The wnt pathway in mood disorders

Abstract

Objectives: To review the evidence of the involvement of the Wnt signalling pathway in mood disorders and in the action of drugs used to treat these disorders.

Methods: We performed a careful PubMed search using as keywords all possible terms relevant to the Wnt pathway and crossing them with each of four areas, i.e., developmental effects, behavioural effects, mood disorders, and drugs used in their treatment. Papers were selected on the basis of their content and their data used for discussion.

Results: Neurodevelopmental and behavioural data point to the possibility of involvement of the Wnt pathway in the pathophysiology of mood disorders. Clinical and post-mortem data are not sufficient to corroborate a definite role for Wnt alterations in any mood disorder. Combining genetic and pharmacological data, we may state that glycogen synthase kinase is the key molecule in bipolar disorder, as it is connected with many other signalling pathways that were shown to be involved in mood disorders, while Wnt molecules in the hippocampus appear to be mainly involved in depressive disorders.

Conclusions: Altered Wnt signalling may play a role in the pathophysiology of mood disorders, although not a central one. It is premature to draw conclusions regarding the possible usefulness of Wnt manipulations in the treatment of mood disorders.

Keywords: Antidepressant Drugs; Antipsychotic Drugs.; Bipolar Disorder; Major Depression; Mood Disorders; Mood Stabilising Agents; Wingless (Wnt) signalling.

Fig. (1)

Schematic drawing of Wnt-related pathways. The canonical pathway depends always on β-catenin, whereas the other, non-canonical pathways may interact with β-catenin–dependent processes, but do not depend on the presence of β-catenin. Different Wnts may have different effects on overall cellular function, depending on the receptors involved and on the availability of co-receptors (LRP, Knypek, Ror2, Ryk etc.) Depicted are also some molecules not strictly belonging to the Wnt pathways, but having a central role in switching on or off β-catenin–regulating steps. Solid arrows in the canonical pathway show events with Wnt stimulating Frizzled; dashed arrows show events occurring in the absence of Wnt. Black arrows for the canonical pathway, grey arrows for the non-canonical; CaMK, calmodulin kinase; CK1, Casein Kinase 1; Dkk, Dickkopf; HDAC, histone deacetylase; Daam1, Disheveled-associated activator of morphogenesis 1; ICAT, Inhibitor of β-catenin and T-cell factor; JNK, Jun kinase; PKB, protein kinase B or Akt; PKC, protein kinase C; PLC, phospholipase Cβ; PP2, protein phosphatase 2A; PPAR-δ, Peroxisome proliferator-activated receptor delta; ROCK, Rho-associated kinase; sFRP1-5, secreted Frizzled-related proteins 1-5; β-TrCP, β-Transducin repeat Containing Protein; WIF-1, Wnt-inhibiting factor 1; +, enhancement, activation; –, down-regulation, inhibition.