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. 2012 Jul;11(7):M111.016428.
doi: 10.1074/mcp.M111.016428. Epub 2012 Feb 6.

Candidate hippocampal biomarkers of susceptibility and resilience to stress in a rat model of depression

Kim Henningsen  1 , Johan Palmfeldt, Sofie Christiansen, Isabel Baiges, Steffen Bak, Ole Nørregaard Jensen, Niels Gregersen, Ove Wiborg
Affiliations

Candidate hippocampal biomarkers of susceptibility and resilience to stress in a rat model of depression

Kim Henningsen et al. Mol Cell Proteomics. 2012 Jul.

Abstract

Susceptibility to stress plays a crucial role in the development of psychiatric disorders such as unipolar depression and post-traumatic stress disorder. In the present study the chronic mild stress rat model of depression was used to reveal stress-susceptible and stress-resilient rats. Large-scale proteomics was used to map hippocampal protein alterations in different stress states. Membrane proteins were successfully captured by two-phase separation and peptide based proteomics. Using iTRAQ labeling coupled with mass spectrometry, more than 2000 proteins were quantified and 73 proteins were found to be differentially expressed. Stress susceptibility was associated with increased expression of a sodium-channel protein (SCN9A) currently investigated as a potential antidepressant target. Differential protein profiling also indicated stress susceptibility to be associated with deficits in synaptic vesicle release involving SNCA, SYN-1, and AP-3. Our results indicate that increased oxidative phosphorylation (COX5A, NDUFB7, NDUFS8, COX5B, and UQCRB) within the hippocampal CA regions is part of a stress-protection mechanism.

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Figures

Fig. 1.
Fig. 1.
Study design showing the experiment lineout and time course.
Fig. 2.
Fig. 2.
A, Four weeks exposure to chronic mild stress (CMS) resulted in a significantly decreased sucrose consumption when compared with unchallenged controls (C) (n = 72–164). B, Seven weeks of stress resulted in a significant decrease in sucrose consumption in stress-susceptible rats (A). A subgroup of the stressed rats did not decrease sucrose intake (R). (n = 9), (*** = p < 0.001), Data are shown as sucrose intake, indexed to baseline (3–4 week and 7–8 week means)+ standard error to the mean.
Fig. 3.
Fig. 3.
Quantitative data were obtained for 1199 and 1054 proteins from the membrane and soluble sample, respectively, with 242 proteins detected in both fractions.
Fig. 4.
Fig. 4.
Hierarchical cluster analysis performed on data from all 2011 proteins (A) and on the 75 proteins that passed selection criteria (B). According to both cluster profiles the resilient (R) group diverged from the anhedonic (A) and the control (C) group demonstrating that the CMS-resilient protein expression profile differed from the other two groups investigated.
Fig. 5.
Fig. 5.
Expression level comparison between data obtained in original experiment using iTRAQ labeling and validation study using the SRM method.
Fig. 6.
Fig. 6.
Saggital SCN9A-stained brain slices of the hippocampus showed increased immunoreactivity in anhedonic rats compared with controls, especially pronounced in the CA1 region. Immunoreactivity was lowest in the dentate gyrus (DG). Immunoreactivity was confirmed in sections of dorsal root ganglion (DRG), known to have a large density of sodium channels.
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