Shaping Synapses by the Neural Extracellular Matrix

Ferrer-Ferrer, Maura; Dityatev, Alexander

doi:10.3389/fnana.2018.00040

Cited by 149 publications

(115 citation statements)

References 221 publications

(269 reference statements)

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“…). Similarly MMP‐9 inhibitors have no effects on baseline properties of neurotransmission and spine size or morphology [reviewed in (Ferrer‐Ferrer and Dityatev )].…”

Section: Resultsmentioning

confidence: 99%

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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“…). Similarly MMP‐9 inhibitors have no effects on baseline properties of neurotransmission and spine size or morphology [reviewed in (Ferrer‐Ferrer and Dityatev )].…”

Section: Resultsmentioning

confidence: 99%

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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“…We thus tested E/I balance in ex vivo murine slices using an approach based on neuronal Similar to other neurophysiological endpoints (Nagy et al, 2006;Ferrer-Ferrer and Dityatev, 2018), significant basal differences in gamma power were not observed.…”

Section: Discussionmentioning

confidence: 99%

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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“…The somata and dendrites of most of these PV+ neurons are surrounded by perineuronal nets (PNNs), condensed extracellular matrix structures that surround synapses and are involved in the control of developmental and adult plasticity (5)(6)(7)(8). Digestion of inhibitory CSPGs (the main effectors of PNNs) with chondroitinase ABC (ChABC), enables increased formation of inhibitory synapses on PV + neurons (2,9), and enhances memory formation and duration in young animals, as does transgenic attenuation of PNNs (10,11). Moreover in animals with defective memory due to pathology from mutant tau or amyloid-beta, CSPG digestion or antibody treatment to block inhibitory 4-sulphated CS-GAGs restores memory to normal levels (12)(13)(14).…”

Section: Resultsmentioning

confidence: 99%

Restoring the pattern of proteoglycan sulphation in perineuronal nets corrects age-related memory loss

Yang

Gigout

Molinaro

et al. 2020

Preprint

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Short title: PNN sulphation corrects restores memory lossOne sentence summary: Sulphation changes in perineuronal nets lead to age-related memory loss; correction of sulphation restores memory. AbstractMemory loss is a usual consequence of ageing. In aged brains, perineuronal nets (PNNs), which limit neuroplasticity and are implicated in memory, become inhibitory due to decreased 6sulphation of their glycan chains (C6S). Aged mice show progressive deficits in memory tasks, but removal of PNNs or digestion of their glycans rescued age-related memory loss. Reduction of permissive C6S by transgenic deletion of 6-sulfotransferase led to very early memory loss.However, restoring C6S levels in aged animals by AAV delivery or transgenic expression of 6sulfotransferase restored memory. Low C6S levels caused loss of cortical long-term potentiation, which was restored by AAV-mediated 6-sulfotransferase delivery. The study shows that loss of C6S in the aged brain leads to declining memory and cognition, which can be restored by C6S replacement.

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Shaping Synapses by the Neural Extracellular Matrix

Cited by 149 publications

References 221 publications

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

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

Restoring the pattern of proteoglycan sulphation in perineuronal nets corrects age-related memory loss

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