Cross-species evidence from human and rat brain transcriptome for growth factor signaling pathway dysregulation in major depression

Abstract

An enhanced understanding of the pathophysiology of depression would facilitate the discovery of new efficacious medications. To this end, we examined hippocampal transcriptional changes in rat models of disease and in humans to identify common disease signatures by using a new algorithm for signature-based clustering of expression profiles. The tool identified a transcriptomic signature comprising 70 probesets able to discriminate depression models from controls in both Flinders Sensitive Line and Learned Helplessness animals. To identify disease-relevant pathways, we constructed an expanded protein network based on signature gene products and performed functional annotation analysis. We applied the same workflow to transcriptomic profiles of depressed patients. Remarkably, a 171-probesets transcriptional signature which discriminated depressed from healthy subjects was identified. Rat and human signatures shared the SCARA5 gene, while the respective networks derived from protein-based significant interactions with signature genes contained 25 overlapping genes. The comparison between the most enriched pathways in the rat and human signature networks identified a highly significant overlap (p-value: 3.85 × 10) of 67 terms including ErbB, neurotrophin, FGF, IGF, and VEGF signaling, immune responses and insulin and leptin signaling. In conclusion, this study allowed the identification of a hippocampal transcriptional signature of resilient or susceptible responses in rat MDD models which overlapped with gene expression alterations observed in depressed patients. These findings are consistent with a loss of hippocampal neural plasticity mediated by altered levels of growth factors and increased inflammatory responses causing metabolic impairments as crucial factors in the pathophysiology of MDD.

Protective effects of leptin against cerebral ischemia/reperfusion injury (Review)

“…Regarding the association of the serum levels of leptin with stroke, the opinion of scholars is divided. By contrast, a prospective study on 4,571 healthy African Americans did not identify any association between leptin levels and ischemic stroke risk in either men or women (8,22,51,86). Only a few small studies evaluated leptin levels during the acute phase of ischemic stroke and reported increased leptin levels (7,26,50,52,87).…”

Fibroblast Growth Factors in Depression

“…On the contrary, no SNPs of FGFR2 gene was associated with depression (Wang et al, 2012). At the transcriptional level, the enrichment of FGF pathways is found both in depressed patients and rat models by gene expression analysis (Carboni et al, 2018).…”

Umbilical cord blood-based gene signatures related to prenatal major depressive disorder: Retracted

“…[14] So far, there are many studies which investigated MDD-related mRNAs in blood tissue and brain tissue, and they are considered to better utilize the rich and comprehensive information in omics data to explore the underlying molecular biology of MDD. [15–17]…”