Involvement of the Endothelial N-Methyl-D-Aspartate Receptor on Vessel-Associated Positioning and Differentiation of Cortical Oligodendrocytes and on Motor Activity.
Auteur : Beranger A, Lafenêtre M, Lacomme S, Lebon A, Genty D, Brosolo M, Janin F, Leroy A, Guérout N, Vivien D, Galas L, Marret S, Marguet F, Gontier E, Gonzalez BJ, Lecointre M
Année : 2025
Journal : J Neurosci 1529-2401
PubMed Id : 40957680
During cortical development, attachment and detachment of oligodendrocyte precursors (OPC) to microvessels play a crucial role in their positioning and differentiation. In the developing brain, endothelial cells are regionally diverse, and previous studies showed a peak in the expression of cortical endothelial NMDA receptors (eNMDAR) during perinatal life, coinciding with OPC migration along cortical microvessels. This raises the hypothesis that eNMDAR might influence the fate of vessel-associated OPC. In this study, a Grin1lox/lox/VeCadCre mouse model was used to investigate in females and males the effects of endothelial GluN1 invalidation (eNMDAR-/-) on i) positioning and differentiation of cortical oligodendrocytes and myelination, ii) OPC/microvessel association and endothelial MMP9-like activity, and iii) motor activity. Results showed that, from P2 to P15, PDGFRα expression was increased in eNMDAR-/- mice and returned to wild-type levels by P45. CNPase and MBP expression was reduced at P15 and remained low in adult eNMDAR-/- mice. Histological analysis revealed no change in OPC-microvessel association, but positioning was altered with increased density in layers VI and V at P15. Myelination was impaired, as evidenced by thinner corpus callosum, reduced myelin sheath thickness, and higher g-ratio. Axonal mitochondria density was significantly increased. Functional tests revealed that glutamate could not stimulate endothelial MMP9-like activity in eNMDAR-/- mice. Molecular, histological and functional changes were linked to sensorimotor disabilities. At P45, despite the absence of observable myelination defects, locomotor impairments persisted, suggesting that early OPC differentiation disruption contributes to lasting motor dysfunction. These findings offer new insights into OPC vulnerability in human preterm infants. During brain development, oligodendrocyte precursors (OPC) integrate the neocortex by migrating along radial microvessels. Here, we show that targeted invalidation of the endothelial NMDA receptor delays the positioning and the differentiation of OPC in layers of the sensorimotor cortex resulting in sustainable under-expression of MBP, in reduced density of myelinated fibers, thinner myelin sheaths and higher g-ratio values. At a functional level, invalidation of the endothelial NMDAR results in the inability for glutamate to stimulate MMP9-like activity. These molecular, cellular, and functional phenotypes are associated with neonatal and long-term motor impairments. Our findings highlight the contribution of the endothelial NMDA receptor on the differentiation of oligodendrocytes entering the sensorimotor cortex along microvessels.