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