VENLAFAXINE INDUCES A MATRIX METALLOPROTEINASE-9-DEPENDENT REMODELING, LEADING TO INCREASED EXCITATORY/INHIBITORY BALANCE

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SEHAM SALEH ALAIYED
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Though the mechanisms that underlie the efficacy of antidepressants in responsive individuals is not yet fully understood, it is known that antidepressant drugs that target monoamines induce structural remodeling in the adult brain and enhance excitatory neuronal transmission. Neuroplasticity and neuronal transmission can be enhanced through modulation of the perineuronal nets (PNNs), lattice-like structures that surrounds the parvalbumin (PV) positive interneurons, and also by enhancing dendritic arborization of pyramidal cells. Gamma rhythm in the hippocampus is associated with cognitive processes. Several studies suggest that gamma rhythm is reduced in depression. PNN disruption reduces PV input and enhances gamma activity. Matrix metalloproteinases (MMPs), including MMP-2, MMP-3, and MMP-9, are expressed in neurons, glia, and endothelial cells and are involved in the modification of the extracellular matrix, as well as modulating PNN integrity and dendritic plasticity. Therefore, we sought to explore the role of MMPs in the efficacy of antidepressant drugs. We observed that mice treated with the antidepressant venlafaxine (VFX; 30 mg/kg) for 2 weeks showed an increase in the levels of pro-MMP9. Golgi staining of pyramidal neurons in the cortex showed an increase in neuronal arborization at the level of the second-order dendritic branches of wild-type mice treated with VFX but not in MMP-9 null mice. Evaluation of PNN in VFXiv treated mice revealed increased PNN degradation and increased cleavage of brevican (BCAN), one of the main PNN structural proteins. Moreover, treatment with VFX increased gamma activity in ex vivo hippocampal slices. Furthermore, we used a mouse model of anxiety/depression induced by chronic administration of corticosterone (CORT) treatment (35 μg/ml) in drinking water for 4 weeks. We observed an increased expression of BCAN proteins in the brain sample of CORT-treated mice. Ex vivo hippocampal slices of CORT-treated mice display a significant reduction in gamma oscillations and impaired working memory, with normalization by VFX. Postmortem human prefrontal cortex samples show that depressed patients treated with antidepressants exhibit an increase in the MMP9/TIMP-1 ratio as compared to depressed untreated and control groups. These data suggest a link between MMP regulation and the excitatory/inhibitory balance in depression.
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