An Essential Role for Histone Deacetylase 4 in Synaptic Plasticity and Memory Formation
Open accessAbstract
Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological HDAC inhibitors, primarily those targeted to class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.
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Brain-specific HDAC4 knockout mice have memory and long-term potentiation deficits.
“In addition, brain-specific HDAC4 knockout mice have memory and LTP deficits.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [61]
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Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,949 · see citing works
Epigenetic programming by maternal behavior
Weaver, I. C. G., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., Dymov, S., Szyf, M., & Meaney, M. J. (2004) · Nature Neuroscience · doi:10.1038/nn1276 · Cited by 6,177 · see citing works
Morris water maze: procedures for assessing spatial and related forms of learning and memory
Vorhees, C. V., & Williams, M. T. (2006) · Nature Protocols · doi:10.1038/nprot.2006.116 · Cited by 4,629 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.
Phillips, R. G., & LeDoux, J. E. (1992) · Behavioral Neuroscience · doi:10.1037/0735-7044.106.2.274 · Cited by 3,292 · see citing works
Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.
Phillips, R. G., & LeDoux, J. E. (1992) · Behavioral Neuroscience · doi:10.1037//0735-7044.106.2.274 · Cited by 3,262 · see citing works
Haberland, M., Montgomery, R. L., & Olson, E. N. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2485 · Cited by 2,541 · see citing works
Self-citationHDAC2 negatively regulates memory formation and synaptic plasticity
Guan, J.-S., Haggarty, S. J., Giacometti, E., Dannenberg, J.-H., Joseph, N., Gao, J., Nieland, T. J. F., Zhou, Y., Wang, X., Mazitschek, R., et al. (2009) · Nature · doi:10.1038/nature07925 · Cited by 1,644 · see citing works
Recovery of learning and memory is associated with chromatin remodelling
Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., & Tsai, L.-H. (2007) · Nature · doi:10.1038/nature05772 · Cited by 1,227 · see citing works
Regulation of histone acetylation during memory formation in the hippocampus
Levenson, J. M., O'Riordan, K. J., Brown, K. D., Trinh, M. A., Molfese, D. L., & Sweatt, J. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402229200 · Cited by 1,131 · see citing works
Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation
McKinsey, T. A., Zhang, C., Lu, J., & Olson, E. N. (2000) · Nature · doi:10.1038/35040593 · Cited by 1,051 · see citing works
Self-citationChromatin Acetylation, Memory, and LTP Are Impaired in CBP+/− Mice
Alarcón, J. M., Malleret, G., Touzani, K., Vronskaya, S., Ishii, S., Kandel, E. R., & Barco, A. (2004) · Neuron · doi:10.1016/j.neuron.2004.05.021 · Cited by 892 · see citing works
Vecsey, C. G., Hawk, J. D., Lattal, K. M., Stein, J. M., Fabian, S., Attner, M. A., Cabrera, S. M., McDonough, C. B., Brindle, P. K., Abel, T. G., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0296-07.2007 · Cited by 828 · see citing works
CBP Histone Acetyltransferase Activity Is a Critical Component of Memory Consolidation
Korzus, E., Rosenfeld, M. G., & Mayford, M. (2004) · Neuron · doi:10.1016/j.neuron.2004.06.002 · Cited by 823 · see citing works
Histone Deacetylase 4 Controls Chondrocyte Hypertrophy during Skeletogenesis
Vega, R. B., Matsuda, K., Oh, J., Barbosa, A. C. C., Yang, X., Meadows, E., McAnally, J., Pomajzl, C., Shelton, J. M., Richardson, J. A., et al. (2004) · Cell · doi:10.1016/j.cell.2004.10.024 · Cited by 805 · see citing works
Self-citationWeaver, I. C. G., Meaney, M. J., & Szyf, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507526103 · Cited by 771 · see citing works
Chromatin Remodeling Is a Key Mechanism Underlying Cocaine-Induced Plasticity in Striatum
Kumar, A., Choi, K.-H., Renthal, W., Tsankova, N. M., Theobald, D. E. H., Truong, H.-T., Russo, S. J., LaPlant, Q., Sasaki, T. S., Whistler, K. N., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.09.023 · Cited by 764 · see citing works
Kilgore, M., Miller, C. A., Fass, D. M., Hennig, K. M., Haggarty, S. J., Sweatt, J. D., & Rumbaugh, G. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.197 · Cited by 727 · see citing works
Essential role of brain-derived neurotrophic factor in adult hippocampal function
Monteggia, L. M., Barrot, M., Powell, C. M., Berton, O., Galanis, V., Gemelli, T., Meuth, S., Nagy, A., Greene, R. W., & Nestler, E. J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402141101 · Cited by 685 · see citing works
Self-citationChang, S., McKinsey, T. A., Zhang, C. L., Richardson, J. A., Hill, J. A., & Olson, E. N. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.19.8467-8476.2004 · Cited by 612 · see citing works
Self-citationHistone Deacetylase 5 Epigenetically Controls Behavioral Adaptations to Chronic Emotional Stimuli
Renthal, W., Maze, I., Krishnan, V., Covington, H. E., Xiao, G., Kumar, A., Russo, S. J., Graham, A., Tsankova, N., Kippin, T. E., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.09.032 · Cited by 599 · see citing works
Self-citationHDAC4 deacetylase associates with and represses the MEF2 transcription factor
Miska, E. A., Karlsson, C., Langley, E., Nielsen, S. J., Pines, J., & Kouzarides, T. (1999) · The EMBO Journal · doi:10.1093/emboj/18.18.5099 · Cited by 551 · see citing works
Lu, J., McKinsey, T. A., Zhang, C., & Olson, E. N. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00025-3 · Cited by 547 · see citing works
Self-citationDecoding the Epigenetic Language of Neuronal Plasticity
Borrelli, E., Nestler, E. J., Allis, C. D., & Sassone‐Corsi, P. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.012 · Cited by 529 · see citing works
Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders
Abel, T. G., & Zukin, R. S. (2008) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2007.12.002 · Cited by 495 · see citing works
Dittgen, T., Nimmerjahn, A., Komai, S., Licznerski, P., Waters, J., Margrie, T. W., Helmchen, F., Denk, W., Brecht, M., & Osten, P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407976101 · Cited by 485 · see citing works
MEF2C Transcription Factor Controls Chondrocyte Hypertrophy and Bone Development
Arnold, M., Kim, Y., Czubryt, M. P., Phan, D., McAnally, J., Qi, X., Shelton, J. M., Richardson, J. A., Bassel‐Duby, R., & Olson, E. N. (2007) · Developmental Cell · doi:10.1016/j.devcel.2007.02.004 · Cited by 456 · see citing works
Self-citationBehavioral phenotyping strategies for mutant mice
Crawley, J. N. (2008) · Neuron · doi:10.1016/j.neuron.2008.03.001 · Cited by 439 · see citing works
Histone deacetylase degradation andMEF2 activation promote the formation of slow-twitch myofibers
Potthoff, M. J., Wu, H., Arnold, M., Shelton, J. M., Backs, J., McAnally, J., Richardson, J. A., Bassel‐Duby, R., & Olson, E. N. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31960 · Cited by 416 · see citing works
Self-citationDistribution of histone deacetylases 1–11 in the rat brain
Broide, R. S., Redwine, J. M., Aftahi, N., Young, W. G., Bloom, F. E., & Winrow, C. J. (2007) · Journal of Molecular Neuroscience · doi:10.1007/bf02686117 · Cited by 347 · see citing works
Barbosa, A. C., Kim, M.-S., Ertunc, M., Adachi, M., Nelson, E. D., McAnally, J., Richardson, J. A., Kavalali, E. T., Monteggia, L. M., Bassel-Duby, R., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802679105 · Cited by 303 · see citing works
Self-citationWilliams, S. R., Aldred, M. A., Der Kaloustian, V. M., Halal, F., Gowans, G., McLeod, D. R., Zondag, S., Toriello, H. V., Magenis, R. E., & Elsea, S. H. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.07.011 · Cited by 302 · see citing works
Deranged neuronal calcium signaling and Huntington disease
Борисович, Б. И., & Hayden, M. R. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.08.035 · Cited by 256 · see citing works
Gemelli, T., Berton, O., Nelson, E. D., Perrotti, L. I., Jaenisch, R., & Monteggia, L. M. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.07.025 · Cited by 237 · see citing works
Self-citationMeCP2-Dependent Transcriptional Repression Regulates Excitatory Neurotransmission
Nelson, E. D., Kavalali, E. T., & Monteggia, L. M. (2006) · Current Biology · doi:10.1016/j.cub.2006.02.062 · Cited by 218 · see citing works
Self-citationEpigenetics in the Nervous System: Figure 1.
Jiang, Y., Langley, B. C., Lubin, F. D., Renthal, W. R., Wood, M. A., Yasui, D. H., Kumar, A., Nestler, E. J., Akbarian, S., & Beckel-Mitchener, A. C. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3797-08.2008 · Cited by 214 · see citing works
Targeted gene mutation approaches to the study of anxiety-like behavior in mice
Holmes, A. (2001) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(01)00012-4 · Cited by 198 · see citing works
HDAC4 Regulates Neuronal Survival in Normal and Diseased Retinas
Chen, B., & Cepko, C. L. (2009) · Science · doi:10.1126/science.1166226 · Cited by 192 · see citing works
Backs, J., Backs, T., Bezprozvannaya, S., McKinsey, T. A., & Olson, E. N. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01611-07 · Cited by 179 · see citing works
Self-citationTrkB Has a Cell-Autonomous Role in the Establishment of Hippocampal Schaffer Collateral Synapses
Luikart, B. W., Nef, S., Virmani, T., Lush, M. E., Liu, Y., Kavalali, E. T., & Parada, L. F. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0041-05.2005 · Cited by 166 · see citing works
Self-citationAkhtar, M. W., Raingo, J., Nelson, E. D., Montgomery, R. L., Olson, E. N., Kavalali, E. T., & Monteggia, L. M. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0097-09.2009 · Cited by 151 · see citing works
Self-citationAdachi, M., Autry, A. E., Covington, H. E., & Monteggia, L. M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4225-08.2009 · Cited by 135 · see citing works
Self-citationDifferential localization of HDAC4 orchestrates muscle differentiation
Miska, E. A. (2001) · Nucleic Acids Research · doi:10.1093/nar/29.16.3439 · Cited by 130 · see citing works
Activity-dependent regulation of synaptic clustering in a hippocampal culture system
Kavalali, E. T., Klingauf, J., & Tsien, R. W. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.22.12893 · Cited by 128 · see citing works
Self-citationMicrosomal triglyceride transfer protein expression during mouse development
Shelton, J. M., Lee, M., Richardson, J. A., & Patel, S. B. (2000) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32400-7 · Cited by 117 · see citing works
Rajan, I., Savelieva, K. V., Ye, G.-L., Ching-yun, W., Malbari, M. M., Friddle, C. J., Lanthorn, T. H., & Zhang, W. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006612 · Cited by 45 · see citing works
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- Authors
- Kim, M.-S., Akhtar, M. W., Adachi, M., Mahgoub, M., Bassel-Duby, R., Kavalali, E. T., Olson, E. N., & Monteggia, L. M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-08-08
- Volume
- 32
- Issue
- 32
- Pages
- 10879-10886
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3480333
- OpenAlex
- W2090611194
- Cited by
- 235
- References
- 47
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 9 · 2023: 14 · 2022: 16 · 2021: 17 · 2020: 10 · 2019: 17 · 2018: 18 · 2017: 15 · 2016: 26 · 2015: 16 · 2014: 35 · 2013: 22 · 2012: 2
- FWCI
- 9.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Welch Foundation
- National Institutes of Health (MH081060)
- National Heart, Lung, and Blood Institute (R01HL093039)
- National Institute of Mental Health (R01MH081060, R56MH081060, MH081060, R01MH066198, MH-066198)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- HDAC4, HDAC5, class II HDACs, synaptic plasticity, learning and memory, hippocampal-dependent memory, long-term potentiation, epigenetic regulation, histone deacetylase inhibitors, gene knockout
- MeSH terms
- Animals, Cells, Cultured, Conditioning, Psychological, Electric Stimulation, Fear, Histone Deacetylases, Humans, Learning Disabilities, Memory, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Picrotoxin, Synapses, Tetrodotoxin, Transfection, Long-Term Potentiation, Patch-Clamp Techniques, GABA Antagonists, Maze Learning, Excitatory Postsynaptic Potentials, Intramolecular Transferases, Sodium Channel Blockers, Arabidopsis Proteins, Rotarod Performance Test, Green Fluorescent Proteins, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2, CA1 Region, Hippocampal, In Vitro Techniques
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