Depressive-like phenotype induced by prenatal dexamethasone in mice is reversed by desipramine.

Exposure to prenatal insults has been associated with an increased risk for neuropsychiatric disorders, including depression, but the mechanisms are still poorly understood. Persistent alterations of the HPA axis feedback mechanism as well as adult impaired neurogenesis are believed to play a relevant role in the etiology of depression. In addition, growing evidence points at epigenetic reprogramming as a key factor. We have previously shown that prenatal exposure to the synthetic glucocorticoid dexamethasone (DEX) impairs neurogenesis and leads to late onset of depression-like behavior that does not respond to the SSRI antidepressant fluoxetine (FLX). The aims of this study were to assess the effect of DEX prenatal exposure on the morphology of hippocampal granule neurons and on the expression of genes related to plasticity; and to test whether the SNRI antidepressant desipramine (DMI), unlike FLX, could counteract the effect of prenatal-DEX. C57Bl/6 mice were exposed to DEX (0.05 mg/kg/day) in utero and received intra-hippocampal injection of GFP expressing retroviral vector for labeling of newborn granule cells at eleven months. By twelve months, DEX mice showed depression-like behavior associated with decreased neurogenesis and morphological alterations of the newborn granule cells in the dentate gyrus (DG). Furthermore DEX mice displayed altered expression of genes controlling neurogenesis and neuronal morphology, such as Cdkn1c, p16, TrkB, DISC1 and Reelin. Chronic treatment with DMI led to a significant decrease in immobility time in the forced swim test. In addition, DMI restored neurogenesis, neuronal morphology in the DG, as well as the expression of all related genes. Our results suggest that (1) prenatal DEX induces early and persistent reprogramming effects resulting in altered neurogenesis and neuronal morphology; and (2) DMI treatment reverses DEX-induced depression by restoring the expression of genes relevant to neuronal plasticity.