Increased Excitability and Reduced Excitatory Synaptic Input Into Fast-Spiking CA2 Interneurons After Enzymatic Attenuation of Extracellular Matrix

Hayani, Hussam; Song, Inseon; Dityatev, Alexander

doi:10.3389/fncel.2018.00149

Cited by 70 publications

(73 citation statements)

References 69 publications

(94 reference statements)

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“…Imipramine normalized stress-associated changes in PNN, though underlying molecular mechanisms were not examined (Riga et al, 2017). Since PNN reductions are linked to pyramidal cell disinhibition (Hayani et al, 2018), our work supports a link between monoamine reuptake inhibition and increased in E/I balance.…”

Section: Discussionsupporting

confidence: 70%

“…Since PV fast spiking interneuron activity is critical to gamma and ripple expression, it is of interest that despite reduced PV activity with PNN attenuation (Hayani et al, 2018;Tewari et al, 2018), gamma oscillations and SWR events are not only maintained but increased in power and event frequency. This is consistent with the possibility that the PV population retains responsivity when excitatory input is strong, and is supported by previous work (Balmer, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…PNNs provide PV neurons with increased membrane capacitance and also localize glutamate input to synaptic contacts, thus facilitating the release of GABA from PV interneurons and thereby inhibiting pyramidal neuron activity (Frischknecht et al, 2009;Tewari et al, 2018). Disruption of the PNN can instead reduce PV-mediated pyramidal cell inhibition (Hayani et al, 2018).…”

Section: Vfx Increases Brevican (Bcan) Cleavage In Wild Type But Not mentioning

confidence: 99%

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

Alaiyed

McCann

Mahajan

et al. 2019

Preprint

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AbstractEmerging 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 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 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 anti-depressant treated MDD patients as compared to controls. These preclinical and postmortem findings highlight a link between extracellular matrix regulation and MDD.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Vfx Increases Brevican (Bcan) Cleavage In Wild Type But Not mentioning

confidence: 99%

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

Alaiyed

McCann

Mahajan

et al. 2019

Preprint

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“…Consistent with this, enzymatic degradation of the PNN reduces the frequency of excitatory post‐synaptic currents in hippocampal fast‐spiking interneurons (Hayani et al . ). Recent work also suggests that PNN disruption can enhance cortical excitation and gamma activity (Lensjo et al .…”

mentioning

confidence: 97%

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

Alaiyed

Bozzelli

Caccavano

et al. 2019

Journal of Neurochemistry

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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. As a result of strong excitatory input, reliable GABA release, and fast firing, PV‐expressing neurons (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 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 up‐regulate PNN‐modulating proteases. We observe that the serotonin/norepinephrine reuptake inhibitor venlafaxine increases hippocampal matrix metalloproteinase (MMP)‐9 levels as determined by ELISA and concomitantly reduces PNN integrity in murine hippocampus as determined by analysis of sections following their staining with a fluorescent PNN‐binding lectin. Moreover, venlafaxine‐treated mice (30 mg/kg/day) show an increase in carbachol‐induced gamma power in ex vivo hippocampal slices as determined by local field potential recording and Matlab analyses. 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 power. In conclusion, our results support the possibility that MMP‐9 activity contributes to antidepressant efficacy through effects on the PNN that may in turn enhance neuronal population dynamics involved in mood and/or memory. Cover Image for this issue: doi: .

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“…Disruption of the PNN leads to increased lateral diffusion of glutamate receptor subunits on PV cells (10), and it may also result in increased diffusion of glutamate. Consistent with this, enzymatic degradation of the PNN reduces the frequency of excitatory post synaptic currents in hippocampal fast spiking interneurons (11). Recent work also suggests that PNN disruption can enhance cortical excitation and gamma activity (12).…”

Section: Introductionmentioning

confidence: 64%

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

Alaiyed¹,

Bozzelli²,

Caccavano³

et al. 2018

Preprint

View full text Add to dashboard Cite

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...

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Increased Excitability and Reduced Excitatory Synaptic Input Into Fast-Spiking CA2 Interneurons After Enzymatic Attenuation of Extracellular Matrix

Cited by 70 publications

References 69 publications

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

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

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

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

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