antidepressants stimulate hippocampal neurogenesis by inhibiting p21 expression in the subgranular zone of the hipppocampus抗抑郁药物刺激海马神经发生通过抑制p21表达hipppocampus subgranular区内.pdfVIP

Antidepressants Stimulate Hippocampal Neurogenesis by Inhibiting p21 Expression in the Subgranular Zone of the Hipppocampus 1,3. 2. 2 2 Robert N. Pechnick , Svetlana Zonis , Kolja Wawrowsky , Rosemarie Cosgayon , Catherine 1 1 2 Farrokhi , Liliana Lacayo , Vera Chesnokova * 1 Department of Psychiatry and Behavioral Neurosciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America, 2 Division of Endocrinology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America, 3 Brain Research Institute, University of California Los Angeles, Los Angeles, California, United States of America Abstract The relationships among hippocampal neurogenesis, depression and the mechanism of action of antidepressant drugs have generated a considerable amount of controversy. The cyclin-dependent kinase (Cdk) inhibitor p21Cip1 (p21) plays a crucial role in restraining cellular proliferation and maintaining cellular quiescence. Using in vivo and in vitro approaches the present study shows that p21 is expressed in the subgranular zone of the dentate gyrus of the hippocampus in early neuronal progenitors and in immature neurons, but not in mature neurons or astroglia. In vitro, proliferation is higher in neuronal progenitor cells derived from p21-/- mice compared to cells derived from wild-type mice. Proliferation is increased in neuronal progenitor cells after suppression of p21 using lentivirus expressing short hairpin RNA against p21. In vivo, chronic treatment with the non-selective antidepressant imipramine as well as the norepinephrine-selective reuptake inhibitor