Circuit-wide proteomics profiling reveals brain region-specific protein signatures in the male WKY rats with endogenous depression

Background: Although the Wistar Kyoto (WKY) rat has been consistently recognized as an animal model with endogenous depression, the exact molecular mechanisms underlying its genetic susceptibility to depression remain undetermined.Methods: Compared with the Wistar rats, the depression-like behaviors of the male WKY ones were evaluated by both the sucrose preference test and forced swimming test. Golgi staining analysis was conducted to access the dendritic morphology. TMT-labelled quantitative proteomics analyses were respectively performed in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and hippocampus (Hip), followed by KEGG enrichment -based clustering analysis, Venn diagram analysis, and Pearson correlation analysis.Results: The WKY strain showed significant differences in both the depression-like behaviors and synaptic plasticity. Moreover, the WKY model displayed markedly distinct differentially-expressed protein (DEP) profiles, with minor differences between the WKY subgroups. A cerebral regional commonality and specificity were evident in the signaling pathways enriched in the WKY model, and a total of 15 brain region-specific DEPs were identified to closely correlate with the depression-like phenotypes (in the mPFC: Lrrc8d, Dcun1d2, and Mtnd5; in the NAc: Ccdc154, Sec14l2, Kif2a, LOC680322, Me1, Mknk1, and Ret7; in the Hip: Sec14l2, Serpinf2, LOC103694855, Fam13c, and Loxl1). Data were available via ProteomeXchange with identifier PXD029079.Limitations: Female WKY rats are not included, and the roles of these candidate DEPs in depression remain further elucidation.Conclusion: The present study further evidences the brain region-specific protein signatures in the male WKY model with endogenous depression, providing novel insights into the pathogenesis of depression in males.

Automated summary

This study investigates the molecular mechanisms underlying the genetic susceptibility to depression in the WKY rat model. Comparison with Wistar rats reveals significant differences in depression-like behaviors and synaptic plasticity in the WKY strain. Proteomic analysis identifies brain region-specific differentially-expressed proteins that closely correlate with depression-like phenotypes. These findings provide novel insights into the pathogenesis of depression in males.