p21Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus
- Robert N. Pechnick*,†,
- Svetlana Zonis‡,
- Kolja Wawrowsky‡,
- Jonathan Pourmorady‡, and
- Vera Chesnokova‡,§
- ‡Department of Medicine, Division of Endocrinology, and
- *Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048; and
- †Brain Research Institute, University of California, Los Angeles, CA 90024
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Communicated by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, November 23, 2007 (received for review July 2, 2007)
Abstract
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. p21Cip1 (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.
Footnotes
- §To whom correspondence should be addressed. E-mail: chesnokovav{at}cshs.org
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Author contributions: R.N.P. and S.Z. contributed equally to this work; R.N.P. and V.C. designed research; S.Z., K.W., and J.P. performed research; R.N.P., S.Z., K.W., and V.C. analyzed data; and R.N.P. and V.C. wrote the paper.
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The authors declare no conflict of interest.
- © 2008 by The National Academy of Sciences of the USA
