Upregulation of HDAC9 in hippocampal neurons mediates depression-like behaviours by inhibiting ANXA2 degradation
Open accessAbstract
Major depressive disorder (MDD) is a pervasive and devastating mental disease. Broad spectrum histone deacetylase (HDAC) inhibitors are considered to have potential for the treatment of depressive phenotype in mice. However, due to its non-specific inhibition, it has extensive side effects and can not be used in clinical treatment of MDD. Therefore, finding specific HDAC subtypes that play a major role in the etiology of MDD is the key to develop corresponding specific inhibitors as antidepressants in the future. Copy number variation in HDAC9 gene is thought to be associated with the etiology of some psychiatric disorders. Herein, we found that HDAC9 was highly expressed in the hippocampus of chronic restraint stress (CRS) mouse model of depression. Upregulation of HDAC9 expression in hippocampal neurons of mice induced depression-like phenotypes, including anhedonia, helplessness, decreased dendritic spine density, and neuronal hypoexcitability. Moreover, knockdown or knockout of HDAC9 in hippocampal neurons alleviated depression-like phenotypes caused by chronic restraint stress (CRS) in WT mice. Importantly, using immunoprecipitation-mass spectrometry (IP-MS), we further found that Annexin A2 (ANXA2) was coupled to and deacetylated by HDAC9. This coupling resulted in the inhibition of ubiquitinated ANXA2 degradation and then mediates depression-like behavior. Overall, we discovered a previously unrecognized role for HDAC9 in hippocampal neurons in the pathogenesis of depression, indicating that inhibition of HDAC9 might be a promising clinical strategy for the treatment of depressive disorders.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HDAC5-mediated H4K12 deacetylation in the hippocampus contributes to stress vulnerability.
“HDAC5-mediated H4K12 deacetylation in the hippocampus contributes to stress vulnerability, indicating its value as a potential therapeutic target in susceptible populations (Dai et al., 2023; Li et al., 2024; Ershadi et al., 2021).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Dai et al., 2023
The Discussion reports that after chronic restraint stress, hippocampal HDAC9 increased while other HDACs did not show significant changes. The paper identifies HDAC9-mediated deacetylation of ANXA2—not HDAC5-mediated H4K12 deacetylation—as its mechanism for depression-like behavior in mice. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredChronic stress is associated with elevated HDAC activity in the hippocampus and prefrontal cortex, resulting in reduced expression of mood-related genes such as BDNF and CREB.
“Chronic stress is associated with elevated HDAC activity in the hippocampus and prefrontal cortex, resulting in reduced expression of mood-related genes such as BDNF and CREB.”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Dai et al., 2023
The Results section, “HDAC9 is upregulated in CRS mice” (page unavailable), reports increased hippocampal HDAC9 expression after chronic restraint stress in mice. It does not establish elevated overall HDAC activity or reduced BDNF and CREB expression; it reports that prefrontal-cortex HDAC9 content remained unchanged. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPharmacological inhibition of HDACs can reverse stress-induced molecular effects and produces antidepressant-like behavioral outcomes in animal models.
“Pharmacological inhibition of HDACs can reverse these molecular effects and produces antidepressant-like behavioral outcomes in animal models (Dai et al., 2023).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Dai et al., 2023
The Introduction reports that sodium butyrate, an HDAC inhibitor, has therapeutic effects in a mouse model of depression; the Discussion describes reduced immobility after its administration. The Results report that genetic HDAC9 knockout or ANXA2 knockdown prevents stress-related neuronal changes, but do not show that pharmacological HDAC inhibition reverses those molecular effects. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 53 · Cited by 22
- Authors
- Dai, Y., Wei, T., Huang, Y., Bei, Y., Lin, H., Shen, Z., Yu, L., Yang, M., Xu, H., He, W., Lin, Z., & Dai, H.
- Affiliations
- Second Affiliated Hospital of Zhejiang University (CN)
- Corresponding author
- Dai, Haibin
- Venue
- Cellular and Molecular Life Sciences
- Published
- 2023-09-10
- Volume
- 80
- Issue
- 10
- Pages
- 289-289
- ISSN
- 1420-682X (ISSN-L)
- 1420-9071
- PMC
- PMC10493204
- OpenAlex
- W4386583387
- Cited by
- 22
- References
- 53
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 12
- FWCI
- 4.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cellular and Molecular Life Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (82271391, 81573402, 82173789, 81773700)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- HDAC9, depression, hippocampal neurons, annexin A2, protein deacetylation, ubiquitination, protein degradation, chronic restraint stress, anhedonia, helplessness, dendritic spine density, histone deacetylase inhibitors, antidepressant targets
- MeSH terms
- Animals, Depression, Major Depressive Disorder, Hippocampus, Histone Deacetylases, Repressor Proteins, Up-Regulation, Annexin A2, Mice, Histone Deacetylase Inhibitors, DNA Copy Number Variations
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
