Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Histone acetylation: molecular mnemonics on the chromatin

Key Points

  • Histone acetylation is an epigenetic modification that is unequivocally associated with increasing the propensity for gene transcription. As gene transcription is a crucial feature of long-lasting forms of memories, increments in histone acetylation generally favour learning and memory, and can be considered molecular memory aids.

  • Histone acetylation readily responds to neuronal activity in terms of neuronal depolarization and synaptic plasticity. So far, two pathways that mediate this response have been identified: the mitogen-activated protein kinase (MAPK) pathway and the dissociation of histone deacetylase 2 (HDAC2) from the chromatin.

  • A reduction in histone acetylation has been causally implicated in memory impairment associated with neurodegeneration, ageing and neurodevelopment disorders such as Rubinstein–Taybi syndrome. From these studies, a gain-of-function of HDAC2 and a loss-of-function of the histone acetyl transferase cyclic AMP-responsive element-binding (CREB)-binding protein (CBP) emerge as chief culprits.

  • The reduction of histone acetylation can be counteracted by the use of small molecule inhibitors of HDACs, so-called HDAC inhibitors (HDACis). Several HDACis have already been proven successful in rescuing cognitive deficits in animal models of neurodegeneration, Alzheimer's disease, ageing, and Rubinstein–Taybi syndrome, and might thus constitute a new template for pharmacological strategies against cognitive impairments.

  • Although their precise mode of action is still not fully characterized, HDACis might act through a process called epigenetic priming, a term originally used in cancer research. Epigenetic priming refers to a support-only mode of action of HDACis, whereby HDACis alone have little effect (on histone acetylation and gene transcription), but when applied in conjunction with ongoing treatments that increase gene expression programmes, HDACis further potentiate them.

  • concept of epigenetic priming can be applied to neuroplasticity as well, in that HDACs would further support neuronal activity-driven gene expression programmes while having little or no effect on genes with constant rates of transcription.


Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms. Of the epigenetic modifications identified in cognitive processes, histone acetylation has spurred considerable interest. Whereas increments in histone acetylation have consistently been shown to favour learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and ageing. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The complexity of the epigenetic code in the brain.
Figure 2: Neuronal activity induces histone acetylation.
Figure 3: The upregulation of HDAC2 in pathological conditions and its relation to cognitive impairment.
Figure 4: Epigenetic priming.


  1. 1

    Crick, F. Memory and molecular turnover. Nature 312, 101 (1984).

    CAS  Article  Google Scholar 

  2. 2

    Levenson, J. M. & Sweatt, J. D. Epigenetic mechanisms in memory formation. Nature Rev. Neurosci. 6, 108–118 (2005). An excellent review that opened up the field of neuroepigenetics in 2005.

    CAS  Article  Google Scholar 

  3. 3

    Bird, A. Perceptions of epigenetics. Nature 447, 396–398 (2007).

    CAS  Article  Google Scholar 

  4. 4

    Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Gräff, J., Kim, D., Dobbin, M. M. & Tsai, L. H. Epigenetic regulation of gene expression in physiological and pathological brain processes. Physiol. Rev. 91, 603–649 (2011).

    Article  CAS  Google Scholar 

  6. 6

    Berndsen, C. E. & Denu, J. M. Catalysis and substrate selection by histone/protein lysine acetyltransferases. Curr. Opin. Struct. Biol. 18, 682–689 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Haberland, M., Montgomery, R. L. & Olson, E. N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature Rev. Genet. 10, 32–42 (2009).

    CAS  Article  Google Scholar 

  8. 8

    Brownell, J. E. & Allis, C. D. Special HATs for special occasions: linking histone acetylation to chromatin assembly and gene activation. Curr. Opin. Genet. Dev. 6, 176–184 (1996).

    CAS  Article  Google Scholar 

  9. 9

    Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    CAS  Article  Google Scholar 

  10. 10

    Li, B., Carey, M. & Workman, J. L. The role of chromatin during transcription. Cell 128, 707–719 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Shahbazian, M. D. & Grunstein, M. Functions of site-specific histone acetylation and deacetylation. Annu. Rev. Biochem. 76, 75–100 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Tweedie-Cullen, R. Y. et al. Identification of combinatorial patterns of post-translational modifications on individual histones in the mouse brain. PLoS ONE 7, e36980 (2012). The first study to comprehensively map all existing post-translational histone modifications in the mouse brain by mass spectrometry.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Miller, C. A., Campbell, S. L. & Sweatt, J. D. DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity. Neurobiol. Learn. Mem. 89, 599–603 (2008).

    CAS  Article  Google Scholar 

  14. 14

    Gräff, J. & Mansuy, I. M. Epigenetic codes in cognition and behaviour. Behav. Brain Res. 192, 70–87 (2008).

    Article  CAS  Google Scholar 

  15. 15

    Koshibu, K. et al. Protein phosphatase 1 regulates the histone code for long-term memory. J. Neurosci. 29, 13079–13089 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Koshibu, K., Graff, J. & Mansuy, I. M. Nuclear protein phosphatase-1: an epigenetic regulator of fear memory and amygdala long-term potentiation. Neuroscience 173, 30–36 (2011).

    CAS  Article  Google Scholar 

  17. 17

    Gräff, J., Woldemichael, B. T., Berchtold, D., Dewarrat, G. & Mansuy, I. M. Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation. Nature Commun. 3, 991 (2012). The first study to show that post-translational histone modifications accompany the spatiotemporal dynamics of memory consolidation.

    Article  CAS  Google Scholar 

  18. 18

    Maharana, C., Sharma, K. P. & Sharma, S. K. Depolarization induces acetylation of histone H2B in the hippocampus. Neuroscience 167, 354–360 (2010).

    CAS  Article  Google Scholar 

  19. 19

    Crosio, C., Heitz, E., Allis, C. D., Borrelli, E. & Sassone-Corsi, P. Chromatin remodeling and neuronal response: multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons. J. Cell Sci. 116, 4905–4914 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Sweatt, J. D. The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J. Neurochem. 76, 1–10 (2001).

    CAS  Article  Google Scholar 

  21. 21

    Levenson, J. M. et al. Regulation of histone acetylation during memory formation in the hippocampus. J. Biol. Chem. 279, 40545–40559 (2004). A ground-breaking study showing that learning itself triggers histone acetylation changes in the mammalian brain.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Latham, J. A. & Dent, S. Y. Cross-regulation of histone modifications. Nature Struct. Mol. Biol. 14, 1 017–1024 (2007). An excellent review about the crosstalks between post-translational histone modifications.

    CAS  Article  Google Scholar 

  23. 23

    Cowansage, K. K., LeDoux, J. E. & Monfils, M. H. Brain-derived neurotrophic factor: a dynamic gatekeeper of neural plasticity. Curr. Mol. Pharmacol. 3, 12–29 (2010).

    CAS  Article  Google Scholar 

  24. 24

    Nott, A., Watson, P. M., Robinson, J. D., Crepaldi, L. & Riccio, A. S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 455, 411–415 (2008). An important paper showing the upstream regulatory mechanisms of HDAC2 following neuronal activity.

    CAS  Article  Google Scholar 

  25. 25

    Chen, W. G. et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Guan, J. S. et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459, 55–60 (2009). A tour-de-force study in which the first HDAC to have a pivotal role in neuroplasticity was identified.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Pittenger, C. & Kandel, E. R. In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus. Phil. Trans. R. Soc. Lond. B 358, 757–763 (2003).

    Article  Google Scholar 

  28. 28

    Guan, Z. H. et al. Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell 111, 483–493 (2002).

    CAS  Article  Google Scholar 

  29. 29

    Hart, A. K. et al. Serotonin-mediated synapsin expression is necessary for long-term facilitation of the Aplysia sensorimotor synapse. J. Neurosci. 31, 18401–18411 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Miller, C. A. & Sweatt, J. D. Covalent modification of DNA regulates memory formation. Neuron 53, 857–869 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Vecsey, C. G. et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J. Neurosci. 27, 6128–6140 (2007).

    CAS  Article  Google Scholar 

  33. 33

    Zeng, Y. et al. Epigenetic enhancement of BDNF signaling rescues synaptic plasticity in aging. J. Neurosci. 31, 17800–17810 (2011).

    CAS  Article  Google Scholar 

  34. 34

    Yeh, S. H., Lin, C. H. & Gean, P. W. Acetylation of nuclear factor-κB in rat amygdala improves long-term but not short-term retention of fear memory. Mol. Pharmacol. 65, 1286–1292 (2004).

    CAS  Article  Google Scholar 

  35. 35

    Sui, L., Wang, Y., Ju, L. H. & Chen, M. Epigenetic regulation of reelin and brain-derived neurotrophic factor genes in long-term potentiation in rat medial prefrontal cortex. Neurobiol. Learn. Mem. 97, 425–440 (2012).

    CAS  Article  Google Scholar 

  36. 36

    Alarcon, J. M. et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42, 947–959 (2004). Together with reference 64, these two papers provided the first causal evidence that (CBP-mediated) histone acetylation is necessary for long-term memory and plasticity.

    CAS  Article  Google Scholar 

  37. 37

    Barrett, R. M. et al. Hippocampal focal knockout of CBP affects specific histone modifications, long-term potentiation, and long-term memory. Neuropsychopharmacology 36, 1545–1556 (2011).

    CAS  Article  Google Scholar 

  38. 38

    Wood, M. A. et al. Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. Learn. Mem. 12, 111–119 (2005).

    Article  Google Scholar 

  39. 39

    Chwang, W. B., Arthur, J. S., Schumacher, A. & Sweatt, J. D. The nuclear kinase mitogen- and stress-activated protein kinase 1 regulates hippocampal chromatin remodeling in memory formation. J. Neurosci. 27, 12732–12742 (2007).

    CAS  Article  Google Scholar 

  40. 40

    Chwang, W. B., O'Riordan, K. J., Levenson, J. M. & Sweatt, J. D. ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. Learn. Mem. 13, 322–328 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Lubin, F. D., Roth, T. L. & Sweatt, J. D. Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J. Neurosci. 28, 10576–10586 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Maddox, S. A. & Schafe, G. E. Epigenetic alterations in the lateral amygdala are required for reconsolidation of a Pavlovian fear memory. Learn. Mem. 18, 579–593 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Monsey, M. S., Ota, K. T., Akingbade, I. F., Hong, E. S. & Schafe, G. E. Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala. PLoS ONE 6, e19958 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Bousiges, O. et al. Spatial memory consolidation is associated with induction of several lysine-acetyltransferase (histone acetyltransferase) expression levels and H2B/H4 acetylation-dependent transcriptional events in the rat hippocampus. Neuropsychopharmacology 35, 2521–2537 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Fontan-Lozano, A. et al. Histone deacetylase inhibitors improve learning consolidation in young and in KA-induced-neurodegeneration and SAMP-8-mutant mice. Mol. Cell. Neurosci. 39, 193–201 (2008).

    CAS  Article  Google Scholar 

  46. 46

    Lesburgueres, E. et al. Early tagging of cortical networks is required for the formation of enduring associative memory. Science 331, 924–928 (2011).

    CAS  Article  Google Scholar 

  47. 47

    Reul, J. M., Hesketh, S. A., Collins, A. & Mecinas, M. G. Epigenetic mechanisms in the dentate gyrus act as a molecular switch in hippocampus-associated memory formation. Epigenetics 4, 434–439 (2009).

    CAS  Article  Google Scholar 

  48. 48

    Bredy, T. W. & Barad, M. The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear. Learn. Mem. 15, 39–45 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Bredy, T. W. et al. Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn. Mem. 14, 268–276 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Lattal, K. M., Barrett, R. M. & Wood, M. A. Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction. Behav. Neurosci. 121, 1125–1131 (2007).

    CAS  Article  Google Scholar 

  51. 51

    Itzhak, Y., Anderson, K. L., Kelley, J. B. & Petkov, M. Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice. Neurobiol. Learn. Mem. 97, 409–417 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Stafford, J. M., Raybuck, J. D., Ryabinin, A. E. & Lattal, K. M. Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction. Biol. Psychiatry 72, 25–33 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Federman, N., Fustinana, M. S. & Romano, A. Reconsolidation involves histone acetylation depending on the strength of the memory. Neuroscience 219, 145–156 (2012).

    CAS  Article  Google Scholar 

  54. 54

    Danilova, A. B., Kharchenko, O. A., Shevchenko, K. G. & Grinkevich, L. N. Histone H3 acetylation is asymmetrically induced upon learning in identified neurons of the food aversion network in the mollusk helix lucorum. Front. Behav. Neurosci. 4, 180 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Federman, N., Fustinana, M. S. & Romano, A. Histone acetylation is recruited in consolidation as a molecular feature of stronger memories. Learn. Mem. 16, 600–606 (2009).

    Article  Google Scholar 

  56. 56

    Lubin, F. D. & Sweatt, J. D. The IκB kinase regulates chromatin structure during reconsolidation of conditioned fear memories. Neuron 55, 942–957 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Fischer, A., Sananbenesi, F., Wang, X. Y., Dobbin, M. & Tsai, L. H. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182 (2007). An important study showing, for the first time, that cognitive capacities can be rescued despite severe neurodegeneration by the use of an HDACi.

    CAS  Article  Google Scholar 

  58. 58

    Hawk, J. D., Florian, C. & Abel, T. Post-training intrahippocampal inhibition of class I histone deacetylases enhances long-term object-location memory. Learn. Mem. 18, 367–370 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    McQuown, S. C. et al. HDAC3 is a critical negative regulator of long-term memory formation. J. Neurosci. 31, 764–774 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Murphy, K. J. et al. Pentyl-4-yn-valproic acid enhances both spatial and avoidance learning, and attenuates age-related NCAM-mediated neuroplastic decline within the rat medial temporal lobe. J. Neurochem. 78, 704–714 (2001).

    CAS  Article  Google Scholar 

  61. 61

    O'Loinsigh, E. D. et al. Differential enantioselective effects of pentyl-4-yn-valproate on spatial learning in the rat, and neurite outgrowth and cyclin D3 expression in vitro. J. Neurochem. 88, 370–379 (2004).

    CAS  Article  Google Scholar 

  62. 62

    Stefanko, D. P., Barrett, R. M., Ly, A. R., Reolon, G. K. & Wood, M. A. Modulation of long-term memory for object recognition via HDAC inhibition. Proc. Natl Acad. Sci. USA 106, 9447–9452 (2009).

    CAS  Article  Google Scholar 

  63. 63

    Zhao, Z., Fan, L. & Frick, K. M. Epigenetic alterations regulate estradiol-induced enhancement of memory consolidation. Proc. Natl Acad. Sci. USA 107, 5605–5610 (2010).

    CAS  Article  Google Scholar 

  64. 64

    Korzus, E., Rosenfeld, M. G. & Mayford, M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42, 961–972 (2004).

    CAS  Article  Google Scholar 

  65. 65

    Oike, Y. et al. Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism. Hum. Mol. Genet. 8, 387–396 (1999).

    CAS  Article  Google Scholar 

  66. 66

    Oliveira, A. M. M., Wood, M. A. & McDonough, C. B. & Abel, T. Transgenic mice expressing an inhibitory truncated form of p300 exhibit long-term memory deficits. Learn. Mem. 14, 564–572 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Wood, M. A., Attner, M. A., Oliveira, A. M., Brindle, P. K. & Abel, T. A transcription factor-binding domain of the coactivator CBP is essential for long-term memory and the expression of specific target genes. Learn. Mem. 13, 609–617 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Scandura, J. M. et al. Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML. Blood 118, 1472–1480 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Gore, S. D. et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 66, 6361–6369 (2006).

    CAS  Article  Google Scholar 

  70. 70

    Miller, C. P., Singh, M. M., Rivera-Del Valle, N., Manton, C. A. & Chandra, J. Therapeutic strategies to enhance the anticancer efficacy of histone deacetylase inhibitors. J. Biomed. Biotechnol. 2011, 514261 (2011).

    PubMed  PubMed Central  Google Scholar 

  71. 71

    Bordone, L. & Guarente, L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nature Rev. Mol. Cell Biol. 6, 298–305 (2005).

    CAS  Article  Google Scholar 

  72. 72

    Haigis, M. C. & Sinclair, D. A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Chen, J. et al. SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling. J. Biol. Chem. 280, 40364–40374 (2005).

    CAS  Article  Google Scholar 

  74. 74

    Kim, D. et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169–3179 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Michan, S. et al. SIRT1 is essential for normal cognitive function and synaptic plasticity. J. Neurosci. 30, 9695–9707 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Gao, J. et al. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466, 1105–1109 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Broide, R. S. et al. Distribution of histone deacetylases 1–11 in the rat brain. J. Mol. Neurosci. 31, 47–58 (2007).

    CAS  Article  Google Scholar 

  78. 78

    Nelson, E. D., Bal, M., Kavalali, E. T. & Monteggia, L. M. Selective impact of MeCP2 and associated histone deacetylases on the dynamics of evoked excitatory neurotransmission. J. Neurophysiol. 106, 193–201 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Gupta-Agarwal, S. et al. G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. J. Neurosci. 32, 5440–5453 (2012). A valuable resource for microarray-deduced hippocampal gene expression changes following contextual fear conditioning.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Kim, D. et al. Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 60, 803–817 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Herrup, K. & Yang, Y. Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nature Rev. Neurosci. 8, 368–378 (2007).

    CAS  Article  Google Scholar 

  82. 82

    Bahari-Javan, S. et al. HDAC1 regulates fear extinction in mice. J. Neurosci. 32, 5062–5073 (2012).

    CAS  Article  Google Scholar 

  83. 83

    Lahm, A. et al. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl Acad. Sci. USA 104, 17335–17340 (2007).

    CAS  Article  Google Scholar 

  84. 84

    Wang, W. H. et al. Intracellular trafficking of histone deacetylase 4 regulates long-term memory formation. Anat. Rec. 294, 1025–1034 (2011).

    CAS  Article  Google Scholar 

  85. 85

    Kim, M. S. et al. An essential role for histone deacetylase 4 in synaptic plasticity and memory formation. J. Neurosci. 32, 10879–10886 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Koseki, T. et al. Exposure to enriched environments during adolescence prevents abnormal behaviours associated with histone deacetylation in phencyclidine-treated mice. Int J. Neuropsychopharmacol. 15, 1489–1450 (2011).

    Article  CAS  Google Scholar 

  87. 87

    Tam, G. W. et al. Confirmed rare copy number variants implicate novel genes in schizophrenia. Biochem. Soc. Trans. 38, 445–451 (2010).

    CAS  Article  Google Scholar 

  88. 88

    Citron, M. Alzheimer's disease: strategies for disease modification. Nature Rev. Drug Discov. 9, 387–398 (2010). A comprehensive overview of the challenges and strategies in AD research.

    CAS  Article  Google Scholar 

  89. 89

    Huang, Y. & Mucke, L. Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204–1222 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Gräff, J. et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483, 222–226 (2012). The first study to causally implicate an HDAC, HDAC2, in cognitive decline associated with neurodegeneration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Cruz, J. C. et al. p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid β in vivo. J. Neurosci. 26, 10536–10541 (2006).

    CAS  Article  Google Scholar 

  92. 92

    Cruz, J. C., Tseng, H. C., Goldman, J. A., Shih, H. & Tsai, L. H. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471–483 (2003).

    CAS  Article  Google Scholar 

  93. 93

    Fischer, A., Sananbenesi, F., Pang, P. T., Lu, B. & Tsai, L. H. Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48, 825–838 (2005).

    CAS  Article  Google Scholar 

  94. 94

    Kimura, R. & Ohno, M. Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol. Dis. 33, 229–235 (2009).

    CAS  Article  Google Scholar 

  95. 95

    Oakley, H. et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006).

    CAS  Article  Google Scholar 

  96. 96

    Frankland, P. W. & Bontempi, B. The organization of recent and remote memories. Nature Rev. Neurosci. 6, 119–130 (2005).

    CAS  Article  Google Scholar 

  97. 97

    Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS  Article  Google Scholar 

  98. 98

    Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer's disease: the challenge of the second century. Sci. Transl. Med. 3, 77sr71 (2011).

    Google Scholar 

  99. 99

    Crapper, D. R., Quittkat, S. & de Boni, U. Altered chromatin conformation in Alzheimer's disease. Brain 102, 483–495 (1979). Together with reference 100, this early report hints at the intriguing possibility of increased heterochromatinization in the AD brain.

    CAS  Article  Google Scholar 

  100. 100

    Lukiw, W. J. & Crapper McLachlan, D. R. Chromatin structure and gene expression in Alzheimer's disease. Brain Res. Mol. Brain Res. 7, 227–233 (1990).

    CAS  Article  Google Scholar 

  101. 101

    Magistretti, P. J. Neuroscience. Low-cost travel in neurons. Science 325, 1349–1351 (2009).

    CAS  Article  Google Scholar 

  102. 102

    Mery, F. & Kawecki, T. J. A cost of long-term memory in Drosophila. Science 308, 1148 (2005). An intriguing report documenting a trade-off between memory and lifespan under certain (stressful) conditions.

    CAS  Article  Google Scholar 

  103. 103

    Laughlin, S. B. Energy as a constraint on the coding and processing of sensory information. Curr. Opin. Neurobiol. 11, 475–480 (2001).

    CAS  Article  Google Scholar 

  104. 104

    Laughlin, S. B., de Ruyter van Steveninck, R. R. & Anderson, J. C. The metabolic cost of neural information. Nature Neurosci. 1, 36–41 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Bishop, N. A., Lu, T. & Yankner, B. A. Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Ricobaraza, A. et al. Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model. Neuropsychopharmacology 34, 1721–1732 (2009).

    CAS  Article  Google Scholar 

  107. 107

    Francis, Y. I. et al. Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer's disease. J. Alzheimers Dis. 18, 131–139 (2009).

    CAS  Article  Google Scholar 

  108. 108

    Govindarajan, N., Agis-Balboa, R. C., Walter, J., Sananbenesi, F. & Fischer, A. Sodium butyrate improves memory function in an Alzheimer's disease mouse model when administered at an advanced stage of disease progression. J. Alzheimers Dis. 26, 187–197 (2011).

    CAS  Article  Google Scholar 

  109. 109

    Walker, M. P., Laferla, F. M., Oddo, S. S. & Brewer, G. J. Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer's disease. Age 12 Jan 2012 (doi:10.1007/s11357-011-9375-5).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Mastroeni, D. et al. Epigenetic changes in Alzheimer's disease: decrements in DNA methylation. Neurobiol. Aging 31, 2025–2037 (2010).

    CAS  Article  Google Scholar 

  111. 111

    Blalock, E. M. et al. Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J. Neurosci. 23, 3807–3819 (2003).

    CAS  Article  Google Scholar 

  112. 112

    Lee, C. K., Weindruch, R. & Prolla, T. A. Gene-expression profile of the ageing brain in mice. Nature Genet. 25, 294–297 (2000).

    CAS  Article  Google Scholar 

  113. 113

    Loerch, P. M. et al. Evolution of the aging brain transcriptome and synaptic regulation. PLoS ONE 3, e3329 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Lu, T. et al. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891 (2004).

    CAS  Article  Google Scholar 

  115. 115

    Peleg, S. et al. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328, 753–756 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Tang, B., Dean, B. & Thomas, E. A. Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders. Transl. Psychiatry 1, e64 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Ryu, S. H., Kang, K., Yoo, T., Joe, C. O. & Chung, J. H. Transcriptional repression of repeat-derived transcripts correlates with histone hypoacetylation at repetitive DNA elements in aged mice brain. Exp. Gerontol. 46, 811–818 (2011).

    CAS  Article  Google Scholar 

  118. 118

    Borrell-Pages, M., Zala, D., Humbert, S. & Saudou, F. Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies. Cell. Mol. Life Sci. 63, 2642–2660 (2006).

    CAS  Article  Google Scholar 

  119. 119

    Garber, K. B., Visootsak, J. & Warren, S. T. Fragile X syndrome. Eur. J. Hum. Genet. 16, 666–672 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Hunter, R. G. et al. Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response. Proc. Natl Acad. Sci. USA 109, 17657–17662 (2012).

    CAS  Article  Google Scholar 

  121. 121

    Kang, J. E., Cirrito, J. R., Dong, H., Csernansky, J. G. & Holtzman, D. M. Acute stress increases interstitial fluid amyloid-β via corticotropin-releasing factor and neuronal activity. Proc. Natl Acad. Sci. USA 104, 10673–10678 (2007).

    CAS  Article  Google Scholar 

  122. 122

    Green, K. N., Billings, L. M., Roozendaal, B., McGaugh, J. L. & LaFerla, F. M. Glucocorticoids increase amyloid-β and tau pathology in a mouse model of Alzheimer's disease. J. Neurosci. 26, 9047–9056 (2006).

    CAS  Article  Google Scholar 

  123. 123

    Porter, N. M. & Landfield, P. W. Stress hormones and brain aging: adding injury to insult? Nature Neurosci. 1, 3–4 (1998).

    CAS  Article  Google Scholar 

  124. 124

    Lupien, S. J. et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nature Neurosci. 1, 69–73 (1998).

    CAS  Article  Google Scholar 

  125. 125

    Oztan, O., Aydin, C. & Isgor, C. Stressful environmental and social stimulation in adolescence causes antidepressant-like effects associated with epigenetic induction of the hippocampal BDNF and mossy fibre sprouting in the novelty-seeking phenotype. Neurosci. Lett. 501, 107–111 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Levine, A., Worrell, T. R., Zimnisky, R. & Schmauss, C. Early life stress triggers sustained changes in histone deacetylase expression and histone H4 modifications that alter responsiveness to adolescent antidepressant treatment. Neurobiol. Dis. 45, 488–498 (2012).

    CAS  Article  Google Scholar 

  127. 127

    Sananbenesi, F. & Fischer, A. The epigenetic bottleneck of neurodegenerative and psychiatric diseases. Biol. Chem. 390, 1145–1153 (2009).

    CAS  Article  Google Scholar 

  128. 128

    McQuown, S. C. & Wood, M. A. HDAC3 and the molecular brake pad hypothesis. Neurobiol. Learn. Mem. 96, 27–34 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Brunmeir, R., Lagger, S. & Seiser, C. Histone deacetylase HDAC1/HDAC2-controlled embryonic development and cell differentiation. Int. J. Dev. Biol. 53, 275–289 (2009).

    CAS  Article  Google Scholar 

  130. 130

    Fischer, A., Sananbenesi, F., Mungenast, A. & Tsai, L. H. Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol. Sci. 31, 605–617 (2010).

    CAS  Article  Google Scholar 

  131. 131

    Haggarty, S. J. & Tsai, L. H. Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticity. Neurobiol. Learn. Mem. 96, 41–52 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Kwon, P., Hsu, M., Cohen, D. & Atadja, P. in Histone Deacetylases: Transcriptional Regulation and Other Cellular Functions (ed. Verdin, E.) 315–332 (Humana Press, 2006).

    Book  Google Scholar 

  133. 133

    Kilgore, M. et al. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 35, 870–880 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Ricobaraza, A., Cuadrado-Tejedor, M. & Garcia-Osta, A. Long-term phenylbutyrate administration prevents memory deficits in Tg2576 mice by decreasing Aβ. Front. Biosci. 3, 1375–1384 (2011).

    Google Scholar 

  135. 135

    Ricobaraza, A., Cuadrado-Tejedor, M., Marco, S., Perez-Otano, I. & Garcia-Osta, A. Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus 22, 1040–1050 (2012).

    CAS  Article  Google Scholar 

  136. 136

    Hockly, E. et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc. Natl Acad. Sci. USA 100, 2041–2046 (2003).

    CAS  Article  Google Scholar 

  137. 137

    Thomas, E. A. et al. The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice. Proc. Natl Acad. Sci. USA 105, 15564–15569 (2008).

    CAS  Article  Google Scholar 

  138. 138

    Ferrante, R. J. et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J. Neurosci. 23, 9418–9427 (2003).

    CAS  Article  Google Scholar 

  139. 139

    Gardian, G. et al. Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease. J. Biol. Chem. 280, 556–563 (2005).

    CAS  Article  Google Scholar 

  140. 140

    Sadri-Vakili, G. et al. Histones associated with downregulated genes are hypo-acetylated in Huntington's disease models. Hum. Mol. Genet. 16, 1293–1306 (2007).

    CAS  Article  Google Scholar 

  141. 141

    Petri, S. et al. Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis. 22, 40–49 (2006).

    CAS  Article  Google Scholar 

  142. 142

    Rouaux, C. et al. Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. J. Neurosci. 27, 5535–5545 (2007).

    CAS  Article  Google Scholar 

  143. 143

    Rossetti, F. et al. Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure. Neurotoxicology 33, 500–511 (2012).

    CAS  Article  Google Scholar 

  144. 144

    Reolon, G. K. et al. Posttraining systemic administration of the histone deacetylase inhibitor sodium butyrate ameliorates aging-related memory decline in rats. Behav. Brain Res. 221, 329–332 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. 145

    Weaver, I. C. G. et al. Epigenetic programming by maternal behavior. Nature Neurosci. 7, 847–854 (2004). A highly influential report showing that early-life stress can trigger lasting epigenetic modifications that influence behaviour later in life in rats. This finding was later replicated in humans (see reference 168).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    Kim, H. S. et al. Inhibition of histone deacetylation enhances the neurotoxicity induced by the C-terminal fragments of amyloid precursor protein. J. Neurosci. Res. 75, 117–124 (2004).

    CAS  Article  Google Scholar 

  147. 147

    Salminen, A., Tapiola, T., Korhonen, P. & Suuronen, T. Neuronal apoptosis induced by histone deacetylase inhibitors. Brain Res. Mol. Brain Res. 61, 203–206 (1998).

    CAS  Article  Google Scholar 

  148. 148

    Khan, O. & La Thangue, N. B. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol. Cell Biol. 90, 85–94 (2012).

    CAS  Article  Google Scholar 

  149. 149

    Cedar, H. & Bergman, Y. Linking DNA methylation and histone modification: patterns and paradigms. Nature Rev. Genet. 10, 295–304 (2009).

    CAS  Article  Google Scholar 

  150. 150

    Scott, G. K., Mattie, M. D., Berger, C. E., Benz, S. C. & Benz, C. C. Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res. 66, 1277–1281 (2006).

    CAS  Article  Google Scholar 

  151. 151

    Tsankova, N., Renthal, W., Kumar, A. & Nestler, E. J. Epigenetic regulation in psychiatric disorders. Nature Rev. Neurosci. 8, 355–367 (2007).

    CAS  Article  Google Scholar 

  152. 152

    Gräff, J. & Mansuy, I. M. Epigenetic dysregulation in cognitive disorders. Eur. J. Neurosci. 30, 1–8 (2009).

    Article  Google Scholar 

  153. 153

    Haettig, J. et al. HDAC inhibition modulates hippocampus-dependent long-term memory for object location in a CBP-dependent manner. Learn. Mem. 18, 71–79 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Malvaez, M., Sanchis-Segura, C., Vo, D., Lattal, K. M. & Wood, M. A. Modulation of chromatin modification facilitates extinction of cocaine-induced conditioned place preference. Biol. Psychiatry 67, 36–43 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Covington, H. E., 3rd et al. Antidepressant actions of histone deacetylase inhibitors. J. Neurosci. 29, 11451–11460 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Schroeder, F. A., Lin, C. L., Crusio, W. E. & Akbarian, S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol. Psychiatry 62, 55–64 (2007).

    CAS  Article  Google Scholar 

  157. 157

    Tsankova, N. M. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neurosci. 9, 519–525 (2006).

    CAS  Article  Google Scholar 

  158. 158

    Kurita, M. et al. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nature Neurosci. 15, 1245–1254 (2012).

    CAS  Article  Google Scholar 

  159. 159

    Mims, A. & Marcucci, G. Epigenetic priming: the target? Blood 118, 1430–1431 (2011).

    CAS  Article  Google Scholar 

  160. 160

    Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome — biological and translational implications. Nature Rev. Cancer 11, 726–734 (2011).

    CAS  Article  Google Scholar 

  161. 161

    Bangert, A., Hacker, S., Cristofanon, S., Debatin, K. M. & Fulda, S. Chemosensitization of glioblastoma cells by the histone deacetylase inhibitor MS275. Anticancer Drugs 22, 494–499 (2011).

    CAS  Article  Google Scholar 

  162. 162

    Marchion, D. C. et al. HDAC2 regulates chromatin plasticity and enhances DNA vulnerability. Mol. Cancer Ther. 8, 794–801 (2009).

    CAS  Article  Google Scholar 

  163. 163

    Milekic, M. H. & Alberini, C. M. Temporally graded requirement for protein synthesis following memory reactivation. Neuron 36, 521–525 (2002).

    CAS  Article  Google Scholar 

  164. 164

    Naqib, F., Sossin, W. Y. & Farah, C. A. Molecular determinants of the spacing effect. Neural Plast. 2012, 581291 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  166. 166

    Liu, B. L. et al. Global histone modification patterns as prognostic markers to classify glioma patients. Cancer Epidemiol. Biomarkers Prev. 19, 2888–2896 (2010).

    CAS  Article  Google Scholar 

  167. 167

    Lee, Y. S. & Silva, A. J. The molecular and cellular biology of enhanced cognition. Nature Rev. Neurosci. 10, 126–140 (2009).

    CAS  Article  Google Scholar 

  168. 168

    McGowan, P. O. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neurosci. 12, 342–348 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  169. 169

    Basha, M. R. et al. The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and β-amyloid in the aging brain. J. Neurosci. 25, 823–829 (2005).

    CAS  Article  Google Scholar 

  170. 170

    Wu, J. et al. Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J. Neurosci. 28, 3–9 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. 171

    Jonsson, T. et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488, 96–99 (2012).

    CAS  Article  Google Scholar 

  172. 172

    Lahiri, D. K., Maloney, B. & Zawia, N. H. The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Mol. Psychiatry 14, 992–1003 (2009). An intriguing review positing that early-life events might epigenetically influence cognitive health later in life.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  173. 173

    Bihaqi, S. W., Huang, H., Wu, J. & Zawia, N. H. Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: implications for Alzheimer's disease. J. Alzheimers Dis. 27, 819–833 (2011).

    CAS  Article  Google Scholar 

  174. 174

    Halagappa, V. K. et al. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease. Neurobiol. Dis. 26, 212–220 (2007).

    CAS  Article  Google Scholar 

  175. 175

    Qin, W. et al. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J. Biol. Chem. 281, 21745–21754 (2006).

    CAS  Article  Google Scholar 

  176. 176

    Wang, J. et al. Caloric restriction attenuates β-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB J. 19, 659–661 (2005).

    Google Scholar 

  177. 177

    Witte, A. V., Fobker, M., Gellner, R., Knecht, S. & Floel, A. Caloric restriction improves memory in elderly humans. Proc. Natl Acad. Sci. USA 106, 1255–1260 (2009).

    CAS  Article  Google Scholar 

  178. 178

    Funato, H., Oda, S., Yokofujita, J., Igarashi, H. & Kuroda, M. Fasting and high-fat diet alter histone deacetylase expression in the medial hypothalamus. PLoS ONE 6, e18950 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  179. 179

    Valor, L. M. et al. Ablation of CBP in forebrain principal neurons causes modest memory and transcriptional defects and a dramatic reduction of histone acetylation but does not affect cell viability. J. Neurosci. 31, 1652–1663 (2011).

    CAS  Article  Google Scholar 

  180. 180

    Brunner, A. M., Tweedie-Cullen, R. Y. & Mansuy, I. M. Epigenetic modifications of the neuroproteome. Proteomics 12, 2404–2420 (2012).

    CAS  Article  Google Scholar 

Download references


We thank S. Jemielity and A. Mungenast for critical reading of the manuscript and acknowledge support from a Bard Richmond grant to J.G., and the US National Institutes of Health (grants, NS078839 and NS51874) to L.-H.T. L.-H.T. is an investigator of the Howard Hughes Medical Institute.

Author information



Corresponding author

Correspondence to Li-Huei Tsai.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links


Li-Huei Tsai's homepage


Histone proteins

Basic proteins with a globular core and loosely structured N- and C-terminal tails that form part of the chromatin. Doublets of the four core histones H2A, H2B, H3 and H4 constitute a histone octamer, which is wrapped around by DNA to form the nucleosome. Post-translational histone modifications modulate the compaction of the DNA around histones and thereby the three-dimensional chromatin structure.

Histone deacetylase inhibitors

(HDACis). Small molecules that inhibit the activity of HDACs, most of them by binding to the HDAC catalytic domain.

Synaptic plasticity

The ability of a synapse to change in strength, which is considered to be a cellular correlate of learning and memory.

Long-term facilitation

(LTF). Transcription-dependent facilitation of electrical transmission across synapses.

Long-term depression

(LTD). Transcription-dependent deterioration of electrical transmission across synapses.

Long-term potentiation

(LTP). An increase in synaptic transmission efficiency as a result of presynaptic high-frequency stimulation.

Fear conditioning

A form of associative learning in which an aversive stimulus (for example, an electric shock) is paired with a neutral context (for example, a chamber) or neutral stimulus (for example, a tone), resulting in the expression of fear responses to the originally neutral context or stimulus in the absence of the aversive stimulus.

Latent inhibition

A decrease of the conditioned response in an associative memory task when the conditioned stimulus is presented alone before the conditioning session.


A time-limited process that allows newly acquired memories to be stabilized and permanently stored.


A time-limited process that allows reactivated memories to be updated with new information and to be stored in a modified form.

Object location memory

Memory for an object's location that is measured by taking advantage of rodents' natural propensity to explore novel objects. The time spent with a novel versus a familiar object serves as an indicator of the memory strength. In object location, the novelty is given by a change in location of a familiar object.

Object recognition memory

The ability to recognize an object as familiar rather than novel. It is measured in a similar way to object location memory but with the novelty given by presenting the animal with an object that is unfamiliar but in the same location..

Fear memory extinction

A decline in conditioned fear responses when there is a reduction in the predictive value of the conditioned stimulus, for example, through repetitive exposure to the conditioned stimulus without the aversive association.

Alzheimer's disease

(AD). The most common type of neurodegenerative dementia. Patients often show impairments in learning and memory. The disease's neuropathology includes neuron loss in the cerebral cortex and in several subcortical regions and the presence of aggregates in the forms of plaques (containing amyloid-β) and neurofibrillary tangles (containing hyperphosphorylated tau).

Braak and Braak stages

A way to categorize the severity of Alzheimer's disease (AD) according to the extent of tau pathology post-mortem. In BB stages I/II (mild AD), tau pathology is mainly restricted to the entorhinal cortex. In stages III/IV (moderate AD), tau pathology has spread to the hippocampal formation and subcortical nuclei. In stages V/VI (severe AD), tau pathology affects the entire brain.

Huntington's disease

(HD). A neurodegenerative disease that is characterized by progressive loss of movement coordination, muscular atrophy and cognitive decline. It is caused by mutations in the huntingtin gene that lead to abnormally high repetitions of the triplet CAG at its 5′-coding region.

Fragile X syndrome

A common form of neurodevelopmental mental retardation caused by unusual trinucleotide expansions and subsequent gene silencing of fragile X mental retardation 1 (FMR1) or FMR2.

Amyotrophic lateral sclerosis

(ALS). A progressive neurological disease that is associated with the degeneration of central and spinal motor neurons. This neuron loss causes muscles to weaken, leading to paralysis. About 90% of all ALS cases are sporadic, the remaining 10% being caused by genetic mutations, for example, in superoxide dismutase 1 (SOD1).

Rubinstein–Taybi syndrome

A monogenic neurodevelopmental disorder caused by mutations in the gene coding for the histone acetyltransferase cyclic AMP-responsive element-binding (CREB)-binding protein (CBP). The disease is characterized by skeletal and facial abnormalities, and varying degrees of mental retardation.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gräff, J., Tsai, LH. Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 14, 97–111 (2013).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing