Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior
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Significance: The molecular pathophysiology associated with depression remains largely unknown. Recent evidence suggests that signaling pathways downstream of mechanistic target of rapamycin complex 1, such as p70 S6 kinase 1 (S6K1), can lead to structural changes in the medial prefrontal cortex (mPFC) of rats, which are associated with antidepressant responses. We used a viral-mediated approach to control S6K1 activity in the mPFC. Enhanced S6K1 activity produced antidepressant-like effects and resilience to chronic stress, whereas decreased S6K1 activity produced prodepressive behavior. Together, these studies demonstrate that aberrant activity of protein synthesis pathways may underlie the pathology of depression, and demonstrate that direct modulation of this pathway can control depressive behavior in a bidirectional manner. Further understanding of these signaling pathways may contribute to improved treatments for major depressive disorder.
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mTORC1 signaling is necessary and may be sufficient to produce rapid synaptic and antidepressant behavioral responses.
“These studies indicate that mTORC1 signaling is necessary and may be sufficient to produce rapid synaptic and antidepressant behavioral responses.”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [13]
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- Authors
- Dwyer, J. M., Maldonado-Avilés, J. G., Lepack, A. E., DiLeone, R. J., & Duman, R. S.
- Affiliations
- Yale University (US)
- Laboratory of Molecular Psychiatry, Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT 06508
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-04-27
- Volume
- 112
- Issue
- 19
- Pages
- 6188-6193
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4434715
- OpenAlex
- W1965008000
- Cited by
- 76
- References
- 24
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 12 · 2018: 7 · 2017: 11 · 2016: 6 · 2015: 5
- FWCI
- 6.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (MH093897, MH102004)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- mTORC1, major depressive disorder, medial prefrontal cortex, antidepressant effects, anhedonia, chronic stress, stress resilience, forced swim test, synaptic protein synthesis, translational regulation, neuronal complexity
- MeSH terms
- Animals, Antidepressive Agents, Behavior, Animal, Major Depressive Disorder, Disease Models, Animal, Ketamine, Male, Neurons, Phenotype, Phosphorylation, Swimming, Signal Transduction, Gene Expression Regulation, Enzymologic, Rats, Sprague-Dawley, Prefrontal Cortex, Maze Learning, Ribosomal Protein S6 Kinases, Sirolimus, Rats
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