Comparative Proteomics in the Chronic Mild Stress Model of Depression - a search for biomarkers of depression in hippocampal subregions

Abstract

Extensive research has focused at unraveling the underlying molecular mechanisms leading to depression and recovery. A combination of the different hypotheses indicates a dynamic interaction between different systems, pathways and molecules, where a dysfunction or dysregulation somewhere can lead to depression and an upregulation due to antidepressant treatment can lead to recovery. The exact mechanisms are still unknown, but are most likely accompanied by changes in protein expression profiles.

Hippocampal granular cell layer proteins important concerning development of depression and recovery are identified by combining Laser Capture Microdissection (Selectively isolates granular cell populations), 2D Differential Gel Electrophoresis (Separates, detects and quantifies proteins) and Tandem Mass Spectrometry (Identifies proteins). This proteomic strategy quantitatively compares the proteomes between different treatment groups in the Chronic Mild Stress (CMS) rat model of depression.

The CMS paradigm induces anhedonic-like behaviour (major symptom of depression) by exposing rats to a series of mild stressors. A significant decline in consumption of a sucrose solution is observed in stressed animals compared to non-stressed animals. This is reversed by antidepressant treatment. Six different groups emerge from our model; stress resistant, drug-responders, drug-nonresponders, stress vehicle, unchallenged drug, unchallenged vehicle.

Specific patterns of protein modulation implicated in development of anhedonic behavior, antidepressive drug respondance (escitalopram, sertraline) and stress resilience are identified. These results give insight into different molecular aspects of depression and provide a greater understanding of depression etiology and pathophysiology. Ultimately, new treatment targets, able to induce a rapid onset of action and increase the percentage of treatment responders, are identified.