Role of NKCC1 and KCC2 during hypoxia-induced neuronal swelling in the neonatal neocortex.

Autor: Takezawa Y; Dept. of Pediatrics, The University of Iowa, Iowa City, Iowa, USA; Iowa Neuroscience Institute, The University of Iowa, Iowa City, Iowa, USA., Langton R; Dept. of Pediatrics, The University of Iowa, Iowa City, Iowa, USA; Iowa Neuroscience Institute, The University of Iowa, Iowa City, Iowa, USA., Baule SM; Dept. of Biomedical Engineering, The University of Iowa, Iowa City, Iowa, USA., Zimmerman MB; Dept. of Biostatistics, The University of Iowa, Iowa City, Iowa, USA., Baek S; School of Data Science, University of Virginia, Charlottesville, Virginia, USA., Glykys J; Dept. of Pediatrics, The University of Iowa, Iowa City, Iowa, USA; Iowa Neuroscience Institute, The University of Iowa, Iowa City, Iowa, USA; Dept. of Neurology, The University of Iowa, Iowa City, Iowa, USA. Electronic address: joseph-glykys@uiowa.edu.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2023 Mar; Vol. 178, pp. 106013. Date of Electronic Publication: 2023 Jan 25.
DOI: 10.1016/j.nbd.2023.106013
Abstrakt: Neonatal hypoxia causes cytotoxic neuronal swelling by the entry of ions and water. Multiple water pathways have been implicated in neurons because these cells lack water channels, and their membrane has a low water permeability. NKCC1 and KCC2 are cation-chloride cotransporters (CCCs) involved in water movement in various cell types. However, the role of CCCs in water movement in neonatal neurons during hypoxia is unknown. We studied the effects of modulating CCCs pharmacologically on neuronal swelling in the neocortex (layer IV/V) of neonatal mice (post-natal day 8-13) during prolonged and brief hypoxia. We used acute brain slices from Clomeleon mice which express a ratiometric fluorophore sensitive to Cl - and exposed them to oxygen-glucose deprivation (OGD) while imaging neuronal size and [Cl - ] i by multiphoton microscopy. Neurons were identified using a convolutional neural network algorithm, and changes in the somatic area and [Cl - ] i were evaluated using a linear mixed model for repeated measures. We found that (1) neuronal swelling and Cl - accumulation began after OGD, worsened during 20 min of OGD, or returned to baseline during reoxygenation if the exposure to OGD was brief (10 min). (2) Neuronal swelling did not occur when the extracellular Cl - concentration was low. (3) Enhancing KCC2 activity did not alter OGD-induced neuronal swelling but prevented Cl - accumulation; (4) blocking KCC2 led to an increase in Cl - accumulation during prolonged OGD and aggravated neuronal swelling during reoxygenation; (5) blocking NKCC1 reduced neuronal swelling during early but not prolonged OGD and aggravated Cl - accumulation during prolonged OGD; and (6) treatment with the "broad" CCC blocker furosemide reduced both swelling and Cl - accumulation during prolonged and brief OGD, whereas simultaneous NKCC1 and KCC2 inhibition using specific pharmacological blockers aggravated neuronal swelling during prolonged OGD. We conclude that CCCs, and other non-CCCs, contribute to water movement in neocortical neurons during OGD in the neonatal period.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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