Induction of the Wnt Antagonist Dickkopf-1 Is Involved in Stress-Induced Hippocampal Damage

Abstract

The identification of mechanisms that mediate stress-induced hippocampal damage may shed new light into the pathophysiology of depressive disorders and provide new targets for therapeutic intervention. We focused on the secreted glycoprotein Dickkopf-1 (Dkk-1), an inhibitor of the canonical Wnt pathway, involved in neurodegeneration. Mice exposed to mild restraint stress showed increased hippocampal levels of Dkk-1 and reduced expression of β-catenin, an intracellular protein positively regulated by the canonical Wnt signalling pathway. In adrenalectomized mice, Dkk-1 was induced by corticosterone injection, but not by exposure to stress. Corticosterone also induced Dkk-1 in mouse organotypic hippocampal cultures and primary cultures of hippocampal neurons and, at least in the latter model, the action of corticosterone was reversed by the type-2 glucocorticoid receptor antagonist mifepristone. To examine whether induction of Dkk-1 was causally related to stress-induced hippocampal damage, we used doubleridge mice, which are characterized by a defective induction of Dkk-1. As compared to control mice, doubleridge mice showed a paradoxical increase in basal hippocampal Dkk-1 levels, but no Dkk-1 induction in response to stress. In contrast, stress reduced Dkk-1 levels in doubleridge mice. In control mice, chronic stress induced a reduction in hippocampal volume associated with neuronal loss and dendritic atrophy in the CA1 region, and a reduced neurogenesis in the dentate gyrus. Doubleridge mice were resistant to the detrimental effect of chronic stress and, instead, responded to stress with increases in dendritic arborisation and neurogenesis. Thus, the outcome of chronic stress was tightly related to changes in Dkk-1 expression in the hippocampus. These data indicate that induction of Dkk-1 is causally related to stress-induced hippocampal damage and provide the first evidence that Dkk-1 expression is regulated by corticosteroids in the central nervous system. Drugs that rescue the canonical Wnt pathway may attenuate hippocampal damage in major depression and other stress-related disorders.

Wnt Signaling Regulates Intermediate Precursor Production in the Postnatal Dentate Gyrus by Regulating Cxcr4 Expression

“…Chronic stress represses Wnt signaling of the DG through expression of a Wnt inhibitor, Dickkopf-1, in the DG [39]. Based on our studies we would predict that this would compromise the ability of the dentate to continue transient precursor-mediated neurogenesis.…”

Molecular mechanisms in the regulation of adult neurogenesis during stress

“…There are several WNT signalling pathways, but the canonical WNT-β-catenin pathway seems to be involved in adult neurogenesis 111 . Interestingly, restraint stress in mice increases the hippocampal level of an inhibitor of the canonical WNT pathway, the protein Dickkopf 1 (DKK1) 112 . DKK1 is also involved in the decreased hippocampal volume induced by chronic stress 112 .…”

“…DKK1 is also involved in the decreased hippocampal volume induced by chronic stress 112 . In this study, a reduction in the expression of DKK1 prevented the stress-induced decreases in neurogenesis seen in control mice, indicating that the WNT pathway might be a link between these volume changes, stress and adult neurogenesis 112 .…”

“…Both manipulations result in increased DKK1 levels and, consequently, reduced WNT signalling in the hippocampus 112 . The stress-induced increase in DKK1 levels is attenuated in adrenalectomized mice and is dependent on glucocorticoid receptors, as the glucocorticoid receptor antagonist mifepristone, but not the mineralocorticoid receptor antagonist spironolactone, inhibits this stressinduced increase.…”

Brain Beta-Catenin Signalling During Stress and Depression

“…Mice exposed to stress show elevated levels of Dickkopf-1 (Dkk-1), which blocks the Wnt signalling pathway resulting in hippocampal damage. Dkk-1 acts to promote endocytosis of LRP5/6, which prevents the Wnt signalling pathway from activating, thus causing dendritic atrophy and neuronal loss [53]. …”