Venlafaxine Stimulates an MMP-9-Dependent Increase in Excitatory/Inhibitory Balance in a Stress Model of Depression

• DOI: 10.1523/jneurosci.2387-19.2020
• Publication Date: 2020-04-08T21:45:18Z
• Authors: Seham Alaiyed; Mondona McCann; Gouri Mahajan; Grazyna Rajkowska; Craig A. Stockmeier; Kenneth J. Kellar; Jian Young Wu; Katherine Conant
• Keywords: Pyramidal cell; Venlafaxine Hydrochloride; Chronic Stress

Emerging evidence suggests that there is a reduction in overall cortical excitatory to inhibitory balance major depressive disorder (MDD), which afflicts ∼14%-20% of individuals. Reduced pyramidal cell arborization occurs with stress and MDD, may diminish neurotransmission. Enhanced deposition perineuronal net (PNN) components also stress. Since parvalbumin-expressing interneurons are the predominant population enveloped by PNNs, enhance their ability release GABA, excess PNN likely increases inhibition. In present study, we investigate potential for matrix metalloprotease-9 (MMP-9), an endopeptidase secreted response neuronal activity, contribute antidepressant efficacy serotonin/norepinephrine reuptake inhibitor venlafaxine male mice. Chronic MMP-9 levels murine cortex, both PSD-95 expression cortex WT but not MMP-9-null We have previously shown reduces power ex vivo γ oscillations conventionally housed increased disinhibition remission from MDD. Herein observe corticosterone-induced model disease reduced venlafaxine. Compared mice receive concurrent venlafaxine, corticosterone-treated display impaired working memory. Autopsy-derived PFC samples show elevated antidepressant-treated MDD patients compared controls. These preclinical postmortem findings highlight link between extracellular regulation SIGNIFICANCE STATEMENT neurotransmission disorder, be normalized treatment. Underlying molecular mechanisms are, however, well understood. role protease, released neurons known play learning memory, antidepressant-associated transmission. Our data suggest this metalloprotease-9, branching concomitantly attenuates potentially reduce input these neurons. Matrix thus excitatory/inhibitory dynamics, important mood