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| Open AccessAstroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model
Fragile X syndrome is a neurodevelopmental disorder with altered neuronal excitability and behavior. Here, the authors show that dysfunction of astroglial Kir4.1 potassium channels drives neuronal and behavioral impairments in a fragile X mouse model.
- Danijela Bataveljic
- , Helena Pivonkova
- & Nathalie Rouach
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Article
| Open AccessReconstruction of macroglia and adult neurogenesis evolution through cross-species single-cell transcriptomic analyses
Macroglia are neural cells that have garnered less interest than neurons despite their crucial functions including neurogenesis. Here the authors use sequencing from several species to investigate the evolution of macroglia and of adult neurogenesis.
- David Morizet
- , Isabelle Foucher
- & Laure Bally-Cuif
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Article
| Open AccessMulticore fiber optic imaging reveals that astrocyte calcium activity in the mouse cerebral cortex is modulated by internal motivational state
Astrocyte calcium increases can alter brain state, but their dynamics during different behaviors have not been fully described. Here, the authors use multicore fiber optic imaging in freely moving mice to show that astrocyte engagement in behavior is influenced by the motivational state.
- Yung-Tian A. Gau
- , Eric T. Hsu
- & Dwight E. Bergles
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Article
| Open AccessShared inflammatory glial cell signature after stab wound injury, revealed by spatial, temporal, and cell-type-specific profiling of the murine cerebral cortex
Glial cells and their crosstalk after injury are crucial for brain regeneration. Here, the authors show the spatial, temporal, and single-cell responses of glial cells after injury and identify shared pathways controlling glial reactivity.
- Christina Koupourtidou
- , Veronika Schwarz
- & Jovica Ninkovic
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Article
| Open AccessAge-progressive interplay of HSP-proteostasis, ECM-cell junctions and biomechanics ensures C. elegans astroglial architecture
Neural circuit architecture must be maintained during an animal’s lifetime. Here, the authors show that a protective mechanism combining proteostasis and biomechanics supports the integrity of glial cells to environmental stressors.
- Francesca Coraggio
- , Mahak Bhushan
- & Georgia Rapti
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Article
| Open AccessExpression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia
Mutations in profilin 1 (PFN1), which modulates actin dynamics, are associated with ALS. Here the authors show that expression of ALS-PFN1 is sufficient to induce deficits in human microglia-like cells, including impaired phagocytosis and lipid metabolism, and that gain-of-function interactions between ALS-PFN1 and PI3P may underlie these deficits.
- Salome Funes
- , Jonathan Jung
- & Daryl A. Bosco
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Article
| Open AccessHypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity
The cellular levels of the critical coenzyme nicotinamide adenine dinucleotide (NAD)+ depend on its salvage pathway. Here, the authors show that the NAD+ salvage pathway in hypothalamic astrocytes is activated to promote obesity in high fat diet-fed mice.
- Jae Woo Park
- , Se Eun Park
- & Min-Seon Kim
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Article
| Open AccessBHLHE40/41 regulate microglia and peripheral macrophage responses associated with Alzheimer’s disease and other disorders of lipid-rich tissues
Factors regulating lipid and lysosomal clearance in microglia and peripheral macrophage are not known. Here, authors nominate and validate transcription factors BHLHE40 and BHLHE41 as regulators of these processes in health and disease.
- Anna Podleśny-Drabiniok
- , Gloriia Novikova
- & Alison Mary Goate
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Article
| Open AccessProfiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation
Microglia nodules are associated with brain pathology. Here, the authors show demyelination in microglia nodules in multiple sclerosis (MS), likely due to oxidized phospholipid phagocytosis and immune activation, suggesting that nodules could be involved in MS lesion formation.
- Aletta M. R. van den Bosch
- , Marlijn van der Poel
- & Jörg Hamann
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Article
| Open AccessCortical astrocyte N-methyl-D-aspartate receptors influence whisker barrel activity and sensory discrimination in mice
The role of astrocyte NMDA receptor signaling in cortical circuits is unclear. Here, the authors show that NMDA receptors contribute to astrocyte calcium events and support neuronal processing of sensory information that maintains sensory activity in mice.
- Noushin Ahmadpour
- , Meher Kantroo
- & Jillian L. Stobart
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Article
| Open AccessIntegrating single-cell and spatially resolved transcriptomic strategies to survey the astrocyte response to stroke in male mice
Astrocytes adopt diverse states in response to brain injuries. Here, the authors develop a platform for spatially resolved, single-cell transcriptomics and proteomics, called tDISCO (tissue-digital microfluidic isolation of single cells for -Omics) to uncover the spatial boundaries of molecularly distinct reactive astrocyte populations in stroke.
- Erica Y. Scott
- , Nickie Safarian
- & Maryam Faiz
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Article
| Open AccessRegulation of stress granule formation in human oligodendrocytes
Oligodendrocyte (OL) injury and loss is a pathologic hallmark of multiple sclerosis. Here, the authors show the presence of stress granules in OLs in multiple sclerosis lesions, and their in vitro studies in human OLs indicate that stress granules formation is a response to a combination of metabolic stress and pro-inflammatory conditions.
- Florian Pernin
- , Qiao-Ling Cui
- & Jack P. Antel
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Article
| Open AccessNeuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation
The glutamate transporter GLAST in astrocyte regulates synapse function by glutamate clearance. Here, the authors show that Down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls synaptogenesis through the intercellular association with GLAST in the developing cerebellum.
- Ken-ichi Dewa
- , Nariko Arimura
- & Mikio Hoshino
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Article
| Open AccessDisruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model
The protein DJ1, encoded by the PARK7 gene, is causally linked to development of early-onset PD. Here the authors observed that the loss of DJ1 function in midbrain organoids led to astrocyte dysfunction, impairing protein clearance, accumulation of α-synuclein.
- Gustavo Morrone Parfitt
- , Elena Coccia
- & Tim Ahfeldt
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Article
| Open AccessMicroglia govern the extinction of acute stress-induced anxiety-like behaviors in male mice
Stress-related anxiety can gradually become extinct but the underlying mechanisms are unclear. Here, the authors show that microglial engulfment of dendritic spines promotes the extinction of acute stress-induced anxiety-like behaviors in mice.
- Danyang Chen
- , Qianqian Lou
- & Yan Jin
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Article
| Open AccessOligodendrocyte calcium signaling promotes actin-dependent myelin sheath extension
The cell biological mechanisms that govern myelin sheath extension remain incompletely understood. Here, the authors find that calcium signaling in oligodendrocytes is required for the actin-dependent extension of myelin sheaths.
- Manasi Iyer
- , Husniye Kantarci
- & J. Bradley Zuchero
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Article
| Open AccessMitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex
How aging affects the brain active milieu remains unknown. Here, the authors reveal atrophy and mitochondrial malfunction of astrocytes but not neurons in older human neocortex.
- Alexander Popov
- , Nadezda Brazhe
- & Alexey Semyanov
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Article
| Open AccessNorepinephrine regulates calcium signals and fate of oligodendrocyte precursor cells in the mouse cerebral cortex
How oligodendrocyte precursor cells (OPCs) integrate calcium signals and neuromodulatory cues to regulate fate is unclear. Here, the authors report that locomotion-induced norepinephrine release modulates OPC calcium dynamics and differentiation.
- Frederic Fiore
- , Khaleel Alhalaseh
- & Amit Agarwal
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Article
| Open AccessCell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease
Alzheimer’s disease genetic risk is enriched in glial genes. Here, the authors derive cell-type-specific polygenic risk scores and link astrocytic genes with Aβ, and microglial genes with Aβ, tau, microglial activation, and cognitive decline.
- Hyun-Sik Yang
- , Ling Teng
- & Reisa A. Sperling
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Article
| Open AccessINPP5D regulates inflammasome activation in human microglia
INPP5D/SHIP1 is a microglial-expressed gene that has been associated with Alzheimer’s disease through genetic studies. This study reveals that reduction in INPP5D activity induces activation of the NLRP3-inflammasome in human microglia.
- Vicky Chou
- , Richard V. Pearse II
- & Tracy L. Young-Pearse
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Article
| Open AccessA toolbox of astrocyte-specific, serotype-independent adeno-associated viral vectors using microRNA targeting sequences
Astrocytes, highly prevalent cells in the central nervous system, have been difficult to specifically target with adeno-associated viruses (AAVs). Here, the authors present a microRNA targeting cassette that de-targets other cells, increasing astrocyte specificity of AAVs to over 99%.
- Amy J. Gleichman
- , Riki Kawaguchi
- & S. Thomas Carmichael
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Article
| Open AccessLipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment
Microglia are brain macrophages that engulf and clear cellular material and protein aggregates. Here, the authors show that lipofuscin-like autofluorescence can confound microglial engulfment analyses, which they can resolve with a photobleaching protocol.
- Jacob M. Stillman
- , Francisco Mendes Lopes
- & Dorothy P. Schafer
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Article
| Open AccessGlia instruct axon regeneration via a ternary modulation of neuronal calcium channels in Drosophila
Limited neuron regeneration is the key barrier to recovery after central nervous system damage. Here, the authors show that axon regeneration is regulated by glia in a multi-layered manner controlling regeneration-dependent neuronal calcium channels.
- Shannon Trombley
- , Jackson Powell
- & Yuanquan Song
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Article
| Open AccessSpecies-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction
The innate immune cells undergo metabolic reprogramming upon inflammation. Here, the authors report that both mouse and human microglia display a metabolic reprogramming in the presence of a TLR4 activation, however species-specific enzymes are responsible for this process.
- Angélica María Sabogal-Guáqueta
- , Alejandro Marmolejo-Garza
- & Amalia Dolga
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Article
| Open AccessEstrogen receptor beta in astrocytes modulates cognitive function in mid-age female mice
Here the authors show in female mice at mid-life that deletion of estrogen receptor β in astrocytes induced cognitive impairment, hippocampal atrophy, glial activation and synaptic loss. ERβ ligand treatment restored cognition and decreased neuropathology in these animals.
- Noriko Itoh
- , Yuichiro Itoh
- & Rhonda R. Voskuhl
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Article
| Open AccessFEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins
When and how microglia engulf synapses and myelin is still unclear. Here, the authors provide a suite of flow cytometry-based approaches to quantify engulfment, paving the way for high-throughput assessment of microglial function in health and disease.
- Lasse Dissing-Olesen
- , Alec J. Walker
- & Beth Stevens
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Article
| Open AccessC9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9
The role of microglia in amyotrophic lateral sclerosis (ALS) is unclear. Here, the authors show that iPSC microglia from C9orf72-ALS patients are toxic to motor neurons and identify microglial MMP9 as a potential therapeutic target.
- Björn F. Vahsen
- , Sumedha Nalluru
- & Kevin Talbot
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Article
| Open AccessLoss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice
The role of lactate in the control of microglial function remains poorly investigated. Here, the authors show that lactate promotes lysosomal acidification in microglia, and that mice lacking the lactate transporter MCT4 in these cells display defective brain development and anxiety-like behavior.
- Katia Monsorno
- , Kyllian Ginggen
- & Rosa Chiara Paolicelli
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Article
| Open AccessPD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation
Co-inhibitory signaling controls immune mechanisms in health and disease. The authors here show that in autoimmune neuroinflammation, astrocytic PD-L1 mitigates autoimmune neuroinflammation through interaction with PD1 expressing microglia.
- Mathias Linnerbauer
- , Tobias Beyer
- & Veit Rothhammer
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Article
| Open AccessAstrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels
Neuroinflammation is a common feature of many neurological disorders. Here, the authors show that the Orai1 calcium channel functions as a signaling hub in astrocytes to control astrocyte-driven brain inflammation and inflammation-induced depression-like behaviors in mice.
- Michaela M. Novakovic
- , Kirill S. Korshunov
- & Murali Prakriya
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Article
| Open AccessPurinergic signaling mediates neuroglial interactions to modulate sighs
Sighs are augmented breaths necessary to maintain normal breathing. Here, the authors show that sighs are generated within the preBötzinger complex by emergent network properties that involve neuroglial interactions mediated by purinergic signaling as well as intrinsic and extrinsic modulatory inputs.
- Liza J. Severs
- , Nicholas E. Bush
- & Jan-Marino Ramirez
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Article
| Open AccessTranslocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
TSPO PET imaging is widely used to quantify microglial activation. Here, the authors show that TSPO expression increases in activated rodent but not human microglia, implying that in humans TSPO informs on microglial density rather than activation status.
- Erik Nutma
- , Nurun Fancy
- & David R. Owen
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Article
| Open AccessMicroglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice
The circadian clock protein REV-ERBα has been implicated in neuroinflammation but mechanisms are poorly understood. Here, the authors show that microglial REV-ERBα regulates inflammatory signaling and lipid droplet formation to exert sex-specific effects on tau pathology in mice.
- Jiyeon Lee
- , Julie M. Dimitry
- & Erik S. Musiek
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Article
| Open AccessAstroglial exosome HepaCAM signaling and ApoE antagonization coordinates early postnatal cortical pyramidal neuronal axon growth and dendritic spine formation
How developing astroglia regulate postnatal axon growth is unknown. Here, the authors define an astroglial exosome surface HepaCAM contact mechanism in regulating axon growth and how its antagonization by ApoE coordinates early postnatal pyramidal neuronal development.
- Shijie Jin
- , Xuan Chen
- & Yongjie Yang
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Article
| Open AccessGlial Draper signaling triggers cross-neuron plasticity in bystander neurons after neuronal cell death in Drosophila
Neuronal death is a feature of development and neurodegeneration. Here, the authors report that ablation of Drosophila motor neurons triggers Draper-dependent signaling in glia to engage ‘cross-neuron plasticity’ in bystander neurons.
- Yupu Wang
- , Ruiling Zhang
- & Robert A. Carrillo
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Article
| Open AccessVγ1 and Vγ4 gamma-delta T cells play opposing roles in the immunopathology of traumatic brain injury in males
Traumatic brain injury is not only a neurological but also an immunological condition in which multiple innate and adaptive immune cell types play roles. Here authors show in a mouse model that the Vγ4 subtype of the unconventional gamma-delta T cells promote neuroinflammation, while the Vγ1 subtype ameliorates immunopathology.
- Hadi Abou-El-Hassan
- , Rafael M. Rezende
- & Howard L. Weiner
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Article
| Open AccessSpatial Transcriptomics-correlated Electron Microscopy maps transcriptional and ultrastructural responses to brain injury
To understand complexity of cellular function, multiple phenotypic readouts are needed. Here, authors devised an approach integrating location, transcriptome, ultrastructure, and lipid content to characterize single-cell states after brain injury.
- Peter Androvic
- , Martina Schifferer
- & Ozgun Gokce
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Article
| Open AccessThe cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells
Niemann-Pick type C disease is characterized by deficiency of the endolysosomal cholesterol transporter NPC1. Here, the authors show in Npc1−/− mice that loss of NPC1 impairs oligodendrocyte lineage cell differentiation and developmental myelination through perturbed epigenetic regulation.
- Thaddeus J. Kunkel
- , Alice Townsend
- & Andrew P. Lieberman
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Comment
| Open AccessCNS-associated macrophages shape the inflammatory response in a mouse model of Parkinson’s disease
In an alpha-synuclein (α-syn) model of Parkinson’s disease (PD), Schonhoff and colleagues have shown that central nervous system (CNS)-associated macrophages (CAMs), but not microglia, potentially orchestrate CD4+ T cell recruitment and mediate an α-syn-induced inflammatory makeup.
- Maximilian Frosch
- , Lukas Amann
- & Marco Prinz
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Article
| Open AccessAAV11 enables efficient retrograde targeting of projection neurons and enhances astrocyte-directed transduction
Viral tracers play a crucial role in studying neural circuits, but current options are limited in areas like retrograde transduction and astrocytic tropism. Here, the authors demonstrate that AAV11 function as a powerful retrograde viral tracer allowing for analyzing circuit connectivity and shows superior astrocytic tropism compared to the commonly used AAV vectors.
- Zengpeng Han
- , Nengsong Luo
- & Fuqiang Xu
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Article
| Open AccessBorder-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease
Neuroinflammatory mechanisms are implicated in Parkinson disease. Here we identify border-associated macrophages (BAMs), as essential for the α-synuclein-mediated neuroinflammatory response via class II antigen presentation, and T cell infiltration.
- A. M. Schonhoff
- , D. A. Figge
- & A. S. Harms
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Article
| Open AccessGalectin-3 activates spinal microglia to induce inflammatory nociception in wild type but not in mice modelling Alzheimer’s disease
In inflammatory arthritis, pain neurons communicate with spinal cord microglia to establish nociception. Here, the authors show that this communication is mediated by pain neurons releasing galectin-3, which activates microglia through TLR4. In a mouse model of Alzheimer’s disease, pain is attenuated because microglia lack expression of TLR4.
- George Sideris-Lampretsas
- , Silvia Oggero
- & Marzia Malcangio
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Article
| Open AccessAstrocyte-oligodendrocyte interaction regulates central nervous system regeneration
The mechanisms regulating central nervous system remyelination efficiency are poorly understood. Here, the authors show that remyelination is driven by astrocytes supporting oligodendrocyte survival, regulated by the Nrf2 and cholesterol pathways.
- Irene Molina-Gonzalez
- , Rebecca K. Holloway
- & Veronique E. Miron
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Article
| Open AccessLC3-associated phagocytosis promotes glial degradation of axon debris after injury in Drosophila models
Glia are housekeepers of the nervous system that eliminate neuronal debris after injury. Here, the authors show that LC3-associated phagocytosis in Drosophila glia promotes debris clearance after wing nerve injury and recovery after traumatic brain injury.
- Áron Szabó
- , Virág Vincze
- & Gábor Juhász
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Article
| Open AccessGlycolytically impaired Drosophila glial cells fuel neural metabolism via β-oxidation
Drosophila are able to survive for several weeks in the absence of glial glycolysis. Here, the authors show that glial cells can utilize fatty acids to supply neurons under restrictive conditions and glial cells act as a metabolic sensor and induce mobilization of peripheral energy stores.
- Ellen McMullen
- , Helen Hertenstein
- & Stefanie Schirmeier
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Article
| Open AccessDistinct astrocytic modulatory roles in sensory transmission during sleep, wakefulness, and arousal states in freely moving mice
The contribution of astrocytic Ca2+ signaling to the modulation of sensory transmission in different brain states remains largely unknown. Here, the authors show two types of Ca2+ signals in the mouse barrel cortex with distinct function in sensory transmission during sleep and arousal states.
- Fushun Wang
- , Wei Wang
- & Jason H. Huang
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Article
| Open AccessAstrocytic chloride is brain state dependent and modulates inhibitory neurotransmission in mice
Astrocytes act as a dynamic Cl− reservoir regulating Cl− homeostasis in the CNS. Astrocytic Cl− is high and stable during sleep, it is lower during wakefulness and fluctuates in response to sensory input and motor activity. Efflux of Cl− from astrocytes supports inhibitory transmission in the CNS.
- Verena Untiet
- , Felix R. M. Beinlich
- & Maiken Nedergaard
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Perspective
| Open AccessAn aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
In this perspective, the authors hypothesise that glial senescence, requiring senescent microglia burden, perpetuates further aging, Alzheimer’s pathologies, and senescence. Increasing glial senescence is proposed as necessary to drive individuals from healthy cognition into cognitive decline and dementia.
- Victor Lau
- , Leanne Ramer
- & Marie-Ève Tremblay
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Article
| Open AccessPurkinje cell dopaminergic inputs to astrocytes regulate cerebellar-dependent behavior
The role of dopamine in the cerebellum remains relatively unexplored. Here, the authors report a dopamine system in the cerebellum in mice, where Purkinje cells supply dopamine and Bergmann glia express D1 receptors. Activation of D1 receptors is found to modulate Purkinje cell activity and to affect locomotor and social behaviors.
- Chang Li
- , Natalie B. Saliba
- & Wei Li