Involvement of the Endothelial N -Methyl-d-Aspartate Receptor on Vessel-Associated Positioning and Differentiation of Cortical Oligodendrocytes and on Motor Activity

During cortical development, oligodendrocyte precursor (OPC) attachment and detachment 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 cortical endothelial NMDA receptor (eNMDAR) expression during perinatal life, coinciding with OPC migration along microvessels. This raises the hypothesis that eNMDAR might influence the fate of vessel-associated OPC. In this study, a Grin1^lox/lox/VeCad^Cre mouse model was used to investigate in females and males the effects of endothelial GluN1 invalidation (eNMDAR^-/-) on (1) positioning and differentiation of cortical oligodendrocytes and myelination, (2) OPC/microvessel association and endothelial MMP9-like activity, and (3) motor activity. Results showed that, from postnatal days (P) 2 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.