Cell cycle regulation, neurogenesis, and depression
- Kathryn A. Cunningham*,†,‡ and
- Cheryl S. Watson†,§
- Departments of *Pharmacology and Toxicology and
- §Biochemistry and Molecular Biology,
- †Center for Addiction Research, University of Texas Medical Branch, Galveston, TX 77555-1031
The mammalian brain was originally thought to birth new neurons only during development. A modern paradigm shift began in the 1960s as experimental evidence of neurogenesis in adult brain and its functional implications began to emerge. Neural stem cells have now been identified to undergo mitosis, proliferate, and differentiate into neurons, astroglia, or oligodendroglia within specialized neurogenic zones that interdigitate especially regions of the corticolimbic brain (e.g., hippocampus, olfactory bulb, amygdala, and cerebral cortices) (1). Multiple chemical and behavioral factors trigger or suppress neurogenic processes, including trophic factors (e.g., growth factors), neurotransmitters [e.g., serotonin (5-HT)], hormones (e.g., glucocorticoids, estrogens), and exposure to stress, physical activity, learning situations, neurotoxins, and other forms of brain damage (1). Thus, neurogenesis is thought to underlie memory processes and may explain several neurological and psychiatric disorders, although contradictory evidence, controversy, and unanswered questions remain.
The discovery of adult neurogenesis has spawned investigations of its molecular mechanisms and role in brain disorders, both those considered neurological (e.g., Alzheimer's) and psychiatric (e.g., depression). In a recent issue of PNAS, Pechnick et al. (2) demonstrate that antidepressant treatment down-regulates expression of the cyclin-dependent kinase (CDK) inhibitor p21Cip1 (p21), a suppressor of cell cycle traverse and, thus, proliferation. This down-regulation of p21 induced by in vivo imipramine administration tracks with both increased hippocampal neurogenesis and increased antidepressant-like behavioral effects. The basal level of proliferation of hippocampal neuroblasts was also elevated in mice that lack the p21 protein. These data suggest a mechanistic link between neurogenesis and the actions of antidepressant treatment.
An appreciation of the importance of the Pechnick et al. research (2) necessitates connecting the hypothetical dots between neurogenesis, cell cycle, and antidepressant effects, which this group has accomplished. As for other somatic cells, neuroblast proliferation is regulated during development by a balance of inhibitory and excitatory …
‡To whom correspondence should be addressed. E-mail: kcunning{at}utmb.edu
