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Ethanol neurotoxicity is mediated by changes in expression, surface localization and functional properties of glutamate AMPA receptors
Ist Teil von
Journal of neurochemistry, 2021-06, Vol.157 (6), p.2106-2118
Ort / Verlag
New York: Blackwell Publishing Ltd
Erscheinungsjahr
2021
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
Modifications in the subunit composition of AMPA receptors (AMPARs) have been linked to the transition from physiological to pathological conditions in a number of contexts, including EtOH‐induced neurotoxicity. Previous work from our laboratory showed that EtOH withdrawal causes CA1 pyramidal cell death in organotypic hippocampal slices and changes in the expression of AMPARs. Here, we investigated whether changes in expression and function of AMPARs may be causal for EtOH‐induced neurotoxicity. To this aim, we examined the subunit composition, localization and function of AMPARs in hippocampal slices exposed to EtOH by using western blotting, surface expression assay, confocal microscopy and electrophysiology. We found that EtOH withdrawal specifically increases GluA1 protein signal in total homogenates, but not in the post‐synaptic density‐enriched fraction. This is suggestive of overall increase and redistribution of AMPARs to the extrasynaptic compartment. At functional level, AMPA‐induced calcium influx was unexpectedly reduced, whereas AMPA‐induced current was enhanced in CA1 pyramidal neurons following EtOH withdrawal, suggesting that increased AMPAR expression may lead to cell death because of elevated excitability, and not for a direct contribution on calcium influx. Finally, the neurotoxicity caused by EtOH withdrawal was attenuated by the non‐selective AMPAR antagonist 2,3‐dioxo‐6‐nitro‐1,2,3,4‐tetrahydrobenzo[f]quinoxaline‐7‐sulfonamide disodium salt as well as by the selective antagonist of GluA2‐lacking AMPARs 1‐naphthyl acetyl spermine. We conclude that EtOH neurotoxicity involves changes in expression, surface localization and functional properties of AMPARs, and propose GluA2‐lacking AMPARs as amenable specific targets for the development of neuroprotective drugs in EtOH‐withdrawal syndrome.
Ethanol (EtOH) abuse causes persistent structural and functional alterations in the brain by mechanisms that are not yet fully understood. We studied the changes in molecular composition, protein trafficking and functional properties of glutamate AMPA receptors accompanying ethanol neurotoxicity in rat hippocampal cultures. Our results suggest that EtOH induces profound changes in overall expression, trafficking and molecular composition of AMPA receptors, promoting the expression of a specific subtype of receptors with enhanced function. Subtype‐selective blockers prevent the neurotoxicity induced by EtOH withdrawal, indicating that AMPA receptor subtypes, specifically up‐regulated by chronic EtOH, represent amenable targets for the development of effective neuroprotectants in EtOH toxicity.