For many years the production of new neurons in mammalian brain was thought to be restricted to development. It is now clear that neurogenesis does occur in adult mammals, including humans (Eriksson et al, 1998). Antidepressant drugs and procedures that reduce depression, such as electroconvulsive shock and exercise, increase neurogenesis. The relationships among adult neurogenesis, antidepressant drugs, and depression have generated considerable interest and controversy (Duman, 2004; Scharfman and Hen, 2007).

p21Cip1, a cyclin-dependent kinase inhibitor, restrains cell-cycle progression and proliferation. It is found in neuroblasts and newly developing neurons in the subgranular zone of the hippocampus (Pechnick et al, 2008). Chronic treatment with the tricyclic antidepressant imipramine decreases p21Cip1 transcript and protein levels and stimulates neurogenesis in this region. Moreover, mice lacking p21Cip1 have increased rates of hippocampal neurogenesis. Thus, p21Cip1 restrains neurogenesis in the hippocampus, and antidepressant-induced stimulation of neurogenesis might be due to decreased p21Cip1 expression. Cell-cycle regulation occurs downstream from the primary site of action of antidepressants, suggesting that new therapeutic strategies might directly target cell-cycle proteins.

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