Synaptoproteomic profiling of the rat prefrontal cortex in the Chronic Mild Stress model of depression
Author
Eriksen, Stine Aistrup
Term
4. term
Publication year
2012
Submitted on
2012-08-31
Pages
69
Abstract
Svær depressiv lidelse (MDD) er en udbredt og invaliderende tilstand, som ofte opstår i samspil mellem livsstress og genetisk sårbarhed. Sygdommen har en neurobiologisk basis med ændringer i hjernens funktion og struktur, især i den præfrontale cortex (PFC). Mange af de molekylære forandringer ved depression findes i synapserne, hvor nerveceller udveksler signaler. For at kortlægge disse ændringer brugte vi proteomik baseret på massespektrometri, der kan måle mange proteiner samtidig. For at fokusere på synaptiske proteiner oprensede vi nerveender (synaptosomer) med differentiel centrifugering på en Percoll-gradient og kvantificerede proteiner med iTRAQ koblet til tandem massespektrometri. Formålet var at undersøge, hvordan mængden af synaptiske proteiner i PFC ændres i en valideret dyremodel: Chronic Mild Stress (CMS). Denne model giver to stress-responsfænotyper: anhedoni (nedsat evne til at opleve glæde) og stressresiliens (modstandsdygtighed). Vi gennemførte en bred, datadrevet proteomikanalyse af begge fænotyper for at identificere markører for stress-sårbarhed og -resiliens. Derudover blev lugte-spanopgaven (Odour Span Task) etableret i et pilotforsøg for at undersøge effekten af CMS på arbejdshukommelse. Resultaterne viste, at proteiner knyttet til synaptisk transmission var særligt reguleret ved sammenligninger mellem resiliente rotter, anhedoniske rotter og kontrolrotter. Proteiner i signaltransduktion var primært reguleret i anhedoniske rotter sammenlignet med kontrol. Metabolisme-relaterede proteiner var signifikant reguleret i resiliente rotter sammenlignet med anhedoniske rotter. Både cytoskeletorganisation og oxidativt stress var påvirkede i begge fænotyper, men med forskellige involverede proteiner. Konklusionen er, at resiliente og anhedoniske rotter havde tydeligt adskilte synaptiske proteomprofiler, der afspejler deres forskellige reaktioner på CMS. Stress-sårbarhed og -resiliens var forbundet med proteomiske ændringer særligt i stofskifte, cytoskelet, synaptisk transmission og signaltransduktion. Disse proteiner bør undersøges nærmere for deres relevans for depression.
Major depressive disorder (MDD) is common and disabling, and often arises from an interplay between life stress and genetic vulnerability. The disorder has a neurobiological basis with functional and structural brain changes, especially in the prefrontal cortex (PFC). Many of the molecular alterations in depression occur at synapses, where nerve cells communicate. To map these changes, we used mass spectrometry–based proteomics, which measures many proteins at once. To focus on synaptic proteins, we enriched nerve terminals (synaptosomes) via differential centrifugation on a Percoll gradient and quantified proteins using iTRAQ coupled to tandem mass spectrometry. Our aim was to examine quantitative changes in synaptic protein abundance in the PFC using a validated animal model: Chronic Mild Stress (CMS). This model yields two stress-response phenotypes: anhedonia (reduced ability to feel pleasure) and stress resilience. We conducted a broad, data-driven proteomic comparison of both phenotypes to identify markers of stress susceptibility and resilience. In addition, the odour span task was established in a pilot study to assess the effect of CMS on working memory. We found that proteins involved in synaptic transmission were particularly regulated when comparing resilient rats, anhedonic-like rats, and controls. Proteins related to signal transduction were primarily regulated in anhedonic-like rats versus controls. Metabolism-related proteins were significantly regulated in resilient rats compared with anhedonic-like rats. Cytoskeletal organization and oxidative stress pathways were affected in both phenotypes, but with different proteins involved in each. In conclusion, resilient and anhedonic-like rats showed clearly separated synaptic proteome profiles that reflect their different hedonic responses to CMS. Stress susceptibility and resilience were associated with proteomic changes, particularly in metabolism, the cytoskeleton, synaptic transmission, and signal transduction. These proteins warrant further investigation to confirm their relevance to depression.
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