Hippocampal HDAC4 Contributes to Postnatal Fluoxetine-Evoked Depression-Like Behavior
Open accessAbstract
Fluoxetine treatment in adulthood evokes antidepressant and anxiolytic responses. Paradoxically, postnatal fluoxetine (PNFlx) induces persistent depression- and anxiety-like behaviors. The mechanistic underpinnings of this paradox remain poorly understood. Here, we examined specific molecular changes in the rat hippocampus that accompany perturbed emotionality observed across life following PNFlx. PNFlx-induced hippocampal gene regulation observed in microarray and quantitative PCR studies indicate functional enrichment of genes involved in response to organic substances, protein kinase pathways, DNA binding, and transcriptional repression. We noted specific transcripts (Hdac4, mammalian target of rapamycin (mTOR), Gnai1, protein kinase C gamma (Prkcc), and hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1)) that were consistently dysregulated across life, and selectively influenced by postnatal, but not adult, fluoxetine. Increased histone deacetylase-4 (HDAC4) recruitment, accompanied by decreased activating histone acetylation marks at the mTOR and Gnai1 promoters, indicate a role for HDAC4 in PNFlx-mediated gene dysregulation. Strikingly, coadministration of the HDAC inhibitor sodium butyrate with PNFlx prevented the dysregulation of Hdac4 and mTOR, and the emergence of depression- and anxiety-like behavior. Importantly, we also find that retreatment of PNFlx animals with fluoxetine in adulthood reversed the increased Hdac4 expression, prevented HDAC4 recruitment to the mTOR and Gnai1 promoters, and attenuated the decline in mTOR and Gnai1 expression, coincident with normalization of PNFlx-evoked depression- and anxiety-like behavior. Further, we show that viral-mediated hippocampal overexpression of Hdac4 was sufficient to induce depression-, but not anxiety-, like behavior in adulthood. Our results highlight the unique nature of molecular signatures evoked by PNFlx, and implicate HDAC4 in the dysregulated gene expression and emergence of perturbed emotionality following fluoxetine exposure in early life.
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Overexpression of HDAC4 in the hippocampus caused adult rats to be depressive but not anxious.
“overexpression of HDAC4 in the hippocampus caused adult rats to be depressive but not anxious.137”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [137]
Virus-mediated overexpression of HDAC4 in the hippocampus induced depression-like behavior but not anxiety-like behavior in adult rats.
“Virus-mediated overexpression of HDAC4 in the hippocampus induced depressionlike behavior but not anxiety-like behavior in adult rats.”
From Epigenetic mechanisms of major depression: Targeting neuronal plasticity (2018) · cites this paper as [85]
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- Authors
- Sarkar, A., Chachra, P., Kennedy, P., Pena, C. J., Desouza, L. A., Nestler, E. J., & Vaidya, V. A.
- Affiliations
- Tata Institute of Fundamental Research (IN)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Vaidya, Vidita A
- Venue
- Neuropsychopharmacology
- Published
- 2014-03-25
- Volume
- 39
- Issue
- 9
- Pages
- 2221-2232
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4104341
- OpenAlex
- W2023316390
- Cited by
- 79
- References
- 52
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 10 · 2023: 2 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 4 · 2018: 5 · 2017: 9 · 2016: 6 · 2015: 6 · 2014: 4
- FWCI
- 6.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tata Institute of Fundamental Research
- University of Queensland
- Indian Institute of Science Education and Research Mohali
- U.S. Public Health Service (NIHDK096139)
- National Institute of Mental Health (P50MH096890, R01MH051399)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIH-DK21397)
- National Institute of Neurological Disorders and Stroke (F31NS084633)
- 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 › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- fluoxetine, depression-like behavior, anxiety-like behavior, hippocampus, HDAC4, histone deacetylase, histone acetylation, mTOR, GNAI1, HCN1, gene expression dysregulation, sodium butyrate, histone deacetylase inhibitors, emotionality
- MeSH terms
- Aging, Animals, Animals, Newborn, Anxiety Disorders, Depressive Disorder, Emotions, Female, Fluoxetine, Hippocampus, Histamine Antagonists, Histone Deacetylases, Male, Gene Expression, Rats, Sprague-Dawley, Antidepressive Agents, Second-Generation, Butyric Acid, Transcriptome
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