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| Open AccessSleep cycle-dependent vascular dynamics in male mice and the predicted effects on perivascular cerebrospinal fluid flow and solute transport
Why fluid and solute transport in perivascular spaces is enhanced upon sleep remains elusive. Here, the authors show that each sleep cycle state displays unique perivascular dynamics, which enhances predicted fluid movement and solute transport.
- Laura Bojarskaite
- , Alexandra Vallet
- & Rune Enger
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Article
| Open AccessSingle-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice
Oligodendrocytes have been increasingly shown to be involved in Alzheimer’s disease (AD). Here, the authors perform single-cell RNA-sequencing on APP NL-G-F mice and describe a disease-associated oligodendrocyte (DAO) population. They find inhibition of Erk1/2 signaling in DAOs rescues impaired axonal myelination and cognitive decline in an AD mouse model.
- Hanseul Park
- , Byounggook Cho
- & Jongpil Kim
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Article
| Open AccessCSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
Tau-mediated neurodegeneration is driven by disease-activated microglia and suppressed by their pharmacological blockade. The authors identified drug dose- and sex-dependent residual microglial phenotypes, neuronal excitotoxicity, and animal survival.
- Noah R. Johnson
- , Peng Yuan
- & Carlo Condello
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Article
| Open AccessAn astrocytic signaling loop for frequency-dependent control of dendritic integration and spatial learning
How glial cells like astrocytes shape complex brain functions remains unclear. Here, the authors identified an astrocyte-mediated excitatory signaling loop between neurons and their own dendritic signal integration that supports spatial memory.
- Kirsten Bohmbach
- , Nicola Masala
- & Christian Henneberger
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Article
| Open AccessAstrocytes amplify neurovascular coupling to sustained activation of neocortex in awake mice
Neuronal activity increases local cerebral blood flow (CBF) to satisfy metabolic demand, yet the role of astrocytes in this phenomenon is controversial. Here, the authors show that astrocytes amplify CBF only when neuronal activity is sustained.
- Adam Institoris
- , Milène Vandal
- & Grant R. Gordon
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Article
| Open AccessEndothelial cells regulate astrocyte to neural progenitor cell trans-differentiation in a mouse model of stroke
Damaged brains try to repair themselves by producing neurons in areas where neurogenesis does not normally occur. Here, the authors show that brain endothelial cells provide microvesicle-encased signals that convert parenchymal astrocytes into neural progenitors, thus improving outcomes after stroke.
- Wenlu Li
- , Emiri T. Mandeville
- & Eng H. Lo
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Article
| Open AccessVascular endothelium deploys caveolin-1 to regulate oligodendrogenesis after chronic cerebral ischemia in mice
OPC-vascular coupling contributes to myelin maintenance. Here the authors show Cav-1 stabilizes interactions and mediates OPC maturation in ischemia.
- Ying Zhao
- , Wusheng Zhu
- & Xinfeng Liu
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Article
| Open AccessHippocampal astrocytes modulate anxiety-like behavior
Astrocytes affect animal behaviors by regulating the tripartite synapse. Here, the authors show that hippocampal astrocytes modulate mouse anxiety-like behavior by regulating synaptic homeostasis of dentate gyrus granule cells via ATP release.
- Woo-Hyun Cho
- , Kyungchul Noh
- & Sung Joong Lee
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Article
| Open AccessMicroglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice
Microglia are professional phagocytes in the CNS. However, which cells scavenge corpses of microglia is largely neglected. Peng and colleagues found that nonprofessional phagocytes (astrocyte) phagocytose the debris of professional phagocytes (microglia).
- Tian Zhou
- , Yuxin Li
- & Bo Peng
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Article
| Open AccessSleep decreases neuronal activity control of microglial dynamics in mice
Microglia survey the parenchyma, which leads to morphology changes over time. Here the authors show using 2 photon imaging of microglia in vivo that sleep modulates microglial morphodynamics through Cx3cr1 signaling.
- I. Hristovska
- , M. Robert
- & O. Pascual
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Article
| Open AccessSingle cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model
Single cell RNA-sequencing of the AstTau neuron-asteroid tau assembloid model reveals excitatory neuron inflammatory signatures and an astrocytic heat shock response similar to that occurring in the brains of individuals with tauopathies, which can be ameliorated with a neuroprotective HSP90 inhibitor.
- Hannah Drew Rickner
- , Lulu Jiang
- & Christine S. Cheng
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Article
| Open AccessBrain milieu induces early microglial maturation through the BAX-Notch axis
The mechanisms by which the brain milieu confers microglial development are not clear. Here, the authors show that the BAX-CaMKII-CREB-Notch signaling axis triggered by the neuronal milieu plays a role in early microglia maturation.
- Fangying Zhao
- , Jiangyong He
- & Li Li
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Article
| Open AccessThe alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury
The neuroimmune interactions driving secondary degeneration in the injured spinal cord remain elusive. Here, the authors reveal that damaged microglia release IL-1α, resulting in neutrophil infiltration and the loss of mature oligodendrocytes through astrocytic and endothelial IL-1R1 in mice.
- Floriane Bretheau
- , Adrian Castellanos-Molina
- & Steve Lacroix
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Article
| Open AccessLesion environments direct transplanted neural progenitors towards a wound repair astroglial phenotype in mice
Effects of lesion environments on transplanted neural progenitor cells (NPC) are not well characterized. Here, the authors show that NPC transplanted into CNS lesions generate cells that share transcriptional and functional features with host wound repair astroglia in mice.
- T. M. O’Shea
- , Y. Ao
- & M. V. Sofroniew
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Article
| Open AccessRejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance
The authors discovered that proinflammatory senescent myeloid cells may recruit peripheral immune cells in the aged mouse brain. Their findings implicate senescent cell clearance as a strategy to counter aged brain inflammation and cognitive decline.
- Xu Zhang
- , Vesselina M. Pearsall
- & Marissa J. Schafer
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Article
| Open AccessCNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes
Understanding myelination is important for CNS plasticity and disease. Here the authors show exocytosis mediated by the vesicular SNARE proteins VAMP2/3 is involved in oligodendrocyte membrane expansion.
- Mable Lam
- , Koji Takeo
- & J. Bradley Zuchero
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Article
| Open AccessCa2+-modulated photoactivatable imaging reveals neuron-astrocyte glutamatergic circuitries within the nucleus accumbens
Neuron-astrocyte communication is fundamental for brain physiology, yet the heterogeneity in the functional interaction between these two elements remains poorly understood. Here we show how different neuron-astrocyte networks integrate information from distinct glutamatergic inputs.
- Irene Serra
- , Julio Esparza
- & Marta Navarrete
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Article
| Open AccessAn interplay between cellular growth and atypical fusion defines morphogenesis of a modular glial niche in Drosophila
Little is known of how the architectural complexity of the neural stem cell niche is achieved. Rujano et al. show that the morphogenesis of a glial niche in Drosophila involves complex proliferative strategies and atypical cell–cell fusion.
- Maria Alexandra Rujano
- , David Briand
- & Pauline Spéder
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Article
| Open AccessOligodendrocyte differentiation alters tRNA modifications and codon optimality-mediated mRNA decay
Mutations in tRNA processing factors can lead to myelin disorders. This study shows that differentiated oligodendrocytes, cells that make the myelin, are characterized by different tRNA modifications and mRNA decay compared to their precursor cells.
- Sophie Martin
- , Kevin C. Allan
- & Jeff Coller
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Article
| Open AccessSirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia
Neonatal hypoxia leads to white matter hypomyelination due to delayed oligodendrocyte maturation. The authors identify Sirt2 as a crucial regulator of oligodendrocyte differentiation during normal white matter development and in response to hypoxia.
- Beata Jablonska
- , Katrina L. Adams
- & Vittorio Gallo
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Article
| Open AccessChimeric GPCRs mimic distinct signaling pathways and modulate microglia responses
Understanding the function of GPCRs requires stimulation with their specific ligands. Here, the authors design chemogenetic G-protein coupled receptors that allows for the study of receptors without knowing the immediate ligand, and demonstrate its use for the β2-adrenergic receptor in microglia.
- Rouven Schulz
- , Medina Korkut-Demirbaş
- & Sandra Siegert
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Article
| Open AccessMicroglia coordinate cellular interactions during spinal cord repair in mice
Here the authors show, using microglia-specific depletion techniques and single cell transcriptomics, that optimal repair after murine spinal cord injury (SCI) requires microglia.
- Faith H. Brennan
- , Yang Li
- & Phillip G. Popovich
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Article
| Open AccessControlled activation of cortical astrocytes modulates neuropathic pain-like behaviour
Astrocytes may contribute to synaptic remodelling in the cortex in chronic pain states. Here the authors describe modulation of astrocyte activity to drive circuit reorganization in somatosensory cortex in mice, along with peripheral nerve block, which could be a potential therapeutic approach for the treatment of chronic pain.
- Ikuko Takeda
- , Kohei Yoshihara
- & Junichi Nabekura
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Matters Arising
| Open AccessMotor deficits seen in microglial ablation mice could be due to non-specific damage from high dose diphtheria toxin treatment
- Jiyun Peng
- , Qian Zou
- & Bao-Ming Li
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Article
| Open AccessMyotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes
Myotonic dystrophy type 1 (DM1) is characterized by debilitating neurological symptoms. Dinca et al. demonstrate the pronounced impact of DM1 on the morphology and RNA metabolism of astrocytes. Their findings suggest astroglial pathology in DM1 brain dysfunction.
- Diana M. Dincã
- , Louison Lallemant
- & Mário Gomes-Pereira
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Article
| Open AccessEndothelial cell heterogeneity and microglia regulons revealed by a pig cell landscape at single-cell level
Pigs are important large animal models for biomedical research. Here, the authors construct a single-cell landscape of pig tissues, unravelling the phenotypic heterogeneity of blood endothelial cells in adipose tissues and the evolutionally conserved regulons of microglia in brains.
- Fei Wang
- , Peiwen Ding
- & Yonglun Luo
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Article
| Open AccessMolecular and functional heterogeneity in dorsal and ventral oligodendrocyte progenitor cells of the mouse forebrain in response to DNA damage
Here the authors show that, depending on their distinct developmental origins and ability to counteract oxidative stress, dorsal and ventral oligodendrocyte progenitor cells of the postnatal mouse brain are differentially vulnerable to DNA damage.
- Enrica Boda
- , Martina Lorenzati
- & Annalisa Buffo
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Article
| Open AccessCO2 signaling mediates neurovascular coupling in the cerebral cortex
The mechanism of neurovascular coupling ensures that the brain energy supply is sufficient to meet demand. Here the authors show that in this mechanism CO2 plays an important role in neuronal activity-dependent regulation of local brain blood flow.
- Patrick S. Hosford
- , Jack A. Wells
- & Alexander V. Gourine
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Article
| Open AccessAstrocyte plasticity in mice ensures continued endfoot coverage of cerebral blood vessels following injury and declines with age
Disruption of the blood brain barrier can occur in several diseases. Here the authors show that targeted ablation of astrocytes results in a plasticity mechanism in nearby cells to maintain cerebrovascular coverage, but that this mechanism is impaired in older animals.
- William A. Mills III
- , AnnaLin M. Woo
- & Harald Sontheimer
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Article
| Open AccessImpaired bidirectional communication between interneurons and oligodendrocyte precursor cells affects social cognitive behavior
Early postnatal interruption of the bidirectional GABA/TNFSF12 signaling between parvalbumin-positive interneurons and oligodendrocyte precursor cells impairs correct prefrontal cortical network activity and social cognitive behavior later in life.
- Li-Pao Fang
- , Na Zhao
- & Xianshu Bai
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Article
| Open AccessRestoring nuclear entry of Sirtuin 2 in oligodendrocyte progenitor cells promotes remyelination during ageing
Age-dependent decline in remyelination in the CNS is associated with declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). Here, the authors show nuclear entry of SIRT2 is impaired and NAD+ levels are reduced during ageing in mouse OPCs. β-nicotinamide mononucleotide (β-NMN) supplement delays myelin aging and enhances remyelination in the aged mice.
- Xiao-Ru Ma
- , Xudong Zhu
- & Jing-Wei Zhao
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Article
| Open AccessWhite matter integrity in mice requires continuous myelin synthesis at the inner tongue
Myelin is formed of proteins of long half-lives. The mechanisms of renewal of such a stable structure are unclear. Here, the authors show that myelin integrity requires continuous myelin synthesis at the inner tongue, contributing to the maintenance of a functional axon-myelin unit.
- Martin Meschkat
- , Anna M. Steyer
- & Wiebke Möbius
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Article
| Open AccessAstrocytic phagocytosis contributes to demyelination after focal cortical ischemia in mice
Ischemic stroke can cause secondary demyelination. Whether phagocytic astrocytes can contribute to such demyelination is unclear. Here, the authors show that lipocalin-2 (LCN-2) expression increased in astrocytes upon injury. LCN-2 expressing astrocytes acquire a phagocytic phenotype and contribute to secondary demyelination in a mouse model of ischemic stroke.
- Ting Wan
- , Wusheng Zhu
- & Xinfeng Liu
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Article
| Open AccessSingle-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain
Microglia subpopulations may differentially contribute to pain. Here, the authors show that peripheral nerve injury induces time- and sex-specific transcriptional changes in mouse spinal cord microglia subpopulations and that ApoE is linked to neuropathic pain hypersensitivity in mice and humans.
- Shannon Tansley
- , Sonali Uttam
- & Arkady Khoutorsky
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Article
| Open AccessPhysiological synaptic activity and recognition memory require astroglial glutamine
The authors present a fluorescent probe that tracks glutamine in live cells. They demonstrate the capabilities of the probe by providing direct visual evidence of an activity-dependent glutamine supply from astroglial networks to presynaptic structures under physiological conditions.
- Giselle Cheung
- , Danijela Bataveljic
- & Nathalie Rouach
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Article
| Open AccessSchwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice
The mechanism of CGRP-evoked peripheral pain is unclear. Here, the authors show that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.
- Francesco De Logu
- , Romina Nassini
- & Pierangelo Geppetti
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Article
| Open AccessReactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology
Alzheimer’s disease is associated with changes in astrocytes. Here the authors investigated the astrocyte translatome associated with amyloid-ß and tau pathology.
- Zoeb Jiwaji
- , Sachin S. Tiwari
- & Giles E. Hardingham
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Article
| Open AccessStroke subtype-dependent synapse elimination by reactive gliosis in mice
Microglia and astrocytes clear neuronal debris after stroke, whether glia remain phagocytic and cause synapse loss at the subacute stage remains unknown. Here, the authors show in a murine model of ischemic stroke that inhibition of phagocytosis by MEGF10 and MERTK deletion in microglia and astrocytes attenuated damage and improved neurological outcomes by preventing synapse loss.
- Xiaojing Shi
- , Longlong Luo
- & Guo-Yuan Yang
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Article
| Open AccessNogoA-expressing astrocytes limit peripheral macrophage infiltration after ischemic brain injury in primates
Astrocytes are important players in ischemic stroke. Here, the authors use single nuclei transcriptomics to characterise marmoset astrocytes following brain injury. At functional level, they show that NogoAexpressing astrocytes limit macrophage infiltration.
- Anthony G. Boghdadi
- , Joshua Spurrier
- & James A. Bourne
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Article
| Open AccessDrosophila ßHeavy-Spectrin is required in polarized ensheathing glia that form a diffusion-barrier around the neuropil
In the invertebrate CNS, synapses and dendrites are clustered in distinct neuropil areas that are separated from neuronal cell bodies by ensheathing glia (EG). Here, the authors show that Drosophila EG are polarized cells that form an internal diffusion barrier. EG cell polarity requires βHeavy-Spectrin and is needed for normal locomotor behaviour.
- Nicole Pogodalla
- , Holger Kranenburg
- & Christian Klämbt
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Article
| Open AccessMicroglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
Whether microglial activation constitutes a primary pathological event in synucleinopathies is not known. Here, the authors generated a mouse model over-expressing α-synuclein in microglial cells and found these mice developed progressive dopaminergic neuron degeneration and microglia developed a reactive, pro-inflammatory state with phagocytic exhaustion.
- Simone Bido
- , Sharon Muggeo
- & Vania Broccoli
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Article
| Open AccessIn situ and transcriptomic identification of microglia in synapse-rich regions of the developing zebrafish brain
Microglia remodel synapses and engulf apoptotic cells. The molecular program underlying these distinct functions are unclear. Here, the authors identify distinct microglial subsets associated with synaptic vs. neurogenic regions of the developing zebrafish brain.
- Nicholas J. Silva
- , Leah C. Dorman
- & Anna V. Molofsky
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Article
| Open AccessNG2 glia-derived GABA release tunes inhibitory synapses and contributes to stress-induced anxiety
Nerve/glial antigen 2 (NG2) glia can sense synaptic inputs from neurons. Here, the authors show NG2 glia form functional GABAergic synapses by regulating inhibitory synaptic transmission onto adjacent hippocampal interneurons, and activation of NG2 glia induces anxiety-like behaviour in a mouse model of chronic social defeat stress.
- Xiao Zhang
- , Yao Liu
- & Xiaoping Tong
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Article
| Open AccessSelective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo
The mechanisms underlying the spreading of α-synuclein in various α-synucleinopathies are unclear. Here, the authors show that targeting the TLR2/MyD88/NF-κB pathway can reduce α-synuclein spreading, reduce neuroinflammation, and protect dopaminergic neurons in vitro and in mouse models
- Debashis Dutta
- , Malabendu Jana
- & Kalipada Pahan
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| Open AccessMicroglia have a grip on brain microvasculature
Microglia are brain resident immune cells with multiple functions. However, little is known about microglia-vascular interactions. In a recent paper published in Nature Communications, Bisht et al. identify a signalling mechanism that attracts and maintains microglia at the capillary wall. Moreover, they show that microglia regulate capillary vascular tone, playing a more significant role in blood flow regulation than previously thought.
- Kassandra Kisler
- , Angeliki Maria Nikolakopoulou
- & Berislav V. Zlokovic
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Article
| Open AccessCapillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice
Microglia are involved in debris clearance and synaptic pruning, among other processes. However, their direct interaction with the brain vasculature is less clear. Here, the authors show that capillary-associated microglia (CAMs) regulate vascular tone via PANX1-P2RY12 signalling.
- Kanchan Bisht
- , Kenneth A. Okojie
- & Ukpong B. Eyo
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Article
| Open AccessOlfactory bulb astrocytes mediate sensory circuit processing through Sox9 in the mouse brain
Astrocytes can regulate neuronal activity. Here, the authors show that astrocyte-specific deletion of Sox9 results in impaired neuronal sensory processing in the mouse adult olfactory bulb.
- Kevin Ung
- , Teng-Wei Huang
- & Benjamin R. Arenkiel
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Article
| Open AccessMicroglia-neuron interaction at nodes of Ranvier depends on neuronal activity through potassium release and contributes to remyelination
Microglia are important for brain homeostasis and plasticity. The mechanisms underlying microglia-neuron interactions are still unclear. Here, the authors show that microglia preferentially interact with the nodes of Ranvier along axons. This interaction is modulated by neuronal activity and contributes to remyelination in mice.
- R. Ronzano
- , T. Roux
- & A. Desmazières
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Article
| Open AccessOligodendrocytic Na+-K+-Cl– co-transporter 1 activity facilitates axonal conduction and restores plasticity in the adult mouse brain
Brain plasticity declines with age. Here, the authors show that NKCC1 regulates oligodendrocyte activity, facilitating neuronal plasticity during juvenile. Inducing activation of oligodendrocytic NKCC1 results in restoration of neuronal plasticity in the adult mouse brain.
- Yoshihiko Yamazaki
- , Yoshifumi Abe
- & Kenji F. Tanaka