Venlafaxine stimulates PNN proteolysis and MMP-9 dependent enhancement of gamma power; relevance to antidepressant efficacy

Abstract

Drugs that target monoaminergic transmission represent a first-line treatment for major depression. Though a full understanding of the mechanisms that underlie antidepressant efficacy is lacking, evidence supports a role for enhanced excitatory transmission. This can occur through two non-mutually exclusive mechanisms. The first involves increased function of excitatory neurons through relatively direct mechanisms such as enhanced dendritic arborization. Another mechanism involves reduced inhibitory function, which occurs with the rapid antidepressant ketamine. Consistent with this, GABAergic interneuron-mediated cortical inhibition is linked to reduced gamma oscillatory power, a rhythm also diminished in depression. Remission of depressive symptoms correlates with restoration of gamma power.Due to strong excitatory input, reliable GABA release and fast firing, PV neurons represent critical pacemakers for synchronous oscillations. PV neurons also represent the predominant GABAergic population enveloped by perineuronal nets (PNNs), lattice-like structures that localize glutamatergic input. Disruption of PNNs enhances lateral diffusion of glutamate receptors, reduces PV excitability, and enhances gamma activity.Studies suggest that monoamine reuptake inhibitors reduce integrity of the PNN. Mechanisms by which these inhibitors reduce PNN integrity, however, remain largely unexplored. A better understanding of these issues might encourage development of therapeutics that best upregulate PNN modulating proteases.We observe that the serotonin/norepinephrine reuptake inhibitor venlafaxine reduces PNN integrity in murine brain. Moreover, venlafaxine treated mice (30 mg/kg/day) show an increase in carbachol-induced gamma power in hippocampal slices. Studies with mice deficient in matrix metalloproteinase-9 (MMP-9), a protease linked to PNN disruption in other settings, suggest that MMP-9 contributes to venlafaxine-enhanced gamma activity.Recent work also suggests that PNN disruption can enhance cortical excitation and gamma activity (12).In terms of antidepressant therapy and the PNN, it is of interest that chronic treatment with fluoxetine decreases PNN staining in murine medial PFC and hippocampus (13). Recently published work has also shown that a stress related model of depression increases PNN staining (14).A relatively unexplored question is whether PNN reduction makes a substantial contribution to antidepressant efficacy and, if so, whether therapeutics or combinations beyond fluoxetine may best achieve this. The significance of this possibility is underlined by the widespread distribution of PNN enwrapped PV interneurons. As opposed to GABA-A α5 subunits, which have a depression-relevant but relatively restricted expression in forebrain, PNN enveloped PV neurons are found in multiple brain areas important to mood and memory.Studies that have examined PNN disruption for its potential to mediate cortical disinhibition have typically employed hyaluronidase, which targets the PNN backbone, or chondroitinase, which tar...