Antidepressants and Cdk inhibitors: releasing the brake on neurogenesis?

It is now clear that neurogenesis occurs in the brain of adult mammals. Many studies have attempted to establish relationships among neurogenesis, depression and the mechanism of action of antidepressant drugs. Therapeutic effects of antidepressants appear to be linked to increased neurogenesis in the hippocampus. Cdk inhibitors are expressed in multiple brain regions, presumably maintaining quiescence in differentiated neurons. Recently, the abundant expression of p21(Cip1) was found in neuroblasts and in newly developing neurons in the subgranular zone of the hippocampus, a region where adult neurogenesis occurs. Chronic treatment with the tricyclic antidepressant imipramine markedly decreased p21(Cip1) mRNA and protein levels and stimulated neurogenesis in this region. These results suggest that p21(Cip1) restrains neurogenesis in the hippocampus, and antidepressant-induced stimulation of neurogenesis might be a consequence of decreased p21(Cip1) expression, with the subsequent release of neuronal progenitor cells from the blockade of proliferation. These findings suggest the potential for new therapeutic strategies for the treatment of depression that target cell cycle proteins. However, there is a possibility that long-term stimulation of neurogenesis might exhaust the proliferation potentials of neuronal progenitors.