LIN Seminar: “Matrix metalloproteases as mediators of antidepressant efficacy” by Katherine Conant (Georgetown University)

Katherine Conant will be sharing her research on Dec. 3 2020 at 4 pm.

Abstract:

Evidence suggests there is a reduction in overall cortical excitatory to inhibitory balance in major depressive disorder (MDD), a disorder with a lifetime prevalence of 20.6 percent in U.S. adults. The co-occurrence of MDD plus stress decreases arborization of cortical pyramidal neurons, and may thereby diminish excitatory neurotransmission. With stress there is also enhanced deposition of perineuronal net (PNN) components. The PNN predominantly envelopes parvalbumin-expressing interneurons, thereby enhancing their ability to release GABA. Thus, excess PNN deposition may increase pyramidal cell inhibition. The present study investigates the ability of matrix metalloprotease-9 (MMP-9), an endopeptidase secreted in response to neuronal activity, to contribute to the antidepressant efficacy of venlafaxine, a serotonin/norepinephrine reuptake inhibitor. Chronic venlafaxine increases MMP-9 levels in murine cortex, and increases both pyramidal cell arborization and PSD-95 expression in wild type but not MMP-9 null mice. We have 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 expression of a PNN-component is increased in a corticosterone-induced stress model and that PNN-component cleavage is enhanced by venlafaxine in wild type but not MMP-9 null animals. Corticosterone- treated mice also display reduced ex vivo gamma power and impaired working memory, which is normalized by venlafaxine.  MMP-9 levels are elevated in the prefrontal cortex in anti-depressant-treated subjects with MDD, as compared to controls. These preclinical and postmortem findings suggest a link between extracellular matrix regulation and MDD.

For zoom details, please email Emily Beaufort (ebeauf2@uic.edu)