The amygdala plays a key role in the pathophysiology of depression, but the molecular mechanisms underlying amygdalar hyperactivity in depression remain unclear. In this study, we used a chronic mild stress (CMS) protocol to separate susceptible and insusceptible rat subgroups. Proteomes in the amygdalae were analyzed differentially across subgroups based on labeling with isobaric tags for relative and absolute quantitation (iTRAQ) combined with mass spectrometry. Of 2562 quantified proteins, 102 were differentially expressed. Several proteins that might be associated with the stress insusceptibility/susceptibility difference, including synapse-related proteins, were identified in the amygdala. Immunoblot analysis identified changes in VGluT1, NMDA GluN2A and GluN2B and AMPA GluA1 receptors, and PSD-95, suggesting that CMS perturbs glutamatergic transmission in the amygdala. Changes in these regulatory and structural proteins provide insight into the molecular mechanisms underlying the abnormal synaptic morphological and functional plasticity in the amygdalae of stress-susceptible rats. Interestingly, the expression level of CaMKIIβ, potentially involved in regulation of glutamatergic transmission, was significantly increased in the susceptible group. Subsequent in vitro experimentation showed that overexpression of CaMKIIβ increased the expression of PSD-95 and GluA1 in cultured hippocampal neurons. This result suggested that CaMKIIβ functions upstream from PSD-95 and GluA1 to affect LTP-based postsynaptic functional plasticity in the amygdalae of susceptible rats. Therefore, amygdalar CaMKIIβ is a potential antidepressant target. Collectively, our findings contribute to a better understanding of amygdalar synaptic plasticity in depression.
Keywords: amygdala; chronic mild stress; depression; proteomics; synaptic plasticity.
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