Attenuation of the extracellular matrix increases the number of synapses but suppresses synaptic plasticity through upregulation of SK channels

Dembitskaya, Yulia; Gavrilov, Nikolay; Kraev, Igor; Doronin, Maxim; Tang, Yong; Li, Li; Semyanov, Alexey

doi:10.1016/j.ceca.2021.102406

Cited by 13 publications

(26 citation statements)

References 76 publications

(78 reference statements)

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“…6 , was increased by a factor 1.5, and (when included) were shifted by 30 and 10 mV, respectively, while and were varied (jointly, when both were included) by factors between 1.5 and 4 as indicated in the figure legends. Upregulation of by such a high factor due to PNN degradation is supported by the experiments by Dembitskaya et al ( 2021 ). It was there found that on average, increased by a factor three after PNN degradation, but changes up to a factor six was within the standard deviation in the experimental data.…”

Section: Resultsmentioning

confidence: 68%

“…The increase in has experimental support, as attenuation of the extracellular matrix through application of chondroitinase ABC have been shown to upregulate SK-channels in hippocampal neurons, leading to an increase in by, on average, a factor 3 (see Fig. 2 f in Dembitskaya et al ( 2021 )). When it comes to , we found no mention in the literature as to whether it is affected by PNNs.…”

Section: Resultsmentioning

confidence: 91%

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Responses in fast-spiking interneuron firing rates to parameter variations associated with degradation of perineuronal nets

et al. 2023

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The perineuronal nets (PNNs) are sugar coated protein structures that encapsulate certain neurons in the brain, such as parvalbumin positive (PV) inhibitory neurons. As PNNs are theorized to act as a barrier to ion transport, they may effectively increase the membrane charge-separation distance, thereby affecting the membrane capacitance. Tewari et al. (2018) found that degradation of PNNs induced a 25%-50% increase in membrane capacitance $$c_\text {m}$$ c m and a reduction in the firing rates of PV-cells. In the current work, we explore how changes in $$c_\text {m}$$ c m affects the firing rate in a selection of computational neuron models, ranging in complexity from a single compartment Hodgkin-Huxley model to morphologically detailed PV-neuron models. In all models, an increased $$c_\text {m}$$ c m lead to reduced firing, but the experimentally reported increase in $$c_\text {m}$$ c m was not alone sufficient to explain the experimentally reported reduction in firing rate. We therefore hypothesized that PNN degradation in the experiments affected not only $$c_\text {m}$$ c m , but also ionic reversal potentials and ion channel conductances. In simulations, we explored how various model parameters affected the firing rate of the model neurons, and identified which parameter variations in addition to $$c_\text {m}$$ c m that are most likely candidates for explaining the experimentally reported reduction in firing rate.

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Section: Resultsmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 91%

Responses in fast-spiking interneuron firing rates to parameter variations associated with degradation of perineuronal nets

et al. 2023

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“…Tortuosity of ECS determines the diffusion path of extrasynaptic signaling molecules (including neurotransmitters and neuromodulators) [79]. The ECM is present throughout the ECS, where it limits rearrangements of cellular compartments (such as the formation of new synapses [80]) and interacts with receptors and channels, regulating their function [81]. The ECS is highly dynamic [82], it changes upon osmotic challenge [43], along the sleep-wake cycle [83], and in aging [84].…”

Section: The Ecs and Ecmmentioning

confidence: 99%

Astrocytic processes: from tripartite synapses to the active milieu

Semyanov

Verkhratsky

2021

Trends in Neurosciences

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145

115

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We define a new concept of 'active milieu' that unifies all components of nervous tissue (neuronal and glial compartments, extracellular space, extracellular matrix, and vasculature) into a dynamic information processing system. Within this framework, we focus on the role of astrocytic processes, classified into organellecontaining branches and organelle-free leaflets. We argue that astrocytic branches with emanating leaflets are homologous to dendritic shafts with spines. Within the active milieu, astrocytic processes are engaged in reciprocal interactions with neuronal compartments and communication with other cellular and non-cellular elements of the nervous tissue. The concept of the active milieuAxons of neurons provide the input and output of the central nervous system, whereas the intricate web of neurons, glia, and vasculature underlies information processing and defines the central nervous system function as an organ. The concept of tripartite synapse [1] has been instrumental in rethinking the role of astrocytes in synaptic transmission. Subsequent morphological analyses identified additional components of the synaptic structure. These components include microglial processes and the extracellular matrix (ECM), thus upgrading the tripartite paradigm to tetra-or pentapartite synapse [2,3]. These convolutions reflect a high degree of complexity of the perisynaptic microenvironment, a subject of remarkable morphological plasticity. In particular, interactions of synapses with their microenvironment are influenced by the interposition of individual synapses and nearby compartments of non-neuronal cells and extracellular space (ECS). Here we argue that the expanding knowledge on physiological interactions of cellular and non-cellular components of nervous tissue necessitates advancing the concept of 'tri-(multi)-partite synapse' to a concept we name 'active milieu'. The active milieu is based on the dynamic interposition and interaction among compartments of neurons, astrocytes, oligodendrocytes, microglia, blood vessels, ECS, and ECM (Box 1 and Figure 1). In the framework of this concept, neuronal activity not only propagates from one neuron to another but also signals to other cellular and noncellular elements, which respond to this signal and affect all components of nervous tissue.

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“…It is possible that the decrease in ECM expression may help increase synaptic function in Shank2-KO mice and memantinetreated WT mice. In line with this idea, a recent study showed that targeted degradation of the ECM with chondroitinase ABC induces an increase in the number of excitatory synapses (Dembitskaya et al, 2021).…”

Section: Discussionmentioning

confidence: 84%

Early Chronic Memantine Treatment-Induced Transcriptomic Changes in Wild-Type and Shank2-Mutant Mice

Yoo

Lee

Kim

et al. 2021

Front. Mol. Neurosci.

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Shank2 is an excitatory postsynaptic scaffolding protein strongly implicated in autism spectrum disorders (ASDs). Shank2-mutant mice with a homozygous deletion of exons 6 and 7 (Shank2-KO mice) show decreased NMDA receptor (NMDAR) function and autistic-like behaviors at juvenile [∼postnatal day (P21)] and adult (>P56) stages that are rescued by NMDAR activation. However, at ∼P14, these mice show the opposite change – increased NMDAR function; moreover, suppression of NMDAR activity with early, chronic memantine treatment during P7–21 prevents NMDAR hypofunction and autistic-like behaviors at later (∼P21 and >P56) stages. To better understand the mechanisms underlying this rescue, we performed RNA-Seq gene-set enrichment analysis of forebrain transcriptomes from wild-type (WT) and Shank2-KO juvenile (P25) mice treated early and chronically (P7–21) with vehicle or memantine. Vehicle-treated Shank2-KO mice showed upregulation of synapse-related genes and downregulation of ribosome- and mitochondria-related genes compared with vehicle-treated WT mice. They also showed a transcriptomic pattern largely opposite that observed in ASD (reverse-ASD pattern), based on ASD-related/risk genes and cell-type–specific genes. In memantine-treated Shank2-KO mice, chromatin-related genes were upregulated; mitochondria, extracellular matrix (ECM), and actin-related genes were downregulated; and the reverse-ASD pattern was weakened compared with that in vehicle-treated Shank2-KO mice. In WT mice, memantine treatment, which does not alter NMDAR function, upregulated synaptic genes and downregulated ECM genes; memantine-treated WT mice also exhibited a reverse-ASD pattern. Therefore, early chronic treatment of Shank2-KO mice with memantine alters expression of chromatin, mitochondria, ECM, actin, and ASD-related genes.

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Attenuation of the extracellular matrix increases the number of synapses but suppresses synaptic plasticity through upregulation of SK channels

Cited by 13 publications

References 76 publications

Responses in fast-spiking interneuron firing rates to parameter variations associated with degradation of perineuronal nets

Responses in fast-spiking interneuron firing rates to parameter variations associated with degradation of perineuronal nets

Astrocytic processes: from tripartite synapses to the active milieu

Early Chronic Memantine Treatment-Induced Transcriptomic Changes in Wild-Type and Shank2-Mutant Mice

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