Review Article | Published:

How the epigenome integrates information and reshapes the synapse

Nature Reviews Neurosciencevolume 20pages133147 (2019) | Download Citation


In the past few decades, the field of neuroepigenetics has investigated how the brain encodes information to form long-lasting memories that lead to stable changes in behaviour. Activity-dependent molecular mechanisms, including, but not limited to, histone modification, DNA methylation and nucleosome remodelling, dynamically regulate the gene expression required for memory formation. Recently, the field has begun to examine how a learning experience is integrated at the level of both chromatin structure and synaptic physiology. Here, we provide an overview of key established epigenetic mechanisms that are important for memory formation. We explore how epigenetic mechanisms give rise to stable alterations in neuronal function by modifying synaptic structure and function, and highlight studies that demonstrate how manipulating epigenetic mechanisms may push the boundaries of memory.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Kandel, E. R., Dudai, Y. & Mayford, M. R. The molecular and systems biology of memory. Cell 157, 163–186 (2014).

  2. 2.

    Johansen, J. P., Cain, C. K., Ostroff, L. E. & LeDoux, J. E. Molecular mechanisms of fear learning and memory. Cell 147, 509–524 (2011).

  3. 3.

    Alberini, C. M. Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 89, 121–145 (2009).

  4. 4.

    Hernandez, P. J. & Abel, T. The role of protein synthesis in memory consolidation: progress amid decades of debate. Neurobiol. Learn. Mem. 89, 293–311 (2008).

  5. 5.

    Day, J. J. & Sweatt, J. D. Epigenetic mechanisms in cognition. Neuron 70, 813–829 (2011).

  6. 6.

    Goldberg, A. D., Allis, C. D. & Bernstein, E. Epigenetics: a landscape takes shape. Cell 128, 635–638 (2007).

  7. 7.

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

  8. 8.

    Reik, W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425–432 (2007).

  9. 9.

    Swank, M. W. & Sweatt, J. D. Increased histone acetyltransferase and lysine acetyltransferase activity and biphasic activation of the ERK/RSK cascade in insular cortex during novel taste learning. J. Neurosci. 21, 3383–3391 (2001).

  10. 10.

    Levenson, J. M. & Sweatt, J. D. Epigenetic mechanisms in memory formation. Nat. Rev. Neurosci. 6, 108–118 (2005).

  11. 11.

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

  12. 12.

    Barrett, R. M. & Wood, M. A. Beyond transcription factors: the role of chromatin modifying enzymes in regulating transcription required for memory. Learn. Mem. 15, 460–467 (2008).

  13. 13.

    Frankland, P. W. & Josselyn, S. A. Neuroscience: in search of the memory molecule. Nature 535, 41–42 (2016).

  14. 14.

    Josselyn, S. A. & Frankland, P. W. Memory allocation: mechanisms and function. Annu. Rev. Neurosci. 41, 389–413 (2018).

  15. 15.

    Penzes, P. & Rafalovich, I. Regulation of the actin cytoskeleton in dendritic spines. Adv. Exp. Med. Biol. 970, 81–95 (2012).

  16. 16.

    Lynch, G., Kramár, E. A. & Gall, C. M. Protein synthesis and consolidation of memory-related synaptic changes. Brain Res. 1621, 62–72 (2015).

  17. 17.

    Malenka, R. C. Synaptic plasticity in the hippocampus: LTP and LTD. Cell 78, 535–538 (1994).

  18. 18.

    Südhof, T. C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008).

  19. 19.

    Carroll, R. C., Beattie, E. C., von Zastrow, M. & Malenka, R. C. Role of AMPA receptor endocytosis in synaptic plasticity. Nat. Rev. Neurosci. 2, 315–324 (2001).

  20. 20.

    Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

  21. 21.

    Riehl, R. et al. Cadherin function is required for axon outgrowth in retinal ganglion cells in vivo. Neuron 17, 837–848 (1996).

  22. 22.

    Park, Y. K. & Goda, Y. Integrins in synapse regulation. Nat. Rev. Neurosci. 17, 745–756 (2016).

  23. 23.

    Konietzny, A., Bär, J. & Mikhaylova, M. Dendritic actin cytoskeleton: structure, functions, and regulations. Front. Cell. Neurosci. 11, 147 (2017).

  24. 24.

    Lynch, G., Rex, C. S. & Gall, C. M. LTP consolidation: substrates, explanatory power, and functional significance. Neuropharmacology 52, 12–23 (2007).

  25. 25.

    Bastle, R. M. & Maze, I. S. Chromatin regulation in complex brain disorders. Curr. Opin. Behav. Sci. 25, 57–65 (2019).

  26. 26.

    López, A. J. & Wood, M. A. Role of nucleosome remodeling in neurodevelopmental and intellectual disability disorders. Front. Behav. Neurosci. 9, 100 (2015).

  27. 27.

    Kwapis, J. L. & Wood, M. A. Epigenetic mechanisms in fear conditioning: implications for treating post-traumatic stress disorder. Trends Neurosci. 37, 706–720 (2014).

  28. 28.

    White, A. O. & Wood, M. A. Does stress remove the HDAC brakes for the formation and persistence of long-term memory? Neurobiol. Learn. Mem. 112, 61–67 (2014).

  29. 29.

    Walker, D. M. & Nestler, E. J. Neuroepigenetics and addiction. Handb. Clin. Neurol. 148, 747–765 (2018).

  30. 30.

    Zovkic, I. B., Paulukaitis, B. S., Day, J. J., Etikala, D. M. & Sweatt, J. D. Histone H2A.Z subunit exchange controls consolidation of recent and remote memory. Nature 515, 582–586 (2014).

  31. 31.

    Stefanelli, G. et al. Learning and age-related changes in genome-wide H2A.Z binding in the mouse hippocampus. Cell Rep. 22, 1124–1131 (2018).

  32. 32.

    Maze, I. et al. Critical role of histone turnover in neuronal transcription and plasticity. Neuron 87, 77–94 (2015).

  33. 33.

    Bharadwaj, R. et al. Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition. Neuron 84, 997–1008 (2014).

  34. 34.

    Watson, L. A. & Tsai, L.-H. In the loop: how chromatin topology links genome structure to function in mechanisms underlying learning and memory. Curr. Opin. Neurobiol. 43, 48–55 (2017).

  35. 35.

    Widagdo, J. et al. Experience-dependent accumulation of N 6-methyladenosine in the prefrontal cortex is associated with memory processes in mice. J. Neurosci. 36, 6771–6777 (2016).

  36. 36.

    Bero, A. W. et al. Early remodeling of the neocortex upon episodic memory encoding. Proc. Natl Acad. Sci. USA 111, 11852–11857 (2014).

  37. 37.

    Savell, K. E. et al. Extra-coding RNAs regulate neuronal DNA methylation dynamics. Nat. Commun. 7, 12091 (2016).

  38. 38.

    Lin, Q. et al. MicroRNA-mediated disruption of dendritogenesis during a critical period of development influences cognitive capacity later in life. Proc. Natl Acad. Sci. USA 114, 9188–9193 (2017).

  39. 39.

    Sim, S.-E. et al. The brain-enriched microRNA miR-9-3p regulates synaptic plasticity and memory. J. Neurosci. 36, 8641–8652 (2016).

  40. 40.

    Heyer, M. P. & Kenny, P. J. Corticostriatal microRNAs in addiction. Brain Res. 1628, 2–16 (2015).

  41. 41.

    Lee, K. et al. An activity-regulated microRNA, miR-188, controls dendritic plasticity and synaptic transmission by downregulating neuropilin-2. J. Neurosci. 32, 5678–5687 (2012).

  42. 42.

    Woldemichael, B. T. et al. The microRNA cluster miR-183/96/182 contributes to long-term memory in a protein phosphatase 1-dependent manner. Nat. Commun. 7, 12594 (2016).

  43. 43.

    Qureshi, I. A. & Mehler, M. F. Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nat. Rev. Neurosci. 13, 528–541 (2012).

  44. 44.

    Agranoff, B. W., Davis, R. E., Casola, L. & Lim, R. Actinomycin D blocks formation of memory of shock-avoidance in goldfish. Science 158, 1600–1601 (1967).

  45. 45.

    Silva, A. J., Kogan, J. H., Frankland, P. W. & Kida, S. CREB and memory. Annu. Rev. Neurosci. 21, 127–148 (1998).

  46. 46.

    Yin, J. C. & Tully, T. CREB and the formation of long-term memory. Curr. Opin. Neurobiol. 6, 264–268 (1996).

  47. 47.

    Chrivia, J. C. et al. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365, 855–859 (1993).

  48. 48.

    Bourtchouladze, R. et al. A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4. Proc. Natl Acad. Sci. USA 100, 10518–10522 (2003).

  49. 49.

    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).

  50. 50.

    Alarcon, J. 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).

  51. 51.

    Korzus, E. Rubinstein-Taybi syndrome and epigenetic alterations. Adv. Exp. Med. Biol. 978, 39–62 (2017).

  52. 52.

    Korzus, E., Rosenfeld, M. G. & Mayford, M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42, 961–972 (2004). This paper demonstrates the importance of histone acetylation in memory formation: transgenic mice with deficient CBP HAT activity exhibit impaired long-term memory, which was rescued by administration of an HDAC inhibitor.

  53. 53.

    Wood, M. A., Attner, M. A., Oliveira, A. M. 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).

  54. 54.

    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).

  55. 55.

    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).

  56. 56.

    Malvaez, M., Mhillaj, E., Matheos, D. P., Palmery, M. & Wood, M. A. CBP in the nucleus accumbens regulates cocaine-induced histone acetylation and is critical for cocaine-associated behaviors. J. Neurosci. 31, 16941–16948 (2011).

  57. 57.

    Maddox, S. A., Watts, C. S. & Schafe, G. E. p300/CBP histone acetyltransferase activity is required for newly acquired and reactivated fear memories in the lateral amygdala. Learn. Mem. 20, 109–119 (2013).

  58. 58.

    Sando, R. et al. HDAC4 governs a transcriptional program essential for synaptic plasticity and memory. Cell 151, 821–834 (2012).

  59. 59.

    Kwapis, J. L. et al. Context and auditory fear are differentially regulated by HDAC3 activity in the lateral and basal subnuclei of the amygdala. Neuropsychopharmacology 42, 1284–1294 (2017).

  60. 60.

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

  61. 61.

    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).

  62. 62.

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

  63. 63.

    Zhang, T., Cooper, S. & Brockdorff, N. The interplay of histone modifications — writers that read. EMBO Rep. 16, 1467–1481 (2015).

  64. 64.

    Peixoto, L. & Abel, T. The role of histone acetylation in memory formation and cognitive impairments. Neuropsychopharmacology 38, 62–76 (2013).

  65. 65.

    Morris, M. J., Mahgoub, M., Na, E. S., Pranav, H. & Monteggia, L. M. Loss of histone deacetylase 2 improves working memory and accelerates extinction learning. J. Neurosci. 33, 6401–6411 (2013).

  66. 66.

    Taniguchi, M. et al. HDAC5 and its target gene, Npas4, function in the nucleus accumbens to regulate cocaine-conditioned behaviors. Neuron 96, 130–144 (2017).

  67. 67.

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

  68. 68.

    Gräff, J. et al. Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories. Cell 156, 261–276 (2014). Although a reconsolidation-updating paradigm fails to alter remote memories, administration of an HDAC2-targeting inhibitor during reconsolidation persistently attenuates remote memories.

  69. 69.

    Zocchi, L. & Sassone-Corsi, P. SIRT1-mediated deacetylation of MeCP2 contributes to BDNF expression. Epigenetics 7, 695–700 (2012).

  70. 70.

    Federman, N. et al. Nuclear factor κB-dependent histone acetylation is specifically involved in persistent forms of memory. J. Neurosci. 33, 7603–7614 (2013).

  71. 71.

    Lopez-Atalaya, J. P. & Barco, A. Can changes in histone acetylation contribute to memory formation? Trends Genet. 30, 529–539 (2014).

  72. 72.

    Rashid, A. J., Cole, C. J. & Josselyn, S. A. Emerging roles for MEF2 transcription factors in memory. Genes Brain Behav. 13, 118–125 (2014).

  73. 73.

    Sartor, G. C., Powell, S. K., Brothers, S. P. & Wahlestedt, C. Epigenetic readers of lysine acetylation regulate cocaine-induced plasticity. J. Neurosci. 35, 15062–15072 (2015).

  74. 74.

    Korb, E., Herre, M., Zucker-Scharff, I., Darnell, R. B. & Allis, C. D. BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice. Nat. Neurosci. 18, 1464–1473 (2015).

  75. 75.

    Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M. & Tsai, L.-H. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182 (2007).

  76. 76.

    Schaefer, A. et al. Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64, 678–691 (2009). Knockdown of GLP–G9a leads to derepression of genes expressed in adult neurons and leads to deficits in learning.

  77. 77.

    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).

  78. 78.

    Snigdha, S. et al. H3k9me3 inhibition improves memory, promotes spine formation, and increases BDNF levels in the aged hippocampus. J. Neurosci. 36, 3611–3622 (2016).

  79. 79.

    Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

  80. 80.

    Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2001).

  81. 81.

    Maze, I. et al. Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 327, 213–216 (2010).

  82. 82.

    Covington, H. E. et al. A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron 71, 656–670 (2011).

  83. 83.

    Anderson, E. M. et al. Overexpression of the histone dimethyltransferase G9a in nucleus accumbens shell increases cocaine self-administration, stress-induced reinstatement, and anxiety. J. Neurosci. 38, 803–813 (2018).

  84. 84.

    Gupta, S. et al. Histone methylation regulates memory formation. J. Neurosci. 30, 3589–3599 (2010).

  85. 85.

    Kerimoglu, C. et al. KMT2A and KMT2B mediate memory function by affecting distinct genomic regions. Cell Rep. 20, 538–548 (2017).

  86. 86.

    Kerimoglu, C. et al. Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J. Neurosci. 33, 3452–3464 (2013).

  87. 87.

    Damez-Werno, D. M. et al. Histone arginine methylation in cocaine action in the nucleus accumbens. Proc. Natl Acad. Sci. USA 113, 9623–9628 (2016).

  88. 88.

    Benevento, M. et al. Histone methylation by the Kleefstra syndrome protein EHMT1 mediates homeostatic synaptic scaling. Neuron 91, 341–355 (2016).

  89. 89.

    Jakovcevski, M. et al. Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory. J. Neurosci. 35, 5097–5108 (2015).

  90. 90.

    Jarome, T. J. & Lubin, F. D. Histone lysine methylation: critical regulator of memory and behavior. Rev. Neurosci. 24, 375–387 (2013).

  91. 91.

    Levenson, J. M. et al. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J. Biol. Chem. 281, 15763–15773 (2006).

  92. 92.

    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).

  93. 93.

    Maddox, S. A., Watts, C. S. & Schafe, G. E. DNA methyltransferase activity is required for memory-related neural plasticity in the lateral amygdala. Neurobiol. Learn. Mem. 107, 93–100 (2014).

  94. 94.

    Miller, C. A. et al. Cortical DNA methylation maintains remote memory. Nat. Neurosci. 13, 664–666 (2010). Associative learning induces gene-specific cortical hypermethylation in rats, and DNMT inhibition 1 month after learning disrupted remote memory.

  95. 95.

    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).

  96. 96.

    Biergans, S. D., Jones, J. C., Treiber, N., Galizia, C. G. & Szyszka, P. DNA methylation mediates the discriminatory power of associative long-term memory in honeybees. PLOS ONE 7, e39349 (2012).

  97. 97.

    Brueckner, B. et al. Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res. 65, 6305–6311 (2005).

  98. 98.

    Oliveira, A. M. M., Hemstedt, T. J. & Bading, H. Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities. Nat. Neurosci. 15, 1111–1113 (2012).

  99. 99.

    Sultan, F. A., Wang, J., Tront, J., Liebermann, D. A. & Sweatt, J. D. Genetic deletion of Gadd45b, a regulator of active DNA demethylation, enhances long-term memory and synaptic plasticity. J. Neurosci. 32, 17059–17066 (2012).

  100. 100.

    Ma, D. K. et al. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323, 1074–1077 (2009).

  101. 101.

    Leach, P. T. et al. Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory. Learn. Mem. 19, 319–324 (2012).

  102. 102.

    Gavin, D. P., Chase, K. A. & Sharma, R. P. Active DNA demethylation in post-mitotic neurons: a reason for optimism. Neuropharmacology 75, 233–245 (2013).

  103. 103.

    Rudenko, A. et al. Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79, 1109–1122 (2013).

  104. 104.

    Halder, R. et al. DNA methylation changes in plasticity genes accompany the formation and maintenance of memory. Nat. Neurosci. 19, 102–110 (2016). Rapid de novo DNA methylation and demethylation occur in the hippocampus in response to fear conditioning.

  105. 105.

    Oliveira, A. M. M. DNA methylation: a permissive mark in memory formation and maintenance. Learn. Mem. 23, 587–593 (2016).

  106. 106.

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

  107. 107.

    Day, J. J. et al. DNA methylation regulates associative reward learning. Nat. Neurosci. 16, 1445–1452 (2013).

  108. 108.

    Webb, W. M. et al. Dynamic association of epigenetic H3K4me3 and DNA 5hmC marks in the dorsal hippocampus and anterior cingulate cortex following reactivation of a fear memory. Neurobiol. Learn. Mem. 142, 66–78 (2017).

  109. 109.

    Hemstedt, T. J., Lattal, K. M. & Wood, M. A. Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom. Neurobiol. Learn. Mem. 142, 55–65 (2017).

  110. 110.

    Spruijt, C. G. & Vermeulen, M. DNA methylation: old dog, new tricks? Nat. Struct. Mol. Biol. 21, 949–954 (2014).

  111. 111.

    Hargreaves, D. C. & Crabtree, G. R. ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res. 21, 396–420 (2011).

  112. 112.

    Wu, J. I. et al. Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56, 94–108 (2007).

  113. 113.

    Yoo, M. et al. BAF53b, a neuron-specific nucleosome remodeling factor, is induced after learning and facilitates long-term memory consolidation. J. Neurosci. 37, 3686–3697 (2017).

  114. 114.

    Vogel Ciernia, A. et al. Mutation of neuron-specific chromatin remodeling subunit BAF53b: rescue of plasticity and memory by manipulating actin remodeling. Learn. Mem. 24, 199–209 (2017).

  115. 115.

    Vogel-Ciernia, A. et al. The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory. Nat. Neurosci. 16, 552–561 (2013). Genetic manipulation of the nBAF nucleosome-remodelling subunit BAF53B alters hippocampal gene expression and leads to impairments in both long-term memory and long-lasting forms of synaptic plasticity.

  116. 116.

    Borrelli, E., Nestler, E. J., Allis, C. D. & Sassone-Corsi, P. Decoding the epigenetic language of neuronal plasticity. Neuron 60, 961–974 (2008).

  117. 117.

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

  118. 118.

    Guan, J.-S. et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459, 55–60 (2009).

  119. 119.

    Feng, J. et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat. Neurosci. 13, 423–430 (2010).

  120. 120.

    Levenson, J. M. et al. Regulation of histone acetylation during memory formation in the hippocampus. J. Biol. Chem. 279, 40545–40559 (2004).

  121. 121.

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

  122. 122.

    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).

  123. 123.

    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).

  124. 124.

    Malvaez, M. et al. HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc. Natl Acad. Sci. USA 110, 2647–2652 (2013).

  125. 125.

    Rogge, G. A., Singh, H., Dang, R. & Wood, M. A. HDAC3 is a negative regulator of cocaine-context-associated memory formation. J. Neurosci. 33, 6623–6632 (2013).

  126. 126.

    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).

  127. 127.

    Bieszczad, K. M. & Weinberger, N. M. Representational gain in cortical area underlies increase of memory strength. Proc. Natl Acad. Sci. USA 107, 3793–3798 (2010).

  128. 128.

    Bieszczad, K. M. et al. Histone deacetylase inhibition via RGFP966 releases the brakes on sensory cortical plasticity and the specificity of memory formation. J. Neurosci. 35, 13124–13132 (2015).

  129. 129.

    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).

  130. 130.

    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).

  131. 131.

    Fujita, Y. et al. Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene. J. Psychiatr. Res. 46, 635–643 (2012).

  132. 132.

    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).

  133. 133.

    Itzhak, Y., Liddie, S. & Anderson, K. L. Sodium butyrate-induced histone acetylation strengthens the expression of cocaine-associated contextual memory. Neurobiol. Learn. Mem. 102, 34–42 (2013).

  134. 134.

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

  135. 135.

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

  136. 136.

    Blank, M. et al. TrkB blockade in the hippocampus after training or retrieval impairs memory: protection from consolidation impairment by histone deacetylase inhibition. J. Neural Transm. 123, 159–165 (2016).

  137. 137.

    Malvaez, M. et al. Habits are negatively regulated by  histone deacetylase 3 in the dorsal striatum. Biol. Psychiatry 84, 383–392 (2018).

  138. 138.

    Penner, M. R., Roth, T. L., Barnes, C. A. & Sweatt, J. D. An epigenetic hypothesis of aging-related cognitive dysfunction. Front. Aging Neurosci. 2, 9 (2010).

  139. 139.

    Kwapis, J. L. et al. Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory. Nat. Commun. 9, 3323 (2018).

  140. 140.

    Spiegel, A. M., Sewal, A. S. & Rapp, P. R. Epigenetic contributions to cognitive aging: disentangling mindspan and lifespan. Learn. Mem. 21, 569–574 (2014).

  141. 141.

    Jarome, T. J., Perez, G. A., Hauser, R. M., Hatch, K. M. & Lubin, F. D. EZH2 methyltransferase activity controls Pten expression and mTOR signaling during fear memory reconsolidation. J. Neurosci. 38, 7635–7648 (2018).

  142. 142.

    Balemans, M. C. M. et al. Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome. Hum. Mol. Genet. 22, 852–866 (2013).

  143. 143.

    Baker-Andresen, D. et al. Persistent variations in neuronal DNA methylation following cocaine self-administration and protracted abstinence in mice. Neuroepigenetics 4, 1–11 (2015).

  144. 144.

    Li, X. et al. Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. Proc. Natl Acad. Sci. USA 111, 7120–7125 (2014). Fear extinction induces a redistribution of 5hmC that is mediated by TET3 in the infralimbic prefrontal cortex.

  145. 145.

    Oliveira, A. M. M., Hemstedt, T. J., Freitag, H. E. & Bading, H. Dnmt3a2: a hub for enhancing cognitive functions. Mol. Psychiatry 21, 1130–1136 (2016).

  146. 146.

    Hawk, J. D. et al. NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors. J. Clin. Invest. 122, 3593–3602 (2012).

  147. 147.

    Berry, K. P. & Nedivi, E. Spine dynamics: are they all the same? Neuron 96, 43–55 (2017).

  148. 148.

    Meyer, D., Bonhoeffer, T. & Scheuss, V. Balance and stability of synaptic structures during synaptic plasticity. Neuron 82, 430–443 (2014).

  149. 149.

    Caroni, P., Donato, F. & Muller, D. Structural plasticity upon learning: regulation and functions. Nat. Rev. Neurosci. 13, 478–490 (2012).

  150. 150.

    Rex, C. S. et al. Myosin IIb regulates actin dynamics during synaptic plasticity and memory formation. Neuron 67, 603–617 (2010).

  151. 151.

    Young, E. J. et al. Selective, retrieval-independent disruption of methamphetamine-associated memory by actin depolymerization. Biol. Psychiatry 75, 96–104 (2014).

  152. 152.

    Babayan, A. H. et al. Integrin dynamics produce a delayed stage of long-term potentiation and memory consolidation. J. Neurosci. 32, 12854–12861 (2012).

  153. 153.

    Tamura, K., Shan, W. S., Hendrickson, W. A., Colman, D. R. & Shapiro, L. Structure-function analysis of cell adhesion by neural (N-) cadherin. Neuron 20, 1153–1163 (1998).

  154. 154.

    Bozdagi, O., Shan, W., Tanaka, H., Benson, D. L. & Huntley, G. W. Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. Neuron 28, 245–259 (2000).

  155. 155.

    Huntley, G. W., Gil, O. & Bozdagi, O. The cadherin family of cell adhesion molecules: multiple roles in synaptic plasticity. Neuroscientist 8, 221–233 (2002).

  156. 156.

    Südhof, T. C. Synaptic neurexin complexes: a molecular code for the logic of neural circuits. Cell 171, 745–769 (2017).

  157. 157.

    Brigidi, G. S. et al. Palmitoylation of δ-catenin by DHHC5 mediates activity-induced synapse plasticity. Nat. Neurosci. 17, 522–532 (2014).

  158. 158.

    Paoletti, P., Bellone, C. & Zhou, Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 14, 383–400 (2013).

  159. 159.

    Lee, S.-J. R., Escobedo-Lozoya, Y., Szatmari, E. M. & Yasuda, R. Activation of CaMKII in single dendritic spines during long-term potentiation. Nature 458, 299–304 (2009).

  160. 160.

    Murakoshi, H., Wang, H. & Yasuda, R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature 472, 100–104 (2011).

  161. 161.

    Rudy, J. W. Variation in the persistence of memory: an interplay between actin dynamics and AMPA receptors. Brain Res. 1621, 29–37 (2015).

  162. 162.

    Ye, X. & Carew, T. J. Small G protein signaling in neuronal plasticity and memory formation: the specific role of ras family proteins. Neuron 68, 340–361 (2010).

  163. 163.

    Cingolani, L. A. & Goda, Y. Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat. Rev. Neurosci. 9, 344–356 (2008).

  164. 164.

    DeMali, K. A., Wennerberg, K. & Burridge, K. Integrin signaling to the actin cytoskeleton. Curr. Opin. Cell Biol. 15, 572–582 (2003).

  165. 165.

    Chen, L. Y., Rex, C. S., Casale, M. S., Gall, C. M. & Lynch, G. Changes in synaptic morphology accompany actin signaling during LTP. J. Neurosci. 27, 5363–5372 (2007).

  166. 166.

    Kim, Y. et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814–817 (2006).

  167. 167.

    Yang, E. J., Yoon, J.-H., Min, D. S. & Chung, K. C. LIM kinase 1 activates cAMP-responsive element-binding protein during the neuronal differentiation of immortalized hippocampal progenitor cells. J. Biol. Chem. 279, 8903–8910 (2004).

  168. 168.

    Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. R. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004).

  169. 169.

    Harvey, C. D. & Svoboda, K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature 450, 1195–1200 (2007).

  170. 170.

    Rudy, J. W. Actin dynamics and the evolution of the memory trace. Brain Res. 1621, 17–28 (2015).

  171. 171.

    Mirisis, A. A., Alexandrescu, A., Carew, T. J. & Kopec, A. M. The contribution of spatial and temporal molecular networks in the induction of long-term memory and its underlying synaptic plasticity. AIMS Neurosci. 3, 356–384 (2016).

  172. 172.

    Goelet, P., Castellucci, V. F., Schacher, S. & Kandel, E. R. The long and the short of long-term memory — a molecular framework. Nature 322, 419–422 (1986).

  173. 173.

    Bailey, C. H., Bartsch, D. & Kandel, E. R. Toward a molecular definition of long-term memory storage. Proc. Natl Acad. Sci. USA 93, 13445–13452 (1996).

  174. 174.

    Frey, U. & Morris, R. G. Synaptic tagging and long-term potentiation. Nature 385, 533–536 (1997).

  175. 175.

    Martin, K. C. in Encyclopedia of Neuroscience (ed. Squire, L. R.) 719–723 (Academic Press, 2009).

  176. 176.

    Martin, K. C. & Kosik, K. S. Synaptic tagging — who’s it? Nat. Rev. Neurosci. 3, 813–820 (2002).

  177. 177.

    Wang, D. O. et al. Synapse- and stimulus-specific local translation during long-term neuronal plasticity. Science 324, 1536–1540 (2009).

  178. 178.

    Martin, K. C. Synaptic tagging during synapse-specific long-term facilitation of Aplysia sensory-motor neurons. Neurobiol. Learn. Mem. 78, 489–497 (2002).

  179. 179.

    Rogerson, T. et al. Synaptic tagging during memory allocation. Nat. Rev. Neurosci. 15, 157–169 (2014).

  180. 180.

    Sharma, M., Shetty, M. S., Arumugam, T. V. & Sajikumar, S. Histone deacetylase 3 inhibition re-establishes synaptic tagging and capture in aging through the activation of nuclear factor kappa B. Sci. Rep. 5, 16616 (2015). This paper examines the role of histone acetylation in synaptic tag and capture and finds that inhibition of HDAC3 augments L-LTP and re-establishes synaptic tag and capture in the hippocampus of aged rats.

  181. 181.

    Merkurjev, D. et al. Synaptic N6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts. Nat. Neurosci. 21, 1004–1014 (2018).

  182. 182.

    Leighton, L. J. et al. Experience-dependent neural plasticity, learning, and memory in the era of epitranscriptomics. Genes Brain Behav. 17, e12426 (2018).

  183. 183.

    Cajigas, I. J. et al. The local transcriptome in the synaptic neuropil revealed by deep sequencing and high-resolution imaging. Neuron 74, 453–466 (2012).

  184. 184.

    Tang, S. & Yasuda, R. Imaging ERK and PKA activation in single dendritic spines during structural plasticity. Neuron 93, 1315–1324 (2017).

  185. 185.

    Cohen, S. M. et al. Calmodulin shuttling mediates cytonuclear signaling to trigger experience-dependent transcription and memory. Nat. Commun. 9, 2451 (2018).

  186. 186.

    Cohen, S. & Greenberg, M. E. Communication between the synapse and the nucleus in neuronal development, plasticity, and disease. Annu. Rev. Cell Dev. Biol. 24, 183–209 (2008).

  187. 187.

    Karpova, A. et al. Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus. Cell 152, 1119–1133 (2013).

  188. 188.

    Harvey, C. D., Yasuda, R., Zhong, H. & Svoboda, K. The spread of Ras activity triggered by activation of a single dendritic spine. Science 321, 136–140 (2008).

  189. 189.

    Zhai, S., Ark, E. D., Parra-Bueno, P. & Yasuda, R. Long-distance integration of nuclear ERK signaling triggered by activation of a few dendritic spines. Science 342, 1107–1111 (2013).

  190. 190.

    Ch’ng, T. H. et al. Activity-dependent transport of the transcriptional coactivator CRTC1 from synapse to nucleus. Cell 150, 207–221 (2012).

  191. 191.

    Ch’ng, T. H. & Martin, K. C. Synapse-to-nucleus signaling. Curr. Opin. Neurobiol. 21, 345–352 (2011).

  192. 192.

    Jordan, B. A. & Kreutz, M. R. Nucleocytoplasmic protein shuttling: the direct route in synapse-to-nucleus signaling. Trends Neurosci. 32, 392–401 (2009).

  193. 193.

    Uchida, S. et al. CRTC1 nuclear translocation following learning modulates memory strength via exchange of chromatin remodeling complexes on the Fgf1 gene. Cell Rep. 18, 352–366 (2017). A strong learning event leads to an exchange of CBP to HAT KAT5 on the Fgf1b promoter to induce persistent expression; these events are mediated by transcriptional activity of the synaptic protein CRTC1.

  194. 194.

    Maze, I., Noh, K.-M. & Allis, C. D. Histone regulation in the CNS: basic principles of epigenetic plasticity. Neuropsychopharmacology 38, 3–22 (2013).

  195. 195.

    Kumar, A. et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303–314 (2005).

  196. 196.

    VanLeeuwen, J.-E. et al. Coordinated nuclear and synaptic shuttling of afadin promotes spine plasticity and histone modifications. J. Biol. Chem. 289, 10831–10842 (2014).

  197. 197.

    Kramár, E. A., Babayan, A. H., Gall, C. M. & Lynch, G. Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton. Neuroscience 239, 3–16 (2013).

  198. 198.

    Rex, C. S. et al. Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J. Neurosci. 27, 3017–3029 (2007).

  199. 199.

    Wiggins, A., Smith, R. J., Shen, H.-W. & Kalivas, P. W. Integrins modulate relapse to cocaine-seeking. J. Neurosci. 31, 16177–16184 (2011).

  200. 200.

    Kramár, E. A., Lin, B., Rex, C. S., Gall, C. M. & Lynch, G. Integrin-driven actin polymerization consolidates long-term potentiation. Proc. Natl Acad. Sci. USA 103, 5579–5584 (2006).

  201. 201.

    Charrier, C. et al. A crosstalk between β1 and β3 integrins controls glycine receptor and gephyrin trafficking at synapses. Nat. Neurosci. 13, 1388–1395 (2010).

  202. 202.

    Mitra, S. K. & Schlaepfer, D. D. Integrin-regulated FAK–Src signaling in normal and cancer cells. Curr. Opin. Cell Biol. 18, 516–523 (2006).

  203. 203.

    Cingolani, L. A. et al. Activity-dependent regulation of synaptic AMPA receptor composition and abundance by β3 integrins. Neuron 58, 749–762 (2008).

  204. 204.

    Rex, C. S. et al. Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J. Cell Biol. 186, 85–97 (2009).

  205. 205.

    Briz, V. et al. Activity-dependent rapid local RhoA synthesis is required for hippocampal synaptic plasticity. J. Neurosci. 35, 2269–2282 (2015).

  206. 206.

    Golden, S. A. et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat. Med. 19, 337–344 (2013).

  207. 207.

    Wolf, M. E. & Tseng, K. Y. Calcium-permeable AMPA receptors in the VTA and nucleus accumbens after cocaine exposure: when, how, and why? Front. Mol. Neurosci. 5, 72 (2012).

  208. 208.

    Ju, W. et al. Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors. Nat. Neurosci. 7, 244–253 (2004).

  209. 209.

    Nicoll, R. A. & Roche, K. W. Long-term potentiation: peeling the onion. Neuropharmacology 74, 18–22 (2013).

  210. 210.

    Huganir, R. L. & Nicoll, R. A. AMPARs and synaptic plasticity: the last 25 years. Neuron 80, 704–717 (2013).

  211. 211.

    Lin, J. W. et al. Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization. Nat. Neurosci. 3, 1282–1290 (2000).

  212. 212.

    Rodenas-Ruano, A., Chávez, A. E., Cossio, M. J., Castillo, P. E. & Zukin, R. S. REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat. Neurosci. 15, 1382–1390 (2012).

  213. 213.

    Singh-Taylor, A. et al. NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience. Mol. Psychiatry 23, 648–657 (2018).

  214. 214.

    Wei, J. et al. Histone modification of Nedd4 ubiquitin ligase controls the loss of AMPA receptors and cognitive impairment induced by repeated stress. J. Neurosci. 36, 2119–2130 (2016).

  215. 215.

    Jayanthi, S. et al. Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms. Biol. Psychiatry 76, 47–56 (2014).

  216. 216.

    Francis, T. C. et al. Molecular basis of dendritic atrophy and activity in stress susceptibility. Mol. Psychiatry 22, 1512–1519 (2017).

  217. 217.

    Krugers, H. J., Hoogenraad, C. C. & Groc, L. Stress hormones and AMPA receptor trafficking in synaptic plasticity and memory. Nat. Rev. Neurosci. 11, 675–681 (2010).

  218. 218.

    Chen, Y. et al. Impairment of synaptic plasticity by the stress mediator CRH involves selective destruction of thin dendritic spines via RhoA signaling. Mol. Psychiatry 18, 485–496 (2013).

  219. 219.

    Andres, A. L. et al. NMDA receptor activation and calpain contribute to disruption of dendritic spines by the stress neuropeptide CRH. J. Neurosci. 33, 16945–16960 (2013).

  220. 220.

    Aoto, J., Martinelli, D. C., Malenka, R. C., Tabuchi, K. & Südhof, T. C. Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking. Cell 154, 75–88 (2013).

  221. 221.

    Luco, R. F., Allo, M., Schor, I. E., Kornblihtt, A. R. & Misteli, T. Epigenetics in alternative pre-mRNA splicing. Cell 144, 16–26 (2011).

  222. 222.

    Hu, Q., Greene, C. & Heller, E. Specific histone modifications associate with alternative exon selection during mammalian development. Preprint at (2018).

  223. 223.

    Ding, X. et al. Activity-induced histone modifications govern neurexin-1 mRNA splicing and memory preservation. Nat. Neurosci. 20, 690–699 (2017). This paper shows that stabilization of memories requires a shift in expression of the Nrxn1 splice isoform within the hippocampus, which occurs through accumulating a repressive histone marker, H3K9me3, at the splicing site.

  224. 224.

    Ripoli, C. Engrampigenetics: Epigenetics of engram memory cells. Behav. Brain Res. 325, 297–302 (2017).

  225. 225.

    Weber, C. M., Ramachandran, S. & Henikoff, S. Nucleosomes are context-specific, H2A.Z-modulated barriers to RNA polymerase. Mol. Cell 53, 819–830 (2014).

  226. 226.

    Dunn, C. J. et al. Histone hypervariants H2A.Z.1 and H2A.Z.2 play independent and context-specific roles in neuronal activity-induced transcription of Arc/Arg3.1 and other immediate early genes. eNeuro 4, ENEURO.0040-17.2017 (2017).

  227. 227.

    Henikoff, S. & Smith, M. M. Histone variants and epigenetics. Cold Spring Harb. Perspect. Biol. 7, a019364 (2015).

  228. 228.

    Dekker, J., Rippe, K., Dekker, M. & Kleckner, N. Capturing chromosome conformation. Science 295, 1306–1311 (2002).

  229. 229.

    Li, Y., Hu, M. & Shen, Y. Gene regulation in the 3D genome. Hum. Mol. Genet. 27, R228–R233 (2018).

  230. 230.

    Quinodoz, S. A. et al. Higher-order inter-chromosomal hubs shape 3D genome organization in the nucleus. Cell 174, 744–757 (2018).

  231. 231.

    Mitchell, A. C. et al. Longitudinal assessment of neuronal 3D genomes in mouse prefrontal cortex. Nat. Commun. 7, 12743 (2016).

  232. 232.

    Engmann, O. et al. Cocaine-induced chromatin modifications associate with increased expression and three-dimensional looping of Auts2. Biol. Psychiatry 82, 794–805 (2017).

  233. 233.

    Wagner, F. F. et al. Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhancers. Chem. Sci. 6, 804–815 (2015).

  234. 234.

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

  235. 235.

    Bowers, M. E., Xia, B., Carreiro, S. & Ressler, K. J. The Class I HDAC inhibitor RGFP963 enhances consolidation of cued fear extinction. Learn. Mem. 22, 225–231 (2015).

  236. 236.

    Rumbaugh, G. et al. Pharmacological selectivity within class I histone deacetylases predicts effects on synaptic function and memory rescue. Neuropsychopharmacology 40, 2307–2316 (2015).

  237. 237.

    Gräff, J. et al. A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration. J. Neurosci. 33, 8951–8960 (2013).

  238. 238.

    Volmar, C.-H. & Wahlestedt, C. Histone deacetylases (HDACs) and brain function. Neuroepigenetics 1, 20–27 (2015).

  239. 239.

    Gräff, J. & Tsai, L.-H. The potential of HDAC inhibitors as cognitive enhancers. Annu. Rev. Pharmacol. Toxicol. 53, 311–330 (2013).

  240. 240.

    Yu, H. et al. Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. Nat. Neurosci. 18, 836–843 (2015).

  241. 241.

    Guzman-Karlsson, M. C., Meadows, J. P., Gavin, C. F., Hablitz, J. J. & Sweatt, J. D. Transcriptional and epigenetic regulation of Hebbian and non-Hebbian plasticity. Neuropharmacology 80, 3–17 (2014).

  242. 242.

    Meadows, J. P. et al. DNA methylation regulates neuronal glutamatergic synaptic scaling. Sci. Signal. 8, ra61 (2015).

  243. 243.

    Blackman, M. P., Djukic, B., Nelson, S. B. & Turrigiano, G. G. A critical and cell-autonomous role for MeCP2 in synaptic scaling up. J. Neurosci. 32, 13529–13536 (2012).

  244. 244.

    Nelson, E. D., Kavalali, E. T. & Monteggia, L. M. MeCP2-dependent transcriptional repression regulates excitatory neurotransmission. Curr. Biol. 16, 710–716 (2006).

  245. 245.

    Qiu, Z. et al. The Rett syndrome protein MeCP2 regulates synaptic scaling. J. Neurosci. 32, 989–994 (2012).

  246. 246.

    Bredy, T. W., Lin, Q., Wei, W., Baker-Andresen, D. & Mattick, J. S. MicroRNA regulation of neural plasticity and memory. Neurobiol. Learn. Mem. 96, 89–94 (2011).

  247. 247.

    Wong, H. H.-W. et al. RNA docking and local translation regulate site-specific axon remodeling in vivo. Neuron 95, 852–868 (2017).

  248. 248.

    Briz, V. et al. The non-coding RNA BC1 regulates experience-dependent structural plasticity and learning. Nat. Commun. 8, 293 (2017).

  249. 249.

    Walters, B. J. et al. The role of the RNA demethylase FTO (fat mass and obesity-associated) and mRNA methylation in hippocampal memory formation. Neuropsychopharmacology 42, 1502–1510 (2017).

  250. 250.

    Bose, D. A. et al. RNA binding to CBP stimulates histone acetylation and transcription. Cell 168, 135–149 (2017).

  251. 251.

    Shu, G. et al. Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b. Learn. Mem. 25, 109–114 (2018).

  252. 252.

    Tang, F. et al. RNA-Seq analysis to capture the transcriptome landscape of a single cell. Nat. Protoc. 5, 516–535 (2010).

  253. 253.

    Konermann, S. et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 517, 583–588 (2015).

  254. 254.

    Heller, E. A. et al. Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Nat. Neurosci. 17, 1720–1727 (2014).

  255. 255.

    Zhou, H. et al. In vivo simultaneous transcriptional activation of multiple genes in the brain using CRISPR-dCas9-activator transgenic mice. Nat. Neurosci. 21, 440–446 (2018).

Download references


This work was supported by the US National Institutes of Health (National Institute on Aging grants AG051807, AG050787 and AG054349; National Institute of Mental Health grant MH101491; and National Institute on Drug Abuse grant DA025922). Initial illustrations were designed by P. Schiffmacher of Schiffmacher Illustration & Design. The authors thank A. López and T. Hemstedt for their intellectual contributions to this Review.

Reviewer information

Nature Reviews Neuroscience thanks S. Bonn and F. Lubin, and the other anonymous reviewer(s), for their contribution to the peer review of this work.

Author information


  1. Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, Center for Addiction Neuroscience, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA

    • Rianne R. Campbell
    •  & Marcelo A. Wood


  1. Search for Rianne R. Campbell in:

  2. Search for Marcelo A. Wood in:


R.R.C. and M.A.W. researched data for the article; contributed substantially to discussion of content; and wrote, reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Marcelo A. Wood.



The collective combination of chemical modifications and proteins that interact with the human genome. The epigenome is dynamically regulated, serves as a signal-integration platform and is unique to each individual.

Histone modification

A post-translational modification — such as acetylation, methylation or phosphorylation — of a histone, a protein that interacts with nuclear DNA and helps to condense genomic DNA into chromatin.

Histone variant exchange

Exchange of variants of the canonical histone proteins (namely, H2A, H2B, H3 and H4). Histone variants include H2AZ and H3.3 and can generate specialized chromatin domains and alter the DNA accessibility and thus gene expression.

Nucleotide modification

Epigenetic modification (mark) of nucleotide bases. For example, DNA methylation involves the attachment of a methyl group to the C5 position of cytosine (5mC). 5-Hydroxymethylcytosine (5hmC) seems to be more abundant in the brain.

Chromatin remodelling

In general, the rearrangement and regulation of chromatin (DNA and associated proteins) by various mechanisms, including modification (for example, histone modification) and nucleosome remodelling.

Epigenetic priming

Stable epigenetic changes (DNA modifications and exchange of transcriptional cofactors and histone variants) produced by exposure to salient stimuli that induce neuronal stimulation; these changes permit efficient transcription of memory-related genes upon re-exposure and reactivation.

Histone acetyltransferase

(HAT). An enzymes that catalyses the transfer of an acetyl group from acetyl-CoA to the ε-amino group of a histone lysine residue on a histone protein.

Rubinstein–Taybi syndrome

A condition characterized by moderate to severe intellectual disability, short stature, distinctive facial features and broad thumbs and first toes. It is often caused by CREBBP (also known as CBP) mutations.

Histone deacetylases

(HDACs). Enzymes that remove acetyl groups from lysine residues on DNA. Acetyl groups help to neutralize the positive charge of histones and/or serve as binding sites for bromodomain-containing proteins.

Long-term facilitation

(LTF). A form of long-term synaptic plasticity observed in Aplysia californica.

Ten-eleven translocation enzymes

(TETs). Enzymes that convert 5-methylcytosine (5mC) DNA marks to 5-hydroxymethylcytosine (5hmC), which is enriched within gene bodies, promoters and transcription-factor-binding regions and may influence gene expression.

Nucleosome-remodelling complexes

(NRCs). Large protein complexes that, through the activity of ATP-dependent enzymes, alter histone–DNA interactions, disassemble or assemble nucleosomes, exchange histone variants or slide or reposition nucleosomes.

Histone code hypothesis

A hypothesis that posits that specific patterns of epigenetic modifications regulate specific gene expression networks for defined cell functions.

Early-phase LTP

(E-LTP). In this context, a form of potentiation that is dependent on covalent protein modifications, yet independent of gene expression. It is transient and short-lived (generally on the order of tens of minutes in slices).

Late-phase LTP

(L-LTP). In this context, a form of potentiation that is dependent on transcription and translation. It is long-lasting (generally on the order of hours in slices and hours to days in vivo).


Weakening of a conditioned response owing to long or repeated trials of memory retrieval in which the conditioned stimulus is removed. Extinction is hypothesized to result from the formation of new memories.


The re-encoding and re-stabilization of a memory after reactivation, during which time the memory is hypothesized to be labile and vulnerable to manipulation.

Remote memories

Here, memories that were encoded a long time previously and that have since become independent of the hippocampus and dependent on cortical regions of the brain (through a process sometimes termed systems consolidation).

Epigenetic hypothesis of age-related cognitive impairments

A hypothesis proposing that the repression of chromatin and alterations in the expression of synapse-related genes lead to cognitive impairment in ageing brains.

Extra-coding RNAs

A form of non-coding, sense-strand RNA that is non-polyadenylated, encoded by a portion of DNA that overlaps the boundaries of another gene.

Enhancer RNAs

A form of non-coding RNA transcribed from active enhancers. They can control mRNA transcription, challenging the idea that enhancers are merely sites of transcription factor assembly.

E3 ubiquitin ligase

A protein that facilitates the interaction of a target (or substrate) protein with an ubiquitin-conjugating E2 enzyme to enable the transfer of ubiquitin to the target protein.


A synaptic vesicle membrane protein that is ubiquitously expressed throughout the brain and has a role in synapse formation.


(Isolation of nuclei tagged in specific cell types). A method to isolate nuclei tagged in specific cell types for further examination for specific proteins or RNAs or high-throughput sequencing.


(Translating ribosome affinity purification). A ribosome-tagging method in which a fusion protein binds ribosomal proteins and immunoprecipitation purification processes isolate biologically relevant mRNA transcripts.

Assay for transposase-accessible chromatin using sequencing

(ATAC-seq). A method for mapping genome-wide chromatin accessibility. A transposase inserts sequencing adaptors into accessible regions of chromatin, before adaptor-ligated DNA fragments are sequenced.

Zinc-finger proteins

(ZFPs). A large family of transcription factors with finger-like DNA-sequence-specific domains. Fusion of a DNA-binding domain specific for an 18–20 bp genomic locus to a chromatin-modifying enzyme enables targeted epigenetic regulation.

About this article

Publication history