title: 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.
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza, Roma, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Matrisciano
authors.forename: Carla L
authors.initials: CL
authors.lastname: Busceti
authors.forename: Domenico
authors.initials: D
authors.lastname: Bucci
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Orlando
authors.forename: Alessandra
authors.initials: A
authors.lastname: Caruso
authors.forename: Gemma
authors.initials: G
authors.lastname: Molinaro
authors.forename: Irene
authors.initials: I
authors.lastname: Cappuccio
authors.forename: Barbara
authors.initials: B
authors.lastname: Riozzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Gradini
authors.forename: Marta
authors.initials: M
authors.lastname: Motolese
authors.forename: Filippo
authors.initials: F
authors.lastname: Caraci
authors.forename: Agata
authors.initials: A
authors.lastname: Copani
authors.forename: Sergio
authors.initials: S
authors.lastname: Scaccianoce
authors.forename: Daniela
authors.initials: D
authors.lastname: Melchiorri
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D055495:Neurogenesis; D009474:Neurons / Q000473:pathology; D013312:Stress, Physiological; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000305:Adrenal Cortex Hormones; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins