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Cerebral Cortex Advance Access published online on September 16, 2009
Cerebral Cortex, doi:10.1093/cercor/bhp181
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Dual Effect of Glutamate on GABAergic Interneuron Survival during Cerebral Cortex Development in Mice Neonates

Arnaud Desfeux1, Faiza El Ghazi1, Sylvie Jégou1, Hélène Legros1, Stéphane Marret1,2, Vincent Laudenbach1,2 and Bruno J. Gonzalez1

1 EA "NeoVasc" 4309, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Rouen Institute for Biomedical Research, European Institute for Peptide Research (IFR 23) University of Rouen, 76183 Rouen, France, 2 Department of Neonatal Paediatrics and Intensive Care, Rouen University Hospital, 76000 Rouen, France

Address correspondence to Dr Bruno J. Gonzalez, EA "NeoVasc" 4309, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Rouen Institute for Biomedical Research, European Institute for Peptide Research (IFRMP 23), University of Rouen, 76183 Rouen Cedex, France. Email: bruno.gonzales{at}univ-rouen.fr.

In term and preterm neonates, massive glutamate release can lead to excitotoxic white-matter and cortical lesions. Because of its high permeability toward calcium, the N-methyl-D-aspartic acid (NMDA) receptor is thought to play an important role in excitotoxic lesions and NMDA antagonists therefore hold promise for neuroprotection. We found that, in neonatal mouse cortex, a given NMDA concentration exerted either excitotoxic or antiapoptotic effects depending on the cortical layers. In layer VI, NMDA led to excitotoxicity, sustained calcium mobilization, and necrosis of Gad67GFP neurons. In the immature layers II–IV, NMDA decreased apoptosis and induced transient calcium mobilization. The NMDA antagonist MK801 acted as a potent caspase-3 activator in immature layers II–IV and affected gamma aminobutyric acid (GABA)ergic interneurons. The apoptotic effect of MK801-induced BAX expression, mitochondrial potential collapse and caspase-9 activation. In vivo Bax small interfering ribonucleic acid and a caspase-9 inhibitor abrogated MK801-induced apoptosis and pyknotic nucleus formation. Ketamine, an anesthetic with NMDA antagonist properties, mimicked the apoptotic effects of MK801. These data indicate a dual effect of glutamate on survival of immature and mature GABAergic neurons and suggest that ketamine may induce apoptosis of immature GABAergic neurons.

Key Words: bax • development • GABA • ketamine • MK801

Arnaud Desfeux and Faiza El Ghazi contributed equally to this work.


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