Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy

Tewari, Bhanu P.; Chaunsali, Lata; Campbell, Susan L.; Patel, Dipan; Goode, Adam E.; Sontheimer, Harald

doi:10.1038/s41467-018-07113-0

Cited by 145 publications

(226 citation statements)

References 62 publications

(87 reference statements)

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“…Several mechanisms may underlie the reduced inhibitory firing rates observed after PNN removal, e.g. increased membrane capacitance (29), reduced excitability (28), increased diffusion of AMPA receptors (27 ). We observed structural changes in synaptic input to PV + cells (Fig.…”

Section: Reducing Excitatory To Inhibitory Synaptic Strength Mimics Tmentioning

confidence: 78%

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Perineuronal nets stabilize the grid cell network

Christensen

Lensjø

Lepperød

et al. 2019

Preprint

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Grid cells are part of a widespread network that supports navigation and spatial memory. Stable grid patterns appear late in development, in concert with extracellular matrix aggregates termed perineuronal nets (PNNs) that condense around inhibitory neurons. To reveal the relationship between stable spatial representations and the presence of PNNs we recorded from populations of neurons in adult rats. We show that removal of PNNs leads to lower inhibitory spiking activity, and reduces grid cells' ability to create stable representations of a novel environment. Furthermore, in animals with disrupted PNNs, exposure to a novel arena corrupted the spatiotemporal relationships within grid cell modules, and the stored representations of a familiar arena. Finally, we show that PNN removal in entorhinal cortex distorted spatial representations in downstream hippocampal neurons. Together this work suggests that PNNs provide a key stabilizing element for the grid cell network.(9, 11). Once established, the periodic spiking pattern of grid cells is remarkably stable when animals revisit the same environment. Local perturbations of different cell types in MEC cause changes to grid field spike rates or an increased number of out-of-field spikes, but the location of the fields remains unaltered (12)(13)(14). Furthermore, when placed in a different environment, neighboring populations of grid cells show a coherent shift of grid fields (15) that retains their relative spatiotemporal relationships (16). In contrast the hippocampal place cells remap by independently and unpredictably changing their activity. This suggests that the mature grid cell network is more hardwired and less plastic than the hippocampal place cell network.The network that controls grid cell spiking is not yet fully understood, but recurrent inhibition appears to be fundamental to the specific activity of grid cells. Stellate cells, one of the two principal cell types that display grid cell firing (7 ), are connected via parvalbumin expressing (PV + ) inhibitory interneurons (17 , 18). PV + cells account for about 50% of the inhibitory cells in MEC (19), making them the main inhibitory mediator in the local grid cell network. In sensory cortex, PV + cells play a central role in shaping the excitatory activity of principal neurons by regulating the onset of periods of high synaptic plasticity (20). Whether PV + inhibitory neurons in MEC play a similar role for development of the grid cell network remains elusive.A hallmark of maturing PV + cells is that aggregates of specialized extracellular matrix, called perineuronal nets (PNNs), condense on the cell soma and proximal dendrites, leaving openings only for synaptic connections (21). PNNs are believed to help stabilize the activity of PV + cells by supporting synaptic integrity and limiting synaptogenesis, in addition to supporting PV + cell physiology (22). By the time PNNs in sensory cortex are fully mature, plasticity in the local network is strongly reduced. However, juvenile levels of plasticity can be r...

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Section: Reducing Excitatory To Inhibitory Synaptic Strength Mimics Tmentioning

confidence: 78%

“…Simulations were conducted to assess the effects of increased membrane capacitance due to removal of PNNs as reported by (29). To this end populations of excitatory and inhibitory neurons were simulated in a continuous attractor model.…”

Section: Continuous Attractor Modelmentioning

confidence: 99%

Perineuronal nets stabilize the grid cell network

Christensen

Lensjø

Lepperød

et al. 2019

Preprint

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“…At the single cell level, PNNs have been shown to decrease membrane capacitance allowing fast‐spiking interneurons to fire at high frequency (Tewari et al . ). In addition, disruption of the PNN has been linked to reduced glutamateric input to PV‐expressing interneurons (Hayani et al .…”

Section: Discussionmentioning

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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“…PV expressing interneurons are also the predominant neuronal population that is surrounded by the PNN, a dense form of extracellular matrix that can be cleaved by MMPs. 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%

“…In terms of E/I balance, MMPs have been shown to stimulate dendritic arborization of pyramidal neurons as well as dendritic spine formation and expansion (Wang et al, 2008;Allen et al, 2016 ). In addition, through cleavage of perineuronal net components, MMPs may reduce glutamate input and membrane capacitance of parvalbumin-expressing GABAreleasing interneurons thereby disinhibiting pyramidal neurons to indirectly enhance E/I balance (Frischknecht et al, 2009;Tewari et al, 2018).…”

Section: Introductionmentioning

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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Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy

Cited by 145 publications

References 62 publications

Perineuronal nets stabilize the grid cell network

Perineuronal nets stabilize the grid cell network

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

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