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.

Ketamine alters cortical integration of GABAergic interneurons and induces long-term sex-dependent impairments in transgenic Gad67-GFP mice

“…19, 20 In particular, migrating neurons arising from the MGE reach the developing neocortex following several routes through the intermediate and marginal zones. 18 As we observed in a previous study that an NMDA antagonist, MK801, induced the death of immature GABAergic interneurons, 7 we raised the hypothesis of a possible deleterious effect of ketamine on the GABAergic population. Indeed, ketamine is an NMDA antagonist used both as an anesthetic in neonatal pediatrics and as a drug of abuse by young adults.…”

“…Indeed, several research groups have described a deleterious effect of molecules such as MK801 or memantine in the immature neocortex. 4, 7, 8, 9 In particular, it has been shown that MK801 exerts a dual effect in cultured cortical slices from mouse neonates; although it reduces excitotoxic death in the deep cortical layers V and VI, it has a pro-apoptotic effect on immature GABAergic interneurons present in the superficial layers II–IV. 7 …”

The Efficiency of Glutamate Uptake Differs between Neonatal and Adult Cortical Microvascular Endothelial Cells

“…12 Glutamate also has age-specific trophic effects in the developing cortex. 3 Although EAATs are not the only glutamate transporters expressed by CMECs, 6 the differential expression patterns of the EAATs in microvessels suggest that glutamate effects in the immature cortex are not subject to the same regulatory processes as in adulthood regarding brain-to-blood efflux. In particular, the molecular and functional specificities of mature versus immature endothelial cells with respect to EAAT expression and glutamate uptake support specific glutamate homeostasis pathways that are essential for cortical development.…”

“…1,2 In fact, in the cortex of neonatal mice, similar glutamate levels exert pro-survival or pro-excitotoxic effects on neurons depending on the cortical layer considered. 3 Cortical microvascular endothelial cells (CMECs) derived from newborn mice present molecular and functional differences from adult mice. 4 For example, neonatal (n)-CMECs express more N-methyl-Daspartate-type glutamate receptors (NMDAR) than adult (a)-CMECs.…”

Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia

“…60 For example, at PND 2 in rodents, many immature neurons positive for NMDARs are still migrating in the cortex, and MK-801 acts as a caspase-3 activator, thereby inducing massive apoptosis in those neurons. 61 By the first 2 weeks of age, peak expression of NMDARs occur in rats, 62 and the NMDA currents in immature neurons are larger with longer duration that adult neurons, 63 due to high expression of GluN2B/2D. NMDA currents are also robust in fast-spiking neurons of mPFC between PND 15–28 64 and of hippocampus between PND 3–8.…”