Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling.
amino acids transporters
astrocytic and neuronal swelling
non-excitatory amino acids
two-photon microscopy
volume-regulated anion channels
Journal
Glia
ISSN: 1098-1136
Titre abrégé: Glia
Pays: United States
ID NLM: 8806785
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
revised:
14
06
2022
received:
19
05
2022
accepted:
24
06
2022
pubmed:
9
7
2022
medline:
15
9
2022
entrez:
8
7
2022
Statut:
ppublish
Résumé
In ischemic stroke and post-traumatic brain injury (TBI), blood-brain barrier disruption leads to leaking plasma amino acids (AA) into cerebral parenchyma. Bleeding in hemorrhagic stroke and TBI also release plasma AA. Although excitotoxic AA were extensively studied, little is known about non-excitatory AA during hypoxic injury. Hypoxia-induced synaptic depression in hippocampal slices becomes irreversible with non-excitatory AA, alongside their intracellular accumulation and increased tissue electrical resistance. Four non-excitatory AA (l-alanine, glycine, l-glutamine, l-serine: AGQS) at plasmatic concentrations were applied to slices from mice expressing EGFP in pyramidal neurons or astrocytes during normoxia or hypoxia. Two-photon imaging, light transmittance (LT) changes, and electrophysiological field recordings followed by electron microscopy in hippocampal CA1 st. radiatum were used to monitor synaptic function concurrently with cellular swelling and injury. During normoxia, AGQS-induced increase in LT was due to astroglial but not neuronal swelling. LT raise during hypoxia and AGQS manifested astroglial and neuronal swelling accompanied by a permanent loss of synaptic transmission and irreversible dendritic beading, signifying acute damage. Neuronal injury was not triggered by spreading depolarization which did not occur in our experiments. Hypoxia without AGQS did not cause cell swelling, leaving dendrites intact. Inhibition of NMDA receptors prevented neuronal damage and irreversible loss of synaptic function. Deleterious effects of AGQS during hypoxia were prevented by alanine-serine-cysteine transporters (ASCT2) and volume-regulated anion channels (VRAC) blockers. Our findings suggest that astroglial swelling induced by accumulation of non-excitatory AA and release of excitotoxins through antiporters and VRAC may exacerbate the hypoxia-induced neuronal injury.
Identifiants
pubmed: 35802030
doi: 10.1002/glia.24241
pmc: PMC9474671
mid: NIHMS1819309
doi:
Substances chimiques
Amino Acids
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2108-2130Subventions
Organisme : NINDS NIH HHS
ID : R01 NS083858
Pays : United States
Organisme : NINDS NIH HHS
ID : R56 NS083858
Pays : United States
Informations de copyright
© 2022 Wiley Periodicals LLC.
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