Abstract: Major depressive disorder is a highly prevalent psychiatric condition. Metalloproteinase 9 (MMP-9), a gelatinase involved in synaptic plasticity, learning and memory processes, is elevated in both chronic stress animal models and human peripheral blood samples of depressed patients. In this study we have evaluated the MMP-9 activity and protein expression in brain areas relevant to depression using the chronic corticosterone mouse model of depression. These mice show a depressive- and anxious-like behaviour. The MMP-9 activity and protein levels are significantly elevated in both the hippocampus and the cortex, and nectin-3 levels are lower in these brain areas in this model. In particular, these mice display an increased gelatinase activity in the CA1 and CA3 subfields of the hippocampus and in the internal layer of the prefrontal cortex. Moreover, the immobility time in the tail suspension test presents a positive correlation with the cortical MMP-9 activity, and a negative correlation with nectin-3 levels. In conclusion, the chronic corticosterone model of depression leads to an increase in the protein expression and activity of MMP-9 and a reduction of its substrate nectin-3 in relevant areas implicated in this disease. The MMP-9 activity correlates with behavioural despair in this model of depression. All these findings support the role of MMP-9 in the pathophysiology of depression, and as a putative target to develop novel antidepressant drugs.

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