Cited by 49Memory and Neural MechanismsHistone Deacetylase Inhibitors ResearchNeuroscience and Neuropharmacology Research

The HDAC inhibitor CI-994 acts as a molecular memory aid by facilitating synaptic and intracellular communication after learning

Open access
Burns, Allison M., Farinelli-Scharly, Mélissa, Hugues-Ascery, Sandrine, Sanchez-Mut, Jose Vicente, Santoni, Giulia, Gräff, Johannes·2022·Proceedings of the National Academy of Sciences

Published version of a preprint

Abstract

Significance: Memory formation relies on a plethora of functions, including epigenetic modifications. Over recent years, multiple studies have indicated the potential of HDAC inhibitors (HDACis) as cognitive enhancers, but their mode of action is not fully understood. Here, we tested whether HDACi treatment improves memory formation via “cognitive epigenetic priming,” stipulating that HDACis—without inherent target specificity—specifically enhance naturally occurring plasticity processes. We found that combining HDACis with fear learning, but not either treatment alone, enhances synaptic plasticity as well as memory-promoting transcriptional signaling in the hippocampus, a brain area recruited by fear learning, but not in unrelated areas. These results lend experimental support to the theory of cognitive epigenetic priming.

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Integrity signals

Registry

Crossref · 10.1073/pnas.2116797119

Cites

112 of 112 references verified0 citation errors · 0 not checkable

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  • CI-994 is a cognitive enhancer / improves cognitive function.

    “CI-994 can cross the blood–brain barrier and is a cognitive enhancer.”

    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 [24]

    The Results section reports that CI-994 improved memory retention in mice when paired with contextual fear conditioning, supporting its description as a cognitive enhancer in that setting. The Discussion reports brain-region-specific effects after systemic administration, but our copy does not directly establish that CI-994 crosses the blood–brain barrier or that it improves cognitive function more generally. (LLM, conf=0.82)

    Experimental — accuracy not yet measured
  • CI-994 acts as a memory enhancer in mouse models of neurodegenerative disorders.

    “CI-994 acts as a memory enhancer and alleviates cognitive deficits in mouse models of neurodegenerative disorders [9, 17, 21–24].”

    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 [24]

    The Results report that CI-994 improved memory retention after contextual fear conditioning, supporting its description as a memory enhancer. But Materials and Methods (Animals) says all experiments used twelve-week-old male C57BL/6J mice; this paper does not show the effect in mouse models of neurodegenerative disorders. No page numbers are available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • CI-994 alleviates cognitive deficits in mouse models of neurodegenerative disorders.

    “CI-994 acts as a memory enhancer and alleviates cognitive deficits in mouse models of neurodegenerative disorders [9, 17, 21–24].”

    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 [24]

    The Results section says CI-994 has shown promise against cognitive dysfunction in preclinical animal models. It does not specify that those models had neurodegenerative disorders or establish that CI-994 alleviated their deficits; this study tested memory enhancement in mice undergoing fear conditioning. (LLM, conf=0.86)

    Experimental — accuracy not yet measured
  • CI-994 is a molecular memory aid and promotes memory formation and cognitive function in vivo.

    “CI-994 is a molecular memory aid and promotes memory formation and cognitive function in vivo [9, 17, 21–24].”

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Cites

1 retracted

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Research works printed but not linked: 1

  1. [92]A. M. Burns, J. Gräff, GEO database release for Burns et al., PNAS (2022). https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE185455. Deposited 6 October 2021.

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Authors
Burns, A. M., Farinelli-Scharly, M., Hugues-Ascery, S., Sanchez-Mut, J. V., Santoni, G., & Gräff, J.
Affiliations
  • École Polytechnique Fédérale de Lausanne (CH)
  • E-Phy-Science (France) (FR)
  • Electrophysiology Platform, E-PHY-SCIENCE, 06410 Biot, France
Corresponding author
Gräff, Johannes
Venue
Proceedings of the National Academy of Sciences
Published
2022-05-25
Volume
119
Issue
22
Pages
e2116797119-e2116797119
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W4281486995
Cited by
49
References
111
Citations by year
2026: 16 · 2025: 14 · 2024: 8 · 2023: 7 · 2022: 3 · 2021: 1
FWCI
4.13
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
Funders
  • National Science Foundation
  • École Polytechnique Fédérale de Lausanne
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (51NF40, 185897, 155898)
  • H2020 European Research Council (678832)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • 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
CI-994, histone deacetylase inhibitors, class I HDACs, long-term memory, contextual fear conditioning, long-term potentiation, hippocampus, dentate gyrus, synaptic plasticity, epigenetic modifications, histone acetylation, enhancers, gene expression, nootropic drugs, striatum
MeSH terms
RNA-Seq, Animals, Benzamides, Cell Communication, Neuronal Plasticity, Neurons, Phenylenediamines, Dentate Gyrus, Mice, Histone Deacetylase Inhibitors, Memory, Long-Term, Single-Cell Analysis

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