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Neuropsychopharmacology. 2018 Sep;43(10):2134-2145. doi: 10.1038/s41386-018-0117-6. Epub 2018 Jun 12.

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

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Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Bologna, Italy.
The Microsoft Research - University of Trento Centre for Computational and Systems Biology, Rovereto, Trento, Italy.
Department of Mathematics, University of Trento, Povo, Trento, Italy.
RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
Department of Integrative Biology and Physiology University of Minnesota, 2231 6th Street SE, Minneapolis, USA.
King's College London, at the Institute of Psychiatry, Psychology and Neuroscience (IOPPN), London, UK.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology (CIBIO), University of Trento, Povo, Trento, Italy.
The Aptuit Center for Drug Discovery & Development, Via Fleming, 4, 37135, Verona, Italy.
Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.


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 × 10-6) 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.

[Available on 2019-09-01]

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