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The positive allosteric modulator of NMDA receptors, GNE‐9278, blocks the ethanol‐induced decrease of excitability in developing retrosplenial cortex neurons from mice

Binge‐like exposure to ethanol during the brain growth spurt triggers apoptotic neurodegeneration in multiple brain regions, including the retrosplenial cortex, a brain region that is part of the hippocampal‐diencephalic‐cingulate memory network. This is mediated, in part, by reduced Ca(2+) influx t...

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Detalles Bibliográficos
Autores principales: Bird, Clark W., Valenzuela, Carlos F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10009431/
https://www.ncbi.nlm.nih.gov/pubmed/36524248
http://dx.doi.org/10.1002/npr2.12306
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author Bird, Clark W.
Valenzuela, Carlos F.
author_facet Bird, Clark W.
Valenzuela, Carlos F.
author_sort Bird, Clark W.
collection PubMed
description Binge‐like exposure to ethanol during the brain growth spurt triggers apoptotic neurodegeneration in multiple brain regions, including the retrosplenial cortex, a brain region that is part of the hippocampal‐diencephalic‐cingulate memory network. This is mediated, in part, by reduced Ca(2+) influx through N‐methyl‐d‐aspartate (NMDA) receptors followed by a decrease in the activation of pro‐survival genes. Here, we tested whether a positive allosteric modulator of NMDA receptors could counteract the inhibitory effect of ethanol on developing retrosplenial cortex pyramidal neurons. We used patch‐clamp electrophysiological techniques in acute slices from postnatal day 6–8 mice to test the effect of the positive allosteric modulator GNE‐9278 on ethanol‐induced inhibition of NMDA receptor function. GNE‐9278 dose‐dependently increased the amplitude, decay time, and total charge of NMDA excitatory postsynaptic currents. At a concentration of 5 μmol L(−1), GNE‐9278 significantly reduced the 90 mmol L(−1) ethanol‐induced inhibition of NMDA excitatory postsynaptic current amplitude, decay time, and total charge. Current‐clamp experiments showed that 5 μmol L(−1) GNE‐9278 ameliorated the 90 mmol L(−1) ethanol‐induced inhibition of synaptically‐evoked action potential firing and compound excitatory postsynaptic potential amplitude. These findings indicate that positive allosteric modulators mitigate ethanol‐induced hypofunction of NMDA receptors in developing cerebral cortex neurons, an effect that could ameliorate its pro‐apoptotic effects during the late stages of fetal development.
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spelling pubmed-100094312023-03-14 The positive allosteric modulator of NMDA receptors, GNE‐9278, blocks the ethanol‐induced decrease of excitability in developing retrosplenial cortex neurons from mice Bird, Clark W. Valenzuela, Carlos F. Neuropsychopharmacol Rep Original Articles Binge‐like exposure to ethanol during the brain growth spurt triggers apoptotic neurodegeneration in multiple brain regions, including the retrosplenial cortex, a brain region that is part of the hippocampal‐diencephalic‐cingulate memory network. This is mediated, in part, by reduced Ca(2+) influx through N‐methyl‐d‐aspartate (NMDA) receptors followed by a decrease in the activation of pro‐survival genes. Here, we tested whether a positive allosteric modulator of NMDA receptors could counteract the inhibitory effect of ethanol on developing retrosplenial cortex pyramidal neurons. We used patch‐clamp electrophysiological techniques in acute slices from postnatal day 6–8 mice to test the effect of the positive allosteric modulator GNE‐9278 on ethanol‐induced inhibition of NMDA receptor function. GNE‐9278 dose‐dependently increased the amplitude, decay time, and total charge of NMDA excitatory postsynaptic currents. At a concentration of 5 μmol L(−1), GNE‐9278 significantly reduced the 90 mmol L(−1) ethanol‐induced inhibition of NMDA excitatory postsynaptic current amplitude, decay time, and total charge. Current‐clamp experiments showed that 5 μmol L(−1) GNE‐9278 ameliorated the 90 mmol L(−1) ethanol‐induced inhibition of synaptically‐evoked action potential firing and compound excitatory postsynaptic potential amplitude. These findings indicate that positive allosteric modulators mitigate ethanol‐induced hypofunction of NMDA receptors in developing cerebral cortex neurons, an effect that could ameliorate its pro‐apoptotic effects during the late stages of fetal development. John Wiley and Sons Inc. 2022-12-15 /pmc/articles/PMC10009431/ /pubmed/36524248 http://dx.doi.org/10.1002/npr2.12306 Text en © 2022 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Bird, Clark W.
Valenzuela, Carlos F.
The positive allosteric modulator of NMDA receptors, GNE‐9278, blocks the ethanol‐induced decrease of excitability in developing retrosplenial cortex neurons from mice
title The positive allosteric modulator of NMDA receptors, GNE‐9278, blocks the ethanol‐induced decrease of excitability in developing retrosplenial cortex neurons from mice
title_full The positive allosteric modulator of NMDA receptors, GNE‐9278, blocks the ethanol‐induced decrease of excitability in developing retrosplenial cortex neurons from mice
title_fullStr The positive allosteric modulator of NMDA receptors, GNE‐9278, blocks the ethanol‐induced decrease of excitability in developing retrosplenial cortex neurons from mice
title_full_unstemmed The positive allosteric modulator of NMDA receptors, GNE‐9278, blocks the ethanol‐induced decrease of excitability in developing retrosplenial cortex neurons from mice
title_short The positive allosteric modulator of NMDA receptors, GNE‐9278, blocks the ethanol‐induced decrease of excitability in developing retrosplenial cortex neurons from mice
title_sort positive allosteric modulator of nmda receptors, gne‐9278, blocks the ethanol‐induced decrease of excitability in developing retrosplenial cortex neurons from mice
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10009431/
https://www.ncbi.nlm.nih.gov/pubmed/36524248
http://dx.doi.org/10.1002/npr2.12306
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