期刊
CEREBRAL CORTEX
卷 20, 期 5, 页码 1092-1108出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhp181
关键词
bax; development; GABA; ketamine; MK801
资金
- University of Rouen
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Agency of National Research
- Regional Platform for Cell Imaging, Conseil Regional de Haute-Normandie
- LARC-Neuroscience Network and Socie te Francxaise d'Anesthe sie et de Reanimation
- French Research Ministry fellowship
- INSERM
- Conseil Regional de Haute-Normandie grant
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.
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