Glutamate controls vessel-associated migration of GABA interneurons from the pial migratory route via NMDA receptors and endothelial protease activation

Cécile Léger,Maryline Lecointre,Michelle Hauchecorne,Denis Vivien,Magalie Bénard,Bruno J Gonzalez,Stéphane Marret,Vincent Henry,Alexis Lebon,Thierry Frebourg,Nicolas Dupré,Caroline Aligny,Ludovic Galas,Philippe Leroux

doi:10.1007/s00018-019-03248-5

Abstract

During cortex development, fine interactions between pyramidal cells and migrating GABA neurons are required to orchestrate correct positioning of interneurons, but cellular and molecular mechanisms are not yet clearly understood. Functional and age-specific expression of NMDA receptors by neonate endothelial cells suggests a vascular contribution to the trophic role of glutamate during cortical development. Associating functional and loss-of-function approaches, we found that glutamate stimulates activity of the endothelial proteases MMP-9 and t-PA along the pial migratory route (PMR) and radial cortical microvessels. Activation of MMP-9 was NMDAR-dependent and abrogated in t-PA−/− mice. Time-lapse recordings revealed that glutamate stimulated migration of GABA interneurons along vessels through an NMDAR-dependent mechanism. In Gad67-GFP mice, t-PA invalidation and in vivo administration of an MMP inhibitor impaired positioning of GABA interneurons in superficial cortical layers, whereas Grin1 endothelial invalidation resulted in a strong reduction of the thickness of the pial migratory route, a marked decrease of the glutamate-induced MMP-9-like activity along the PMR and a depopulation of interneurons in superficial cortical layers. This study supports that glutamate controls the vessel-associated migration of GABA interneurons by regulating the activity of endothelial proteases. This effect requires endothelial NMDAR and is t-PA-dependent. These neurodevelopmental data reinforce the debate regarding safety of molecules with NMDA-antagonist properties administered to preterm and term neonates.

Highlights

At the cellular and molecular levels, there is increasing evidence that, in the developing cortex, endothelial cells are not phenotypically or regionally similar [1, 2]
Because tissue-plasminogen activator (t-PA) and matrix metalloproteinase-9 (MMP-9) are involved in the remodeling of the extracellular matrix following ischemic stroke [38], and because the present study revealed NMDA-dependent effects of glutamate on the endothelial activity of these two proteases, we hypothesized that glutamate could regulate the vascular-associated migration of GABA interneurons along the pial migratory route
In vitro studies revealed age-specific expression of functional NMDA receptors by endothelial cells during perinatal life [6, 42] and, interestingly, at a pathological level, several recent studies reported links between NMDA receptor hypofunction during early life and GABA interneurons that could contribute to adult diseases [22,23,24]

Summary

Introduction

At the cellular and molecular levels, there is increasing evidence that, in the developing cortex, endothelial cells are not phenotypically or regionally similar [1, 2]. It has been shown that there are region-specific and age-specific changes in the expression of both NMDA receptor subunits and excitatory amino acid transporters by neonatal endothelial cells [5, 6] and in vitro studies showed that NMDA is able to promote secretion of two endothelial proteases, i.e., matrix metalloproteinase-9 (MMP-9) and tissue-plasminogen activator (t-PA) by cultured neonatal endothelial cells [6] These two proteases are involved in the control of cell migration in physiological and/or pathological conditions [7, 8] and the preferential expression pattern of NMDA receptors by endothelial cells during the perinatal period coincides with the late migration of GABA interneurons [9]. Consistent with this hypothesis, several recent data showed that the migration of GABAergic neurons is regulated by excitatory neurons [12] and that exposure of mouse neonate cortices to molecules with NMDA-antagonist properties such as ketamine, alcohol, or MK801 resulted in endothelial cell autophagy followed by massive apoptotic death of migrating tangential GABA interneurons present in the superficial cortical layers [13,14,15,16,17]

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Conclusion