Venlafaxine stimulates an MMP-9-dependent increase in excitatory/inhibitory balance in a stress model of depression

Abstract

We would like to acknowledge outstanding veterinary support from the Department of Comparative Medicine and we would also like to apologize to investigators whose excellent work was not directly cited. We would also like to thank Adam Caccavano for software development and sharing and assistance with images. Katherine Conant received funds for support and supplies from NIMH (R21MH118749) as well as Deborah Wilson and Anthony Herman through the Georgetown University Partners in Research program. Seham Alaiyed received support from the Saudi Arabian government, Qassim University scholarship program. Mondona McCann was supported with funding from T32 NS041218. The authors deeply appreciate the invaluable contributions made by the families consenting to donate brain tissue and be interviewed. We also gratefully acknowledge the support of the staff of the Cuyahoga County Medical Examiner's Office, Cleveland, Ohio. We gratefully acknowledge the assistance of Drs. James Overholser and George Jurjus, and of Lesa Dieter in the psychiatric assessments, and of Timothy M. De Jong and Lisa Konick in acquiring written consent and collecting tissues. The work performed by the Postmortem Brain Core is supported, in part, by funds from the IDeA Program of the National Institute of General Medical Sciences of the National Institutes of Health, Center for Psychiatric Neuroscience (CPN)-COBRE (P30GM103328) and by National Institute of Mental Health (R01 MH67996). Emerging evidence suggests that there is a reduction in overall cortical excitatory to inhibitory balance in major depressive disorder (MDD), which afflicts approximately 14-20% of individuals. Reduced pyramidal cell arborization occurs with stress and MDD, and may diminish excitatory neurotransmission. Enhanced deposition of perineuronal net (PNN) components also occurs with stress. Since parvalbumin-expressing interneurons are the predominant cell population that is enveloped by PNNs, which enhance their ability to release GABA, excess PNN deposition likely increases pyramidal cell inhibition. In the present study we investigate the potential for matrix metalloprotease-9 (MMP-9), an endopeptidase secreted in response to neuronal activity, to contribute to the antidepressant efficacy of the serotonin/norepinephrine reuptake inhibitor venlafaxine in male mice. Chronic venlafaxine increases MMP-9 levels in murine cortex, and increases both pyramidal cell arborization and PSD-95 expression in the cortex of wild-type but not MMP-9 null mice. We have previously shown that venlafaxine reduces PNN deposition and increases the power of ex vivo gamma oscillations in conventionally-housed mice. Gamma power is increased with pyramidal cell disinhibition and with remission from MDD. Herein we observe that PNN expression is increased in a corticosterone-induced stress model of disease and reduced by venlafaxine. As compared to mice that receive concurrent venlafaxine, corticosterone treated mice also display reduced ex vivo gamma power and impaired working memory. Autopsy-derived prefrontal cortex samples show elevated MMP-9 levels in antidepressant treated MDD patients as compared to controls. These preclinical and postmortem findings highlight a link between extracellular matrix regulation and MDD.