NMDA receptor blockade in the developing cortex induces autophagy-mediated death of immature cortical GABAergic interneurons: An ex vivo and in vivo study in Gad67-GFP mice

Experimental Neurology
Christian RouxSoumeya Bekri

Abstract

In neonates, excitotoxicity is a major process involved in hypoxic-ischemic brain lesions, and several research groups have suggested the use of NMDA antagonists for neuroprotection. However, despite their clinical interest, there is more and more evidence suggesting that, in the immature brain, these molecules exert deleterious actions on migrating GABAergic interneurons by suppressing glutamatergic trophic inputs. Consequently, preventing the side effects of NMDA antagonists would be therapeutically useful. Because macroautophagy is involved in the adaptive response to trophic deprivation, the aim of the present study was to investigate the impact of autophagy modulators on the MK801-induced death of immature GABAergic interneurons and to characterize the crosstalk between autophagic and apoptotic mechanisms in this cell type. Ex vivo, using cortical slices from NMRI and Gad67-GFP mice, we show that blockade of the NMDA receptor results in an accumulation of autophagosomes due to the disruption of the autophagic flux. This effect precedes the activation of the mitochondrial apoptotic pathway, and the degeneration of immature GABAergic neurons present in developing cortical layers II-IV and is prevented by 3-MA, an autophagy i...Continue Reading

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Citations

Feb 10, 2017·Cell Death & Disease·Virginie GiraultSoumeya Bekri
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Jan 19, 2017·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Amir ShojaeiNafiseh Atapour
Mar 5, 2021·Autophagy·Ruoxi ZhangDaolin Tang
Jul 24, 2021·Cerebral Cortex Communications·Odile BartholomeBernard Rogister
Jul 19, 2021·Seminars in Fetal & Neonatal Medicine·Joanne O DavidsonUNKNOWN Newborn Brain Society Guidelines and Publications Committee

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