Endothelial NMDA Receptor Involvement in Retinal Neurovascular Damage Following Prenatal Alcohol Exposure in a Mouse Model.

Abstract

Prenatal alcohol exposure (PAE) induces neurodevelopmental damage leading to fetal alcohol spectrum disorders (FASD) by altering both brain and ocular development. Recent data showed that PAE impairs brain cortical and retinal vasculature leading to defective positioning of interneurons. In the retina, PAE disturbs vascular development and the association of calretinin neurons with vessels. The NMDA receptor (NMDAR) is a major target of alcohol in the brain, and both ligand binding to NMDARs and the expression of NMDAR subunits are altered in FASD. Given that NMDAR is also expressed in endothelial cells and that glutamate stimulation of endothelial NMDAR (eNMDAR) regulates cortical interneuron positioning along blood vessels, we hypothesize that eNMDAR is critical for retinal vascular development and mediates PAE-induced defects. Using an in vivo model of FASD and transgenic mice lacking the endothelial GluN1 subunit of the NMDAR, this study aimed to characterize the neurovascular phenotype of the developing retina in mice of either sex. Our findings show that deletion of the eNMDAR reproduces key PAE-like alterations, including impaired progression of the superficial vascular plexus and changes in neuronal density, particularly in cells located closest to the retinal vasculature. Conversely, in eNMDAR knock-out mice, some of the retinal defects typically induced by PAE are prevented. Moreover, eNMDAR deletion led to an increased number of calretinin-positive interneurons contacting vessels and prevented the PAE-induced decrease. Together, these findings demonstrate that eNMDARs contribute to normal retinal neurovascular development and mediate, at least in part, the adverse effects of ethanol exposure in FASD.