The role of histone deacetylase 6 in synaptic plasticity and memory
Open accessAbstract
Histone deacetylases (HDACs) have been extensively studied as drug targets in neurodegenerative diseases, but less is known about their role in healthy neurons. We tested zinc-dependent HDACs using RNAi in Drosophila melanogaster and found memory deficits with RPD3 and HDAC6. We demonstrate that HDAC6 is required in both the larval and adult stages for normal olfactory memory retention. Neuronal expression of HDAC6 rescued memory deficits, and we demonstrate that the N-terminal deacetylase (DAC) domain is required for this ability. This suggests that deacetylation of synaptic targets associated with the first DAC domain, such as the active-zone scaffold Bruchpilot, is required for memory retention. Finally, electrophysiological experiments at the neuromuscular junction reveal that HDAC6 mutants exhibit a partial block of homeostatic plasticity, suggesting that HDAC6 may be required for the stabilization of synaptic strength. The learning deficit we observe in HDAC6 mutants could be a behavioral consequence of these synaptic defects.
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HDAC6 contributes to mitochondrial trafficking and misfolded protein clearance.
“HDAC6 also contributes to mitochondrial trafficking and misfolded protein clearance (Perry et al., 2017; Finnin et al., 1999), highlighting the HDAC6–microtubule–mitochondria axis as an important regulatory node beyond chromatin-dependent mechanisms.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Perry et al., 2017
The Introduction (page not provided) says HDAC6 binds ubiquitin and regulates protein degradation, and describes a role in alpha-synuclein inclusion. This provides some support for a role in handling misfolded proteins, but the paper does not specifically establish misfolded-protein clearance or address mitochondrial trafficking. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe HDAC6-microtubule-mitochondria axis is an important regulatory node beyond chromatin-dependent mechanisms.
“HDAC6 also contributes to mitochondrial trafficking and misfolded protein clearance (Perry et al., 2017; Finnin et al., 1999), highlighting the HDAC6–microtubule–mitochondria axis as an important regulatory node beyond chromatin-dependent mechanisms.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Perry et al., 2017
The Introduction (page unavailable) describes HDAC6 as predominantly cytoplasmic and says it deacetylates tubulin and regulates protein degradation. The Discussion (page unavailable) likewise places its functions beyond chromatin modification. These passages support a non-chromatin role, but the paper does not establish mitochondrial trafficking or an HDAC6–microtubule–mitochondria regulatory axis; protein degradation is also less specific than misfolded-protein clearance. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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Cites
HDAC6 is a microtubule-associated deacetylase
Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., Yoshida, M., Wang, X.-F., & Yao, T.-P. (2002) · Nature · doi:10.1038/417455a · Cited by 2,403 · see citing works
HDAC6 Regulates Hsp90 Acetylation and Chaperone-Dependent Activation of Glucocorticoid Receptor
Kovacs, J. J., Murphy, P. J. M., Gaillard, S., Zhao, X., Wu, J.-T., Nicchitta, C. V., Yoshida, M., Toft, D. O., Pratt, W. B., & Yao, T.-P. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.04.021 · Cited by 1,153 · see citing works
Wagh, D. A., Rasse, T. M., Asan, E., Hofbauer, A., Schwenkert, I., Dürrbeck, H., Buchner, S., Dabauvalle, M.-C., Schmidt, M., Qin, G., et al. (2006) · Neuron · doi:10.1016/j.neuron.2006.02.008 · Cited by 908 · 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
Bruchpilot Promotes Active Zone Assembly, Ca <sup>2+</sup> Channel Clustering, and Vesicle Release
Kittel, R. J., Wichmann, C., Rasse, T. M., Fouquet, W., Schmidt, M., Schmid, A., Wagh, D. A., Pawlu, C., Kellner, R. R., Willig, K. I., et al. (2006) · Science · doi:10.1126/science.1126308 · Cited by 772 · see citing works
HDAC6 Modulates Cell Motility by Altering the Acetylation Level of Cortactin
Zhang, X. M., Yuan, Z., Zhang, Y., Yong, S., Salas-Burgos, A., Koomen, J. M., Olashaw, N., Parsons, J. T., Yang, X., Dent, S., et al. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.05.033 · Cited by 731 · see citing works
A further study of the statistical composition of the end‐plate potential
Martin, A. R. (1955) · The Journal of Physiology · doi:10.1113/jphysiol.1955.sp005397 · Cited by 698 · see citing works
HDAC6: a key regulator of cytoskeleton, cell migration and cell–cell interactions
Valenzuela-Fernández, A., Cabrero, J. R., Serrador, J. M., & Sánchez‐Madrid, F. (2008) · Trends in Cell Biology · doi:10.1016/j.tcb.2008.04.003 · Cited by 500 · see citing works
Petersen, S. A., Fetter, R. D., Noordermeer, J. N., Goodman, C. S., & DiAntonio, A. (1997) · Neuron · doi:10.1016/s0896-6273(00)80415-8 · Cited by 476 · see citing works
HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination
Boyault, C., Sadoul, K., Pabion, M., & Khochbin, S. (2007) · Oncogene · doi:10.1038/sj.onc.1210614 · Cited by 397 · see citing works
Maturation of active zone assembly by Drosophila Bruchpilot
Fouquet, W., Owald, D., Wichmann, C., Mertel, S., Depner, H., Dyba, M., Hallermann, S., Kittel, R. J., Eimer, S., & Sigrist, S. J. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200812150 · Cited by 396 · see citing works
Mechanisms Underlying the Rapid Induction and Sustained Expression of Synaptic Homeostasis
Frank, C. A., Kennedy, M. J., Goold, C. P., Marek, K. W., & Davis, G. W. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.029 · Cited by 384 · see citing works
Inside HDAC with HDAC inhibitors
Bertrand, P. (2010) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2010.02.030 · Cited by 363 · see citing works
A genome-wide resource for the analysis of protein localisation in Drosophila
Sarov, M., Barz, C., Jambor, H. K., Hein, M. Y., Schmied, C., Suchold, D., Stender, B., Janosch, S., Vinay Vikas, K. J., Krishnan, R., et al. (2016) · eLife · doi:10.7554/elife.12068 · Cited by 361 · see citing works
Targeting the correct HDAC(s) to treat cognitive disorders
Fischer, A., Sananbenesi, F., Mungenast, A. E., & Tsai, L. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.09.003 · Cited by 355 · see citing works
Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease
Govindarajan, N., Rao, P., Burkhardt, S., Sananbenesi, F., Schlüter, O. M., Bradke, F., Lu, J., & Fischer, A. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201201923 · Cited by 346 · see citing works
Deconstructing Memory in Drosophila
Margulies, C. E., Tully, T., & Dubnau, J. (2005) · Current Biology · doi:10.1016/j.cub.2005.08.024 · Cited by 336 · see citing works
DiAntonio, A., Petersen, S. A., Heckmann, M., & Goodman, C. S. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-08-03023.1999 · Cited by 300 · see citing works
Krashes, M. J., & Waddell, S. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5333-07.2008 · Cited by 292 · see citing works
Homeostatic Control of Presynaptic Neurotransmitter Release
Davis, G. W., & Müller, M. (2015) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021014-071740 · Cited by 261 · see citing works
The Drosophila Larva as a Model for Studying Chemosensation and Chemosensory Learning: A Review
Gerber, B., & Stocker, R. F. (2006) · Chemical Senses · doi:10.1093/chemse/bjl030 · Cited by 252 · see citing works
Thirty years of olfactory learning and memory research in Drosophila melanogaster
McGuire, S. E., Deshazer, M., & Davis, R. L. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.09.003 · Cited by 220 · see citing works
The Schizophrenia Susceptibility Gene dysbindin Controls Synaptic Homeostasis
Dickman, D. K., & Davis, G. W. (2009) · Science · doi:10.1126/science.1179685 · Cited by 206 · see citing works
Self-citationDavis, G. W., DiAntonio, A., Petersen, S. A., & Goodman, C. S. (1998) · Neuron · doi:10.1016/s0896-6273(00)80458-4 · Cited by 205 · see citing works
Olfactory Learning in Individually Assayed Drosophila LarvaePreprint
Scherer, S., Stocker, R. F., & Gerber, B. (2003) · Learning & Memory · doi:10.1101/lm.57903 · Cited by 174 · see citing works
Rapid Active Zone Remodeling during Synaptic Plasticity
Rings, A., Hallermann, S., Wagner, N., & Eilers, J. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.6698-10.2011 · Cited by 173 · see citing works
Liu, Y., Peng, L., Seto, E., Huang, S., & Qiu, Y. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.371120 · Cited by 144 · see citing works
Drosophila Dorsal Paired Medial Neurons Provide a General Mechanism for Memory Consolidation
Keene, A. C., Krashes, M. J., Leung, B., Bernard, J. A., & Waddell, S. (2006) · Current Biology · doi:10.1016/j.cub.2006.06.022 · Cited by 137 · see citing works
Radish, a Drosophila mutant deficient in consolidated memory.
Folkers, E., Drain, P. F., & Quinn, W. G. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8123 · Cited by 137 · see citing works
Wagner, F. F., Olson, D. E., Gale, J. P., Kaya, T., Weïwer, M., Aidoud, N., Thomas, M., Davoine, E. L., Lemercier, B. C., Zhang, Y., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm301355j · Cited by 121 · see citing works
Du, G., Liu, X., Chen, X., Song, M. L., Yan, Y., Jiao, R., & Wang, C.-C. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-03-0200 · Cited by 114 · see citing works
ELP3 Controls Active Zone Morphology by Acetylating the ELKS Family Member Bruchpilot
Miśkiewicz, K., Jose, L. E., Bento‐Abreu, A., Fislage, M., Taes, I., Kasprowicz, J., Swerts, J., Sigrist, S. J., Versées, W., Robberecht, W., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.10.010 · Cited by 105 · see citing works
Pauls, D., Selcho, M., Gendre, N., Stocker, R. F., & Thum, A. S. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1281-10.2010 · Cited by 103 · see citing works
Naked Dense Bodies Provoke Depression
Hallermann, S., Kittel, R. J., Wichmann, C., Rings, A., Fouquet, W., Mertel, S., Owald, D., Eimer, S., Depner, H., Schwärzel, M., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2495-10.2010 · Cited by 97 · see citing works
Outcome expectations drive learned behaviour in larval Drosophila
Gerber, B., & Hendel, T. (2006) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2006.3673 · Cited by 93 · see citing works
HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila
Xiong, Y., Zhao, K., Wu, J., Xu, Z., Jin, S., & Zhang, Y. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1207586110 · Cited by 88 · see citing works
The Drosophila miR-310 Cluster Negatively Regulates Synaptic Strength at the Neuromuscular Junction
Tsurudome, K., Tsang, K., Liao, E. H., Ball, R. W., Penney, J., Yang, J.-S., Elazzouzi, F., He, T., Chishti, A. H., Lnenicka, G. A., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.016 · Cited by 87 · see citing works
Epigenetic programming of neurodegenerative diseases by an adverse environment
Babenko, O., Kovalchuk, I., & Metz, G. A. S. (2012) · Brain Research · doi:10.1016/j.brainres.2012.01.038 · Cited by 80 · see citing works
Advances in Epigenetics and Epigenomics for Neurodegenerative Diseases
Qureshi, I., & Mehler, M. F. (2011) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-011-0210-2 · Cited by 79 · see citing works
Fragile X protein controls neural stem cell proliferation in the Drosophila brain
Callan, M. A., Cabernard, C., Heck, J., Luois, S., Doe, C. Q., & Zarnescu, D. C. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq213 · Cited by 77 · see citing works
Sleiman, S. F., Basso, M., Mahishi, L., Kozikowski, A. P., Donohoe, M. E., Langley, B. C., & Ratan, R. R. (2009) · Expert Opinion on Investigational Drugs · doi:10.1517/13543780902810345 · Cited by 75 · see citing works
Individual histone deacetylases in Drosophila modulate transcription of distinct genes
Cho, Y., Griswold, A., Campbell, C., & Min, K.-T. (2005) · Genomics · doi:10.1016/j.ygeno.2005.07.007 · Cited by 71 · see citing works
Hendel, T., Michels, B., Neuser, K., Schipanski, A., Kaun, K. R., Sokolowski, M. B., Marohn, F., Michel, R., Heisenberg, M., & Gerber, B. (2005) · Journal of Comparative Physiology A · doi:10.1007/s00359-004-0574-8 · Cited by 68 · see citing works
Bruchpilot, A Synaptic Active Zone Protein for Anesthesia-Resistant Memory
Knapek, S., Sigrist, S. J., & Tanimoto, H. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2585-10.2011 · Cited by 65 · see citing works
HDAC6 Is a Bruchpilot Deacetylase that Facilitates Neurotransmitter Release
Miśkiewicz, K., Jose, L. E., Yeshaw, W. M., Valadas, J. S., Swerts, J., Munck, S., Feiguin, F. M., Dermaut, B., & Verstreken, P. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.05.051 · Cited by 44 · see citing works
Genetic Modulation of Rpd3 Expression Impairs Long-Term Courtship Memory in Drosophila
Fitzsimons, H. L., & Scott, M. J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0029171 · Cited by 41 · see citing works
Mollinari, C., Lange, B. M. H., & González, C. (2002) · Biology of the Cell · doi:10.1016/s0248-4900(02)01181-4 · Cited by 25 · see citing works
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Kumar, V., Kundu, S., Singh, A., & Singh, S. (2022) · Current Neuropharmacology · doi:10.2174/1570159x19666210609160017 · Cited by 210 · see citing works
Trzeciakiewicz, H., Ajit, D., Tseng, J.-H., Chen, Y., Ajit, A., Tabassum, Z., Lobrovich, R., Peterson, C., Riddick, N. V., Itano, M. S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19317-4 · Cited by 102 · see citing works
Li, Y., Sang, S., Ren, W., Pei, Y., Bian, Y., Chen, Y., & Sun, H. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113874 · Cited by 77 · see citing works
Lv, L.-Z., Wang, Z.-D., Ren, J.-J., Li, L.-H., Liu, X.-B., Li, J.-L., Zhu, H., Jiang, B., Han, Y.-P., Zhou, X.-M., et al. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2025.1722453 · Cited by 7 · see citing works
“HDAC6 also contributes to mitochondrial trafficking and misfolded protein clearance (Perry et al., 2017; Finnin et al., 1999), highlighting the HDAC6–microtubule–mitochondria axis as an important regulatory node beyond chromatin-dependent mechanisms.”
- Authors
- Perry, S., Kiragasi, B., Dickman, D., & Ray, A.
- Affiliations
- University of California, Riverside (US)
- University of Southern California (US)
- Corresponding author
- Ray, Anandasankar
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 18
- Issue
- 6
- Pages
- 1337-1345
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5387061
- OpenAlex
- W2587308118
- Cited by
- 49
- References
- 47
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 6 · 2023: 2 · 2022: 3 · 2021: 9 · 2020: 3 · 2019: 7 · 2018: 1 · 2017: 3
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- NIH (NINDS) (R21NS085765)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- HDAC6, synaptic plasticity, memory, olfactory memory, Bruchpilot, active zone, homeostatic plasticity, neuromuscular junction, Drosophila melanogaster, learning deficits
- MeSH terms
- Histone Deacetylase 6, Animals, Drosophila melanogaster, Learning, Memory, Neuromuscular Junction, Neuronal Plasticity, Neurons, Neurodegenerative Diseases, Drosophila Proteins, Histone Deacetylase 1
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