In utero alcohol exposure exacerbates endothelial protease activity from pial microvessels and impairs GABA interneuron positioning
Abstract
In utero alcohol exposure can induce severe neurodevelopmental disabilities leading to long-term behavioral deficits. Because alcohol induces brain defects, many studies have focused on nervous cells. However, recent reports have shown that alcohol markedly affects cortical angiogenesis in both animal models and infants with fetal alcohol spectrum disorder (FASD). In addition, the vascular system is known to contribute to controlling gamma-aminobutyric acid (GABA)ergic interneuron migration in the developing neocortex. Thus, alcohol-induced vascular dysfunction may contribute to the neurodevelopmental defects in FASD. The present study aimed at investigating the effects of alcohol on endothelial activity of pial microvessels. Ex vivo experiments on cortical slices from mouse neonates revealed that in endothelial cells from pial microvessels acute alcohol exposure inhibits both glutamate-induced calcium mobilization and activities of matrix metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA). The inhibitory effect of alcohol on glutamate-induced MMP-9 activity was abrogated in tPA-knockout and Grin1flox/VeCadcre mice suggesting that alcohol interacts through the endothelial NMDAR/tPA/MMP-9 vascular pathway. Contrasting with the effects from acute alcohol exposure, in mouse neonates exposed to alcohol in utero during the last gestational week, glutamate exacerbated both calcium mobilization and endothelial protease activities from pial microvessels. This alcohol-induced vascular dysfunction was associated with strong overexpression of the N-methyl-d-aspartate receptor subunit GluN1 and mispositioning of the Gad67-GFP interneurons that normally populate the superficial cortical layers. By comparing several human control fetuses with a fetus chronically exposed to alcohol revealed that alcohol exposure led to mispositioning of the calretinin-positive interneurons, whose density was decreased in the superficial cortical layers II-III and increased in deepest layers. This study provides the first mechanistic and functional evidence that alcohol impairs glutamate-regulated activity of pial microvessels. Endothelial dysfunction is characterized by altered metalloproteinase activity and interneuron mispositioning, which was also observed in a fetus with fetal alcohol syndrome. These data suggest that alcohol-induced endothelial dysfunction may contribute in ectopic cortical GABAergic interneurons, that has previously been described in infants with FASD.
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BibTeX
@article{leger2026utero,
title = {{In utero alcohol exposure exacerbates endothelial protease activity from pial microvessels and impairs GABA interneuron positioning}},
author = {Cécile Léger and Nicolas Dupré and Annie Laquerrière and Maryline Lecointre and Marion Dumanoir and François Janin and Michelle Hauchecorne and Maëlle Fabre and Sylvie Jégou and Thierry Frébourg and Carine Cleren and Philippe Leroux and Pascale Marcorelles and Carole Brasse-Lagnel and Stéphane Marret and Florent Marguet and Bruno Gonzalez},
journal = {Neurobiology of Disease},
year = {2026},
month = oct,
doi = {10.1016/j.nbd.2020.105074},
url = {https://hal.science/hal-05798115v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - In utero alcohol exposure exacerbates endothelial protease activity from pial microvessels and impairs GABA interneuron positioning
AU - Cécile Léger
AU - Nicolas Dupré
AU - Annie Laquerrière
AU - Maryline Lecointre
AU - Marion Dumanoir
AU - François Janin
AU - Michelle Hauchecorne
AU - Maëlle Fabre
AU - Sylvie Jégou
AU - Thierry Frébourg
AU - Carine Cleren
AU - Philippe Leroux
AU - Pascale Marcorelles
AU - Carole Brasse-Lagnel
AU - Stéphane Marret
AU - Florent Marguet
AU - Bruno Gonzalez
PY - 2026
DA - 2026/10/13
JO - Neurobiology of Disease
DO - 10.1016/j.nbd.2020.105074
UR - https://hal.science/hal-05798115v1
AB - In utero alcohol exposure can induce severe neurodevelopmental disabilities leading to long-term behavioral deficits. Because alcohol induces brain defects, many studies have focused on nervous cells. However, recent reports have shown that alcohol markedly affects cortical angiogenesis in both animal models and infants with fetal alcohol spectrum disorder (FASD). In addition, the vascular system is known to contribute to controlling gamma-aminobutyric acid (GABA)ergic interneuron migration in the developing neocortex. Thus, alcohol-induced vascular dysfunction may contribute to the neurodevelopmental defects in FASD. The present study aimed at investigating the effects of alcohol on endothelial activity of pial microvessels. Ex vivo experiments on cortical slices from mouse neonates revealed that in endothelial cells from pial microvessels acute alcohol exposure inhibits both glutamate-induced calcium mobilization and activities of matrix metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA). The inhibitory effect of alcohol on glutamate-induced MMP-9 activity was abrogated in tPA-knockout and Grin1flox/VeCadcre mice suggesting that alcohol interacts through the endothelial NMDAR/tPA/MMP-9 vascular pathway. Contrasting with the effects from acute alcohol exposure, in mouse neonates exposed to alcohol in utero during the last gestational week, glutamate exacerbated both calcium mobilization and endothelial protease activities from pial microvessels. This alcohol-induced vascular dysfunction was associated with strong overexpression of the N-methyl-d-aspartate receptor subunit GluN1 and mispositioning of the Gad67-GFP interneurons that normally populate the superficial cortical layers. By comparing several human control fetuses with a fetus chronically exposed to alcohol revealed that alcohol exposure led to mispositioning of the calretinin-positive interneurons, whose density was decreased in the superficial cortical layers II-III and increased in deepest layers. This study provides the first mechanistic and functional evidence that alcohol impairs glutamate-regulated activity of pial microvessels. Endothelial dysfunction is characterized by altered metalloproteinase activity and interneuron mispositioning, which was also observed in a fetus with fetal alcohol syndrome. These data suggest that alcohol-induced endothelial dysfunction may contribute in ectopic cortical GABAergic interneurons, that has previously been described in infants with FASD.
SN - 0969-9961
SN - 1095-953X
ER -