Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic Transmission and Promotes Brain Damage in Stroke

Yang, Junhua; Vitery, Maria del Carmen; Chen, Jianan; Osei-Owusu, James; Chu, Jiachen; Qiu, Zhaozhu

doi:10.1016/j.neuron.2019.03.029

Cited by 170 publications

(222 citation statements)

References 62 publications

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“…However, our brain-specific LRRC8A KO mice developed apparently normally and then died suddenly. Notably, our findings are in contrast with the study of Yang et al that produced the first conditional deletion of LRRC8A in the brain, using the relatively astrocyte-selective GFAP promoter (Yang et al 2019). In their publication, removal of astrocytic LRRC8A reduced neuronal excitability, impaired long-term potentiation and learning, and protected against experimental stroke; however, no increased mortality or developmental abnormalities in the CNS were reported (Yang et al 2019).…”

Section: Discussioncontrasting

confidence: 99%

“…Notably, our findings are in contrast with the study of Yang et al that produced the first conditional deletion of LRRC8A in the brain, using the relatively astrocyte-selective GFAP promoter (Yang et al 2019). In their publication, removal of astrocytic LRRC8A reduced neuronal excitability, impaired long-term potentiation and learning, and protected against experimental stroke; however, no increased mortality or developmental abnormalities in the CNS were reported (Yang et al 2019). These latter findings are consistent with the longstanding idea that astrocytic VRAC promotes neuronal excitability and brain damage via physiological and pathological release of the excitatory amino acid transmitters, aspartate and glutamate (Kimelberg and Mongin 1998;Kimelberg 2005;Mongin 2016;Mongin 2007).…”

Section: Discussioncontrasting

confidence: 99%

“…More recent seminal work by Zhaozhu Qiu and coworkers produced the first conditional deletion of VRAC in the CNS. Their laboratory used a Gfap Cre -driven excision to delete Lrrc8a in astrocytes and reported reduced hippocampal excitability, impaired long-term potentiation (LTP), spatial and contextual learning deficits, and resistance to cerebral ischemia (Yang et al 2019).…”

Section: Introductionmentioning

confidence: 99%

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Late adolescence mortality in mice with brain-specific deletion of the volume-regulated anion channel subunit LRRC8A

Wilson

Dohare

Orbeta

et al. 2020

Preprint

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The leucine-rich repeat-containing family 8 member A (LRRC8A) is an essential subunit of the volume-regulated anion channel (VRAC). VRAC is indispensable for cell volume regulation but its broader physiological functions remain under investigation. Astrocyte-targeted Lrrc8a deletion in the nervous system reduces neuronal excitability, impairs synaptic plasticity and memory, and protects against ischemic damage. Here we show that deletion of LRRC8A in all brain cells, using Nestin Cre -driven Lrrc8a fl/fl excision, is lethal. Mice devoid of brain LRRC8A are born close to the expected Mendelian ratio and develop without overt histological abnormalities. Nevertheless, they all die between 5 to 8 weeks of age with a seizure-like phenotype. Consistent with seizures, we found disruptions in cell excitability, GABAergic signaling, and astrocytic production of the GABA precursor glutamine, all of which might contribute to mortality. This work provides the first evidence of a critical role for VRAC in control of brain excitability during maturation.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Late adolescence mortality in mice with brain-specific deletion of the volume-regulated anion channel subunit LRRC8A

Wilson

Dohare

Orbeta

et al. 2020

Preprint

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“…Such evidence supporting VRACs as astrocytic glutamate-releasing channels were indirect and based on pharmacological inhibitors, which may affect the function of other membrane proteins, including those directly involved in the glutamate transport (Bowens et al, 2013). Nevertheless, the latest work of Yang et al (2019) revealed astrocytic VRACs as major candidates mediating glutamate release in FCI. They took advantage of recent findings, which revealed that the leucine-rich repeat-containing protein 8A (LRRC8A, also named SWELL1) and its four other associated homologs (LRRC8B-E) form heteromeric VRACs (Voss et al, 2014;Schober et al, 2017;Osei-Owusu et al, 2018).…”

Section: Astrocytes Add Significantly To Glutamate Excitotoxicitymentioning

confidence: 99%

“…They took advantage of recent findings, which revealed that the leucine-rich repeat-containing protein 8A (LRRC8A, also named SWELL1) and its four other associated homologs (LRRC8B-E) form heteromeric VRACs (Voss et al, 2014;Schober et al, 2017;Osei-Owusu et al, 2018). In a well-designed approach, which employed a conditional knockout of Swell1 in astrocytes in an experimental model of stroke, Yang et al (2019) proved that the Swell1 -/mice had significantly smaller infarct volumes and better scores for overall neurological function than the control mice. In contrast to the role of VRACs in astrocytic glutamate release, their activation in neurons was shown to mediate Cl − influx and further contribute to cell damage by promoting neuronal swelling (Inoue and Okada, 2007;Zhang et al, 2011).…”

Section: Astrocytes Add Significantly To Glutamate Excitotoxicitymentioning

confidence: 99%

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

Kirdajová

Kriška

Tureckova

et al. 2020

Front. Cell. Neurosci.

246

150

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A plethora of neurological disorders shares a final common deadly pathway known as excitotoxicity. Among these disorders, ischemic injury is a prominent cause of death and disability worldwide. Brain ischemia stems from cardiac arrest or stroke, both responsible for insufficient blood supply to the brain parenchyma. Glucose and oxygen deficiency disrupts oxidative phosphorylation, which results in energy depletion and ionic imbalance, followed by cell membrane depolarization, calcium (Ca 2+ ) overload, and extracellular accumulation of excitatory amino acid glutamate. If tight physiological regulation fails to clear the surplus of this neurotransmitter, subsequent prolonged activation of glutamate receptors forms a vicious circle between elevated concentrations of intracellular Ca 2+ ions and aberrant glutamate release, aggravating the effect of this ischemic pathway. The activation of downstream Ca 2+ -dependent enzymes has a catastrophic impact on nervous tissue leading to cell death, accompanied by the formation of free radicals, edema, and inflammation. After decades of "neuron-centric" approaches, recent research has also finally shed some light on the role of glial cells in neurological diseases. It is becoming more and more evident that neurons and glia depend on each other. Neuronal cells, astrocytes, microglia, NG2 glia, and oligodendrocytes all have their roles in what is known as glutamate excitotoxicity. However, who is the main contributor to the ischemic pathway, and who is the unsuspecting victim? In this review article, we summarize the so-far-revealed roles of cells in the central nervous system, with particular attention to glial cells in ischemiainduced glutamate excitotoxicity, its origins, and consequences.

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Inhibition of NFAT5‐Dependent Astrocyte Swelling Alleviates Neuropathic Pain

He,

Ma,

Ding

et al. 2024

Advanced Science

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Astrocyte swelling is implicated in various neurological disorders. However, whether astrocyte swelling contributes to neuropathic pain remains elusive. This study elucidates the pivotal role of the nuclear factor of activated T‐cells 5 (NFAT5) emerges as a master regulator of astrocyte swelling in the spinal dorsal horn (SDH) during neuropathic pain. Despite the ubiquitous expression of NFAT5 protein in SDH cell types, it selectively induces swelling specifically in astrocytes, not in microglia. Mechanistically, NFAT5 directly controls the expression of the water channel aquaporin‐4 (AQP4), a key regulator exclusive to astrocytes. Additionally, aurora kinase B (AURKB) orchestrates NFAT5 phosphorylation, enhancing its protein stability and nuclear translocation, thereby regulating AQP4 expression. The findings establish NFAT5 as a crucial regulator for neuropathic pain through the modulation of astrocyte swelling. The AURKB‐NFAT5‐AQP4 pathway in astrocytes emerges as a potential therapeutic target to combat neuropathic pain.

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Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic Transmission and Promotes Brain Damage in Stroke

Cited by 170 publications

References 62 publications

Late adolescence mortality in mice with brain-specific deletion of the volume-regulated anion channel subunit LRRC8A

Late adolescence mortality in mice with brain-specific deletion of the volume-regulated anion channel subunit LRRC8A

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

Inhibition of NFAT5‐Dependent Astrocyte Swelling Alleviates Neuropathic Pain

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