOH effects on class I HDAC isoforms and strongly support a correlation between BDNF and class I HDACs, suggesting a possible influence of BNDF on these enzymes.
    Drug and alcohol dependence 08/2015; 155. DOI:10.1016/j.drugalcdep.2015.08.015 · 3.42 Impact Factor
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    • "Forced neuron-specific overexpression of HDAC2, but not HDAC1, reduced dendritic spine density, synapse number, synaptic plasticity, and memory formation in mice (Guan et al., 2009). Consistently, reduction of synapse number and learning impairment of Hdac2-overexpressing mice were ameliorated by chronic HDACi treatment (Guan et al., 2009). In the mouse models of neurodegeneration and in brains of patients with Alzheimer's disease, cognitive capacities were severely impaired by the epigenetic blockade of gene transcription at specific genetic loci important for learning and memory, which is mediated by the increased HDAC2 activity at these sites (Gräff et al., 2012). "
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    ABSTRACT: Genome-wide proximity placement analysis of 10,598 HSGRL within the context of the principal regulatory structures of the interphase chromatin, namely topologically-associating domains (TADs) and specific sub-TAD structures termed super-enhancer domains (SEDs) revealed that 0.8%-10.3% of TADs contain more than half of HSGRL. Of the 3,127 TADs in the hESC genome, 24 (0.8%); 53 (1.7%); 259 (8.3%); and 322 (10.3%) harbor 1,110 (52.4%); 1,936 (50.9%); 1,151 (59.6%); and 1,601 (58.3%) HSGRL sequences from four distinct families, respectively. TADs that are enriched for HSGRL and termed rapidly-evolving in humans TADs (revTADs) manifest distinct correlation patterns between HSGRL placements and recombination rates. There are significant enrichment within revTAD boundaries of hESC-enhancers, primate-specific CTCF-binding sites, human-specific RNAPII-binding sites, hCONDELs, and H3K4me3 peaks with human-specific enrichment at TSS in prefrontal cortex neurons (p < 0.0001 in all instances). In hESC genome, 331 of 504 (66%) of SE-harboring TADs contain HSGRL and 68% of SEs co-localize with HSGRL, suggesting that HSGRL rewired SE-driven GRNs within revTADs by inserting novel and/or erasing existing regulatory sequences. Consequently, markedly distinct features of chromatin structures evolved in hESC compared to mouse: the SE quantity is 3-fold higher and the median SE size is significantly larger; concomitantly, the TAD number is increased by 42% while the median TAD size is decreased (p=9.11E-37). Present analyses revealed a global role for HSGRL in increasing both quantity and size of SEs and increasing the number and size reduction of TADs, which may facilitate a convergence of TAD and SED architectures of interphase chromatin and define a trend of increasing regulatory complexity during evolution of GRNs.
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