Title : Blockade of NMDA receptors in the developing cortex and consequences on the autophagic death of migrating interneurons
I n neonates, excitotoxicity is a major process involved in hypoxic-ischemic brain lesions, and several studies reported neuroprotective effects of NMDA antagonists. However, there is more and more evidence indicating that, in the developing brain, glutamate exerts trophic effects on migrating GABAergic interneurons and that NMDA antagonists would present neurodevelopmental side effects. Thus, characterizing the mechanisms leading to developmental impairments of NMDA antagonists would be therapeutically useful. Because macroautophagy is involved in the adaptive response to trophic deprivation, we investigated the impact of autophagy modulators on MK801-induced death of immature GABAergic interneurons. Using cortical slices from wild type and Gad67-GFP mice, we showed that blockade of the NMDA receptor resulted in an accumulation of autophagosomes due to the disruption of the autophagic flux. This effect preceded the activation of the mitochondrial apoptotic pathway, and the degeneration of immature GABAergic neurons present in the developing cortical layers II-IV. The autophagy inhibitor, 3-MA, prevented the apoptotic death of GABA interneurons whereas modulators of autophagy (3-MA, rapamycin) did not interfere with the anti-excitotoxic effect of MK801 observed in deep layers V and VI. In vivo, 3-MA blocked the rapid increase in caspase-3 cleavage induced by NMDA antagonists and prevented death of Gad67- GFP neurons in layers II-IV. Together, these data suggest that, in the developing cortex, blockade of theNMDA receptor in the developing cortex induces autophagy-mediated death of migrating cortical GABAergic interneurons. These results point out the risk of side effects regarding the use of some anesthetics such as ketamine when administered to preterm neonates. They also suggest that autophagy modulators would open new opportunities to prevent side effects of NMDA antagonists used for neuroprotection in the developing brain.