title: Dual effect of glutamate on GABAergic interneuron survival during cerebral cortex development in mice neonates.
abstract: 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.
authors.affiliation: 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.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Desfeux
authors.forename: Faiza
authors.initials: F
authors.lastname: El Ghazi
authors.forename: Sylvie
authors.initials: S
authors.lastname: Jégou
authors.forename: Hélène
authors.initials: H
authors.lastname: Legros
authors.forename: Stéphane
authors.initials: S
authors.lastname: Marret
authors.forename: Vincent
authors.initials: V
authors.lastname: Laudenbach
authors.forename: Bruno J
authors.initials: BJ
authors.lastname: Gonzalez
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology* / Q000254:growth & development*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000235:genetics; D018698:Glutamic Acid / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D007395:Interneurons / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D009336:Necrosis / Q000139:chemically induced; D034741:RNA, Small Interfering / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D002118:Calcium