Depression, antidepressants, and neurogenesis: a critical reappraisal.

The neurogenesis hypothesis of depression posits (1) that neurogenesis in the subgranular zone of the dentate gyrus is regulated negatively by stressful experiences and positively by treatment with antidepressant drugs and (2) that alterations in the rate of neurogenesis play a fundamental role in the pathology and treatment of major depression. This hypothesis is supported by important experimental observations, but is challenged by equally compelling contradictory reports. This review summarizes the phenomenon of adult hippocampal neurogenesis, the initial and continued evidence leading to the development of the neurogenesis hypothesis of depression, and the recent studies that have disputed and/or qualified those findings, to conclude that it can be affected by stress and antidepressants under certain conditions, but that these effects do not appear in all cases of psychological stress, depression, and antidepressant treatment.

Several stressors fail to reduce adult hippocampal neurogenesis.

Neurogenesis in the dentate gyrus of the hippocampus of adult laboratory animals has been widely reported to be vulnerable to many psychological and physical stressors. However, we have found no effects of acute restraint stress, acute or subchronic tailshock stress, or acute, subchronic, or chronic resident-intruder stress on neural progenitor cell (NPC) proliferation, short or long term survival of newborn cells, or brain-derived neurotrophic factor (BDNF) mRNA expression in adult rats. In addition, we did not observe any effect of chronic resident-intruder stress on NPC proliferation in adolescent rats. A selectively bred stress-sensitive line was also found to exhibit no alterations in NPC proliferation following tailshock stress, although this line did exhibit a lower proliferation rate under baseline (unstressed) conditions when compared with non-selected rats. These results challenge the prevailing hypothesis that any stressor of sufficient intensity and duration has a marked negative impact upon the rate of hippocampal neurogenesis, and suggest that some yet unidentified factors related to stress and experimental conditions are crucial in the regulation of neurogenesis.

Lithium, but not fluoxetine or the corticotropin-releasing factor receptor 1 receptor antagonist R121919, increases cell proliferation in the adult dentate gyrus.

Several antidepressant drugs have previously been reported to increase neurogenesis in the dentate gyrus of the hippocampus in laboratory animals. We found no effect of the selective serotonin reuptake inhibitor fluoxetine or the corticotropin-releasing factor receptor 1 antagonist R121919 [3-[6-(dimethylamino)-4-methylpyridin-3-yl]-2,5-dimethyl-N,N-dipropyl-1H-pyrazolo[1,5-a]pyrimidin-8-ium-7-amine] on the rate of cell proliferation or hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression in either adult or adolescent rats after long-term administration. In adults, the mood stabilizer lithium was found to significantly increase cell proliferation; the atypical antipsychotic paliperidone did not affect proliferation, either alone or when combined with lithium. Fourteen-day survival of neuronally fated cells showed a significant interaction effect of lithium and paliperidone but no effect of either drug alone. BDNF mRNA expression was significantly decreased by lithium in the CA1/2 cell fields and increased by paliperidone in the CA1/2, CA3, and dentate gyrus. These results raise questions concerning the hypothesis that all antidepressants increase neurogenesis under nonstressed conditions. They also confirm and extend previous reports of lithium-induced increases in cell proliferation but not survival.

Inhibition of Jun N-terminal kinase (JNK) enhances glucocorticoid receptor-mediated function in mouse hippocampal HT22 cells.

Mitogen-activated protein kinases (MAPKs), including Jun N-terminal kinase (JNK), promote inflammatory and proliferative responses to infection and other environmental stimuli including stress. Relevant to negative regulation of inflammatory pathways by glucocorticoids and the development of glucocorticoid resistance (observed in inflammatory disorders as well as certain neuropsychiatric disorders such as major depression), activation of JNK has been reported to inhibit glucocorticoid receptor (GR) function. In this study, the role of JNK pathways in modulating GR function was further investigated. Treatment of mouse hippocampal (HT22) cells with the selective JNK inhibitor, SP-600125 (0.1-10 microM), resulted in dose-dependent induction of GR-mediated MMTV-luciferase activity. SP-600125 also significantly enhanced dexamethasone-induced MMTV-luciferase activity, while increasing GR binding to the glucocorticoid responsive element, both in the presence and absence of Dex. Similar effects were observed in mouse fibroblast cells (LMCAT), and in HT22 cells treated with a JNK specific antisense oligonucleotide. The induction of GR-mediated function by SP-600125 was not due to altered cytosolic GR binding or GR protein expression or enhancement of GR nuclear translocation as determined by Western blot. Taken together, the data indicate that constitutive expression of JNK plays a tonic inhibitory role in GR function, which is consistent with findings that activation of JNK pathways inhibits GR. The data also identify potential pathways involved in the pathogenesis of the glucocorticoid resistance found in certain chronic immune/inflammatory diseases and subgroups of patients with major depression. Moreover, JNK pathways may represent a therapeutic target for normalization of GR function in these disorders.