p21 Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus
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The subgranular zone (SGZ) of the dentate gyrus of the hippocampus is a brain region where robust neurogenesis continues throughout adulthood. Cyclin-dependent kinases (CDKs) have a primary role in controlling cell division and cellular proliferation. p21 Cip1 (p21) is a CDK inhibitor that restrains cell cycle progression. Confocal microscopy revealed that p21 is abundantly expressed in the nuclei of cells in the SGZ and is colocalized with NeuN, a marker for neurons. Doublecortin (DCX) is a cytoskeletal protein that is primarily expressed by neuroblasts. By using FACS analysis it was found that, among DCX-positive cells, 42.8% stained for p21, indicating that p21 is expressed in neuroblasts and in newly developing neurons. p21-null ( p21 −/− ) mice were examined, and the rate of cellular proliferation, as measured by BrdU incorporation, was increased in the SGZ of p21 −/− compared with WT mice. In addition, the levels of both DCX and NeuN protein were increased in p21 −/− mice, further demonstrating increased hippocampal neuron proliferation. Chronic treatment with the tricyclic antidepressant imipramine (10 mg/kg per day i.p. for 21 days) markedly decreased hippocampal p21 mRNA and protein levels, produced antidepressant-like behavioral changes in the forced swim test, and stimulated neurogenesis in the hippocampus. These results suggest that p21 restrains neurogenesis in the SGZ and imipramine-induced stimulation of neurogenesis might be a consequence of decreased p21 expression and the subsequent release of neuronal progenitor cells from the blockade of proliferation. Because many antidepressants stimulate neurogenesis, it is possible that their shared common mechanism of action is suppression of p21.
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The genes chosen for expression analysis have all recently been implicated in antidepressant drug action and neurogenesis.
“These genes were chosen because they have all recently been implicated in antidepressant drug action and neurogenesis.35, 36, 37, 38, 39, 12, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [36]
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- Authors
- Pechnick, R. N., Zonis, S., Wawrowsky, K., Pourmorady, J., & Chesnokova, V.
- Affiliations
- Cedars-Sinai Medical Center (US)
- Department of Medicine, Division of Endocrinology, and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-01-29
- Volume
- 105
- Issue
- 4
- Pages
- 1358-1363
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2234143
- OpenAlex
- W2050238055
- Cited by
- 103
- References
- 60
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 7 · 2019: 5 · 2018: 7 · 2017: 9 · 2016: 6 · 2015: 9 · 2014: 7 · 2013: 10 · 2012: 3
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R21MH079988, MH 079988)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- p21 Cip1, subgranular zone, dentate gyrus, adult neurogenesis, neuronal proliferation, cyclin-dependent kinase inhibitors, neuroblasts, doublecortin, imipramine, antidepressant mechanism, forced swim test, hippocampus, cell cycle regulation
- MeSH terms
- Doublecortin Protein, Animals, Female, Growth Inhibitors, Male, Mice, Transgenic, Neural Inhibition, Neurons, Mice, Knockout, Gene Expression Regulation, Developmental, Dentate Gyrus, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Mice
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