Role of Janus-Kinases in Major Depressive Disorder.

BACKGROUND/AIMS Major depressive disorder is a severe, common and often chronic disease with a significant mortality due to suicide. The pathogenesis of major depression is still unknown. It is assumed that a reduction of neurogenesis in the hippocampus plays an important role in the development of major depressive disorder. However, the mechanisms that control proliferation of neuronal stem cells in the hippocampus require definition. Here, we investigated the role of Janus-Kinase 3 (Jak-3) for stress-induced inhibition of neurogenesis and the induction of major depression symptoms in mice. METHODS Stress was induced by the application of glucocorticosterone. Brain sections were stained with phospho-specific antibodies and analysed by confocal microscopy to measure phosphorylation of Jak-3 specifically in the hippocampus. Jak-3 inhibitors and the antidepressant amitriptyline were applied to counteract stress. The effects of the inhibitors were determined by a set of behavioural tests and analysis of Jak-3 phosphorylation in brain sections. Acid sphingomyelinase-deficient mice were employed to test whether Jak3 is downstream of ceramide. RESULTS The data show that stress reduces neurogenesis, which is restored by simultaneous application of Jak-3 inhibitors. Inhibition of neurogenesis correlated with an anxious-depressive behaviour that was also normalized upon application of a Jak-3-inhibitor. Confocal microscopy data revealed that stress triggers a phosphorylation and thereby activation of Jak-3 in the hippocampus. Amitriptyline, a commonly used antidepressant that blocks the acid sphingomyelinase, or acid sphingomyelinase-deficiency reduced stress-induced phosphorylation of Jak-3. CONCLUSION Our data show that Jak-3 is activated by stress at least partially via the acid sphingomyelinase and is involved in the mediation of stress-induced major depression.