Attenuated Notch signaling in schizophrenia and bipolar disorder

Abstract

The Notch signaling pathway plays a crucial role in neurodevelopment and in adult brain homeostasis. We aimed to further investigate Notch pathway activity in bipolar disorder (BD) and schizophrenia (SCZ) by conducting a pathway analysis. We measured plasma levels of Notch ligands (DLL1 and DLK1) using enzyme immunoassays in a large sample of patients (SCZ n = 551, BD n = 246) and healthy controls (HC n = 639). We also determined Notch pathway related gene expression levels by microarray analyses from whole blood in a subsample (SCZ n = 338, BD n = 241 and HC n = 263). We found significantly elevated Notch ligand levels in plasma in both SCZ and BD compared to HC. Significant gene expression findings included increased levels of RFNG and KAT2B (p < 0.001), and decreased levels of PSEN1 and CREBBP in both patient groups (p < 0.001). RBPJ was significantly lower in SCZ vs HC (p < 0.001), and patients using lithium had higher levels of RBPJ (p < 0.001). We provide evidence of altered Notch signaling in both SCZ and BD compared to HC, and suggest that Notch signaling pathway may be disturbed in these disorders. Lithium may ameliorate aberrant Notch signaling. We propose that drugs targeting Notch pathway could be relevant in the treatment of psychotic disorders.

Figure 1

Summary of significant and nominally significant findings in Notch pathway mRNA expression between the schizophrenia and the healthy control group after controlling for age, gender and Bmal1. Results are given as p-values, adjusted for multiple testing, where significant results 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). Non-significant results are depicted as boxes with white background. The figure is based on the Notch signaling pathway in the KEGG database (hsa04330, version date 5/9/17). Hey1 is included by the authors due to its known role as a target gene for Notch signaling.

Figure 2

Summary of significant and nominally significant findings in Notch pathway mRNA expression between the bipolar disorder and the healthy control group after controlling for age, gender and Bmal1. Results are given as p-values, adjusted for multiple testing, where significant results 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). Non-significant results are depicted as boxes with white background. The figure is based on the Notch signaling pathway in the KEGG database (hsa04330, version date 5/9/17). Hey1 is included by the authors due to its known role as a target gene for Notch signaling.