Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder

Abstract

The Wnt signaling pathway plays a crucial role in neurodevelopment and in regulating the function and structure of the adult nervous system. Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders with evidence of subtle neurodevelopmental, structural and functional neuronal abnormalities. We aimed to elucidate the role of aberrant regulation of the Wnt system in these disorders by evaluating plasma levels of secreted Wnt modulators in patients (SCZ = 551 and BD = 246) and healthy controls (HCs = 639) using enzyme immune-assay. We also investigated the expression of 141 Wnt-related genes in whole blood in a subsample (SCZ = 338, BD = 241, and HCs = 263) using microarray analysis. Both SCZ and BD had dysregulated mRNA expression of Wnt-related genes favoring attenuated canonical (beta-catenin-dependent) signaling, and there were also indices of enhanced non-canonical Wnt signaling. In particular, FZD7, which may activate all Wnt pathways, but favors non-canonical signaling, and NFATc3, a downstream transcription factor and readout of the non-canonical Wnt/Ca²⁺ pathway, were significantly increased in SCZ and BD (p < 3 × 10^-4). Furthermore, patients had lower plasma levels of soluble dickkopf 1 and sclerostin (p < 0.01) compared with HC. Our findings suggest that SCZ and BD are characterized by abnormal Wnt gene expression and plasma protein levels, and we propose that drugs targeting the Wnt pathway may have a role in the treatment of severe mental disorders.

Fig. 1. Differences in Wnt pathway gene expression between patients with schizophrenia spectrum disorder and healthy controls after controlling for age, gender, and Bmal1.

Results are given as p-values where significant results (p-values adjusted for multiple testing) are indicated in red/dark blue (for increased/decreased mRNA expression) and nominally significant results (0.001 < p < 0.05) are shown as pink/light blue (for increased/decreased mRNA expression). The figure summarizes relevant genes for the three Wnt pathways (i.e., canonical pathway, non-canonical planar cell polarity pathway, and the non-canonical Wnt/Ca²⁺ pathway). The figure is based on the Wnt signaling pathway in the KEGG database

Fig. 2. Differences in Wnt pathway gene expression between patients with bipolar spectrum disorder and healthy controls after controlling for age, gender, and Bmal1.

Results are given as p-values where significant results (p-values adjusted for multiple testing) are indicated in red/dark blue (for increased/decreased mRNA expression) and nominally significant results (0.001 < p < 0.05) are shown as pink/light blue (for increased/decreased mRNA expression). The figure summarizes relevant genes for the three Wnt pathways (i.e., canonical pathway, non-canonical planar cell polarity pathway, and the non-canonical Wnt/Ca²⁺ pathway). The figure is based on the Wnt signaling pathway in the KEGG database