5-HT1A receptors on mature dentate gyrus granule cells are critical for the antidepressant response
Open accessAbstract
Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, but the mechanisms by which they influence behavior are only partially resolved. Adult hippocampal neurogenesis is necessary for some of the responses to SSRIs, but it is not known whether mature dentate gyrus granule cells (DG GCs) also contribute. We deleted the serotonin 1A receptor (5HT1AR, a receptor required for the SSRI response) specifically from DG GCs and found that the effects of the SSRI fluoxetine on behavior and the hypothalamic-pituitary-adrenal (HPA) axis were abolished. By contrast, mice lacking 5HT1ARs only in young adult-born GCs (abGCs) showed normal fluoxetine responses. Notably, 5HT1AR-deficient mice engineered to express functional 5HT1ARs only in DG GCs responded to fluoxetine, indicating that 5HT1ARs in DG GCs are sufficient to mediate an antidepressant response. Taken together, these data indicate that both mature DG GCs and young abGCs must be engaged for an antidepressant response.
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SSRIs can impact the 5-HT signaling pathway, activating 5-HT1A.
“Second, SSRIs can impact the 5-HT signaling pathway, activating 5-HT 1A. 358 , 359”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [358]
In mice, knocking out the 5-HT1A receptor on dentate gyrus granule cells reduces fluoxetine-induced BDNF expression and blocks proliferation of new hippocampal neurons.
“For example, knocking out the 5-HT1A receptor on granule cells in the dentate gyrus decreases fluoxetine-induced expression of BDNF and blocks proliferation of new hippocampal neurons in mice [97].”
From Beyond the serotonin deficit hypothesis: Communicating a neuroplasticity framework of major depressive disorder (2024) · cites this paper as [97]
Activation of multiple serotonin receptor types enhances neuroplasticity through downstream mechanisms such as increased growth factor expression.
“The first major role of typical antidepressants is supported by rodent studies suggesting that activation of multiple types of serotonin receptors results in downstream effects that enhance neuroplasticity through many of the mechanisms previously discussed, such as increased expression of growth factors.”
From Beyond the serotonin deficit hypothesis: Communicating a neuroplasticity framework of major depressive disorder (2024) · cites this paper as [97]
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References 58 · Cited by 200
Research works printed but not linked: 1
- [53]Samuels BA Hen R Novelty-Suppressed Feeding in the Mouse Mood and Anxiety Related Phenotypes in Mice: Characterization Using Behavioral Tests II Gould TD 107 121 Humana Press Totowa, NJ, USA 2011
- Authors
- Samuels, B. A., Anacker, C., Hu, A., Levinstein, M. R., Pickenhagen, A., Tsetsenis, T., Madroñal, N., Donaldson, Z. R., Drew, L. J., Dranovsky, A., Gross, C. T., Tanaka, K. F., & Hen, R.
- Affiliations
- Columbia University Irving Medical Center (US)
- European Molecular Biology Laboratory (IT)
- Keio University (JP)
- Corresponding author
- Hen, René
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2015-09-21
- Volume
- 18
- Issue
- 11
- Pages
- 1606-1616
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4624493
- OpenAlex
- W1821567097
- Cited by
- 200
- References
- 58
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 25 · 2023: 12 · 2022: 15 · 2021: 25 · 2020: 20 · 2019: 25 · 2018: 16 · 2017: 22 · 2016: 10 · 2015: 3
- FWCI
- 12.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (15H03123)
- National Institute of Mental Health (R37MH068542, R01MH091844, R01MH083862, K08MH001844, K01MH098188, R01MH01844, T32MH015144, R01MH068542)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- 5-HT1A receptor, dentate gyrus granule cells, antidepressant response, fluoxetine, selective serotonin reuptake inhibitors, adult hippocampal neurogenesis, hypothalamic-pituitary-adrenal axis, mature neurons
- MeSH terms
- Animals, Cytoplasmic Granules, Fluoxetine, Mice, Transgenic, Neurons, Antidepressive Agents, Second-Generation, Dentate Gyrus, Receptor, Serotonin, 5-HT1A, Neurogenesis
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