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LRRC8A-dependent volume-regulated anion channels contribute to ischemia-induced brain injury and glutamatergic input to hippocampal neurons.
- Source :
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Experimental neurology [Exp Neurol] 2020 Oct; Vol. 332, pp. 113391. Date of Electronic Publication: 2020 Jun 27. - Publication Year :
- 2020
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Abstract
- Volume-regulated anion channels (VRACs) are critically involved in regulating cell volume, and leucine-rich repeat-containing protein 8A (LRRC8A, SWELL1) is an obligatory subunit of VRACs. Cell swelling occurs early after brain ischemia, but it is unclear whether neuronal LRRC8a contributes to ischemia-induced glutamate release and brain injury. We found that Lrrc8a conditional knockout (Lrrc8a-cKO) mice produced by crossing Nestin <superscript>Cre+/-</superscript> with Lrrc8a <superscript>flox+/+</superscript> mice died 7-8 weeks of age, indicating an essential role of neuronal LRRC8A for survival. Middle cerebral artery occlusion (MCAO) caused an early increase in LRRC8A protein levels in the hippocampus in wild-type (WT) mice. Whole-cell patch-clamp recording in brain slices revealed that oxygen-glucose deprivation significantly increased the amplitude of VRAC currents in hippocampal CA1 neurons in WT but not in Lrrc8a-cKO mice. Hypotonicity increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in hippocampal CA1 neurons in WT mice, and this was abolished by DCPIB, a VRAC blocker. But in Lrrc8a-cKO mice, hypotonic solution had no effect on the frequency of sEPSCs in these neurons. Furthermore, the brain infarct volume and neurological severity score induced by MCAO were significantly lower in Lrrc8a-cKO mice than in WT mice. In addition, MCAO-induced increases in cleaved caspase-3 and calpain activity, two biochemical markers of neuronal apoptosis and death, in brain tissues were significantly attenuated in Lrrc8a-cKO mice compared with WT mice. These new findings indicate that cerebral ischemia increases neuronal LRRC8A-dependent VRAC activity and that VRACs contribute to increased glutamatergic input to hippocampal neurons and brain injury caused by ischemic stroke.<br />Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest with the contents of this article.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Behavior, Animal
CA1 Region, Hippocampal pathology
Excitatory Postsynaptic Potentials
Glucose deficiency
Hypoxia pathology
Infarction, Middle Cerebral Artery pathology
Ischemic Stroke pathology
Ischemic Stroke psychology
Membrane Proteins metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Nestin genetics
Patch-Clamp Techniques
Glutamic Acid metabolism
Hippocampus pathology
Ion Channels metabolism
Ischemic Stroke genetics
Membrane Proteins genetics
Neurons pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2430
- Volume :
- 332
- Database :
- MEDLINE
- Journal :
- Experimental neurology
- Publication Type :
- Academic Journal
- Accession number :
- 32598930
- Full Text :
- https://doi.org/10.1016/j.expneurol.2020.113391