Quantitative proteomic analysis reveals molecular adaptations in the hippocampal synaptic active zone of chronic mild stress-unsusceptible rats

While stressful events are recognized as an important cause of major depressive disorder (MDD), some individuals exposed to life stressors maintain normal psychological functioning. The molecular mechanisms underlying this phenomenon remain unclear. Abnormal transmission and plasticity of hippocampal synapses have been implied to play a key role in the pathoetiology of MDD. In the present study, a chronic mild stress (CMS) protocol was applied to generate susceptible and unsusceptible rat subpopulations. Proteomic analysis using an isobaric tag for relative and absolute quantitation (iTRAQ) coupled with tandem mass spectrometry was performed to identify differential proteins in enriched hippocampal synaptic junction preparations. More than 4000 proteins were quantified, and 85 membrane proteins were present in differential amounts. Of these, SynaptomeDB identified 78 (92%) having a synapse-specific localization. The unbiased profiles identified several candidate proteins within the synaptic junction that may be associated with stress vulnerability or insusceptibility. Subsequent functional categorization revealed that protein systems particularly involved in membrane trafficking at the synaptic active zone exhibited a positive strain as potential molecular adaptaions in the unsusceptible rats. Moreover, through STRING and immumoblotting analysis, membrane-associated GTP-bound Rab3a and Munc18-1 appear to co-regulate syntaxin-1/SNAP25/VAMP2 assembly at the hippocampal presynaptic active zone of unsusceptible rats, facilitating SNARE-mediated membrane fusion and neurotransmitter release, and may be part of a stress-protection mechanism in actively maintaining an emotional homeostasis.