Ethanol neurotoxicity is mediated by changes in expression, surface localization and functional properties of glutamate AMPA receptors
Articolo
Data di Pubblicazione:
2021
Citazione:
Ethanol neurotoxicity is mediated by changes in expression, surface localization and functional properties of glutamate AMPA receptors / E. Gerace, A. Ilari, L. Caffino, D. Buonvicino, D. Lana, F. Ugolini, F. Resta, D. Nosi, M. Grazia Giovannini, R. Ciccocioppo, F. Fumagalli, D.E. Pellegrini-Giampietro, A. Masi, G. Mannaioni. - In: JOURNAL OF NEUROCHEMISTRY. - ISSN 0022-3042. - 157:6(2021 Jun), pp. 2106-2118. [10.1111/jnc.15223]
Abstract:
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. (Figure presented.).
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
AMPA receptors; CA1 injury; ethanol withdrawal; organotypic hippocampal slices; scaffold proteins
Elenco autori:
E. Gerace, A. Ilari, L. Caffino, D. Buonvicino, D. Lana, F. Ugolini, F. Resta, D. Nosi, M. Grazia Giovannini, R. Ciccocioppo, F. Fumagalli, D.E. Pellegrini-Giampietro, A. Masi, G. Mannaioni
Link alla scheda completa: