Pharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory Rescue
Open accessAbstract
Histone deacetylases (HDACs) are promising therapeutic targets for neurological and psychiatric disorders that impact cognitive ability, but the relationship between various HDAC isoforms and cognitive improvement is poorly understood, particularly in mouse models of memory impairment. A goal shared by many is to develop HDAC inhibitors with increased isoform selectivity in order to reduce unwanted side effects, while retaining procognitive effects. However, studies addressing this tack at the molecular, cellular and behavioral level are limited. Therefore, we interrogated the biological effects of class I HDAC inhibitors with varying selectivity and assessed a subset of these compounds for their ability to regulate transcriptional activity, synaptic function and memory. The HDAC-1, -2, and -3 inhibitors, RGFP963 and RGFP968, were most effective at stimulating synaptogenesis, while the selective HDAC3 inhibitor, RGFP966, with known memory enhancing abilities, had minimal impact. Furthermore, RGFP963 increased hippocampal spine density, while HDAC3 inhibition was ineffective. Genome-wide gene expression analysis by RNA sequencing indicated that RGFP963 and RGFP966 induce largely distinct transcriptional profiles in the dorsal hippocampus of mature mice. The results of bioinformatic analyses were consistent with RGFP963 inducing a transcriptional program that enhances synaptic efficacy. Finally, RGFP963, but not RGFP966, rescued memory in a mouse model of Alzheimer's Disease. Together, these studies suggest that the specific memory promoting properties of class I HDAC inhibitors may depend on isoform selectivity and that certain pathological brain states may be more receptive to HDAC inhibitors that improve network function by enhancing synapse efficacy.
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Small molecule inhibitors of class I HDACs can alleviate memory deficits in mouse AD models.
“small molecule inhibitors of class I HDACs can alleviate memory deficits in mouse AD models [9–11].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [11]
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“Notably, a previous study using the same HDAC3-selective inhibitor, RGFP966, also reported no effect on contextual fear memory [61].”
Habits are negatively regulated by HDAC3 in the dorsal striatum
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“Post-training intra-DLS infusion of the selective HDAC3 inhibitor RGFP966 (Bieszczad et al., 2015; Malvaez et al., 2013; Rumbaugh et al., 2015) elevated H4K8Ac in the DLS (Fig.”
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Current Challenges with HDAC Inhibitor-Based Therapeutic Intervention Against Neurological Maladies
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Self-citation
- Authors
- Rumbaugh, G., Daws, S. E., Ozkan, E. D., Rojas, C. S., Hubbs, C. R., Aceti, M., Kilgore, M., Kudugunti, S., Puthanveettil, S. V., Sweatt, J. D., Rusche, J., & Miller, C. A.
- Affiliations
- Scripps Research Institute (US)
- University of Alabama at Birmingham (US)
- Repligen (United States) (US)
- Corresponding author
- Rumbaugh, Gavin
- Miller, Courtney A
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2015-04-03
- Volume
- 40
- Issue
- 10
- Pages
- 2307-2316
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4538358
- OpenAlex
- W1975144326
- Cited by
- 89
- References
- 43
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 4 · 2019: 10 · 2018: 13 · 2017: 10 · 2016: 10 · 2015: 5
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH57014, R01MH104158, R01MH057014, R01MH096847)
- National Institute on Drug Abuse (R01DA034116, R03DA033499)
- National Institute of Neurological Disorders and Stroke (R01NS064079, R21NS082640)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- class I histone deacetylases, histone deacetylase inhibitors, isoform selectivity, RGFP966, HDAC3, HDAC1, HDAC2, synaptogenesis, synaptic function, memory enhancement, Alzheimer's disease, dorsal hippocampus, gene expression profiling, cognitive impairment
- MeSH terms
- Alzheimer Disease, Animals, Animals, Newborn, Cells, Cultured, Conditioning, Psychological, Disease Models, Animal, Fear, Histone Deacetylases, Humans, Hydroxamic Acids, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Neurons, Synapses, Amyloid beta-Protein Precursor, Synaptophysin, Gene Expression Profiling, Green Fluorescent Proteins, Mice, Presenilin-1, Histone Deacetylase Inhibitors
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