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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    • "Knockout of transcriptional coactivators with intrinsic HAT activity , such as CBP (CREB-binding protein), p300 (EP300-binding protein), PCAF (p300/CBP-associated factor) leads to an impairment of LTM in aversive and appetitive learning (Oliveira et al. 2007, 2011; Barrett et al. 2011). Accordingly, the knockout of HDACs results in an enhanced LTM (Guan et al. 2009; McQuown and Wood 2011). This picture is supported by studies using pharmacological tools to target different HATs and HDACs (Dekker and Haisma 2009; Bowers et al. 2010; Selvi et al. 2010). "
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    ABSTRACT: Acetylation of histones changes the efficiency of the transcription processes and thus contributes to the formation of long-term memory (LTM). In our comparative study, we used two inhibitors to characterize the contribution of different histone acetyl transferases (HATs) to appetitive associative learning in the honeybee. For one we applied garcinol, an inhibitor of the HATs of the p300 (EP300 binding protein)/CBP (CREB-binding protein) family, and the HATs of the PCAF (p300/CBP-associated factor) family. As comparative agent we applied C646, a specific inhibitor that selectively blocks HATS of the p300/CBP family. Immunochemical analysis reveals differences in histone H3 acetylation in the honeybee brain, in response to the injection of either C646 or garcinol. Behavioral assessment reveals that the two drugs cause memory impairment of different nature when injected after associative conditioning: processes disturbed by garcinol are annihilated by the established transcription blocker actinomycin D and thus seem to require transcription processes. Actions of C646 are unaltered by actinomycin D, and thus seem to be independent of transcription. The outcome of our different approaches as summarized suggests that distinct HATs contribute to different acetylation-mediated processes in memory formation. We further deduce that the acetylation-mediated processes in memory formation comprise transcription-dependent and transcription-independent mechanisms.
    Preview · Article · Feb 2016 · Learning & memory (Cold Spring Harbor, N.Y.)
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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.
    Preview · Article · Sep 2015 · Learning & memory (Cold Spring Harbor, N.Y.)
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    • "Specifically, the Drosophila HDAC1/2 homolog Rpd3 regulates class I da sensory neuron morphology (Parrish et al. 2006) and olfactory PN dendritic targeting (Tea et al. 2010). In addition, HDAC2 suppresses dendritic spine density of hippocampal CA1 and dentate granule neurons (Guan et al. 2009). The HAT enzyme Pcaf also regulates class I da sensory neuron dendrite morphology (Parrish et al. 2006). "
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    ABSTRACT: A complex array of genetic factors regulates neuronal dendrite morphology. Epigenetic regulation of gene expression represents a plausible mechanism to control pathways responsible for specific dendritic arbor shapes. By studying the Drosophila dendritic arborization (da) neurons, we discovered a role of the double-bromodomain and extraterminal (BET) family proteins in regulating dendrite arbor complexity. A loss-of-function mutation in the single Drosophila BET protein encoded by female sterile 1 homeotic [fs(1)h] causes loss of fine, terminal dendritic branches. Moreover, fs(1)h is necessary for the induction of branching caused by a previously identified transcription factor, Cut (Ct), which regulates subtype-specific dendrite morphology. Finally, disrupting fs(1)h function impairs the mechanosensory response of class III da sensory neurons without compromising the expression of the ion channel NompC, which mediates the mechanosensitive response. Thus, our results identify a novel role for BET family proteins in regulating dendrite morphology and a possible separation of developmental pathways specifying neural cell morphology and ion channel expression. Since the BET proteins are known to bind acetylated histone tails, these results also suggest a role of epigenetic histone modifications and the "histone code," in regulating dendrite morphology.
    Full-text · Article · Sep 2015 · Genes & development
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