In utero alcohol exposure impairs retinal angiogenesis and the microvessel-associated positioning of calretinin interneurons.

Abstract

In addition to brain disorders, which constitute a devastating consequence of prenatal alcohol exposure (PAE), eye development is also significantly affected. Given that the retina is a readily accessible part of the central nervous system, a better understanding of the impact of ethanol on retinal development might provide ophthalmological landmarks helpful for early diagnosis of foetal alcohol syndrome. This study aimed to provide a fine morphometric and cellular characterization of the development of retinal microvasculature and neurovascular interactions in a mouse model of foetal alcohol spectrum disorder. The data revealed that PAE impaired superficial vascular plexus development. In particular, progression of the vascular migration front was significantly decreased in PAE retinas, supporting a delay in plexus progression. Moreover, a significant decrease in the vessel density and number of perforating vessels was quantified in PAE mice, supporting less angiogenesis. The present study provides also the first evidence of a close interaction between migrating calretinin-positive interneurons and perforating microvessels in the inner nuclear layer of the developing retina. This neurovascular association was significantly impaired by PAE. Moreover, projections of amacrine cells were abnormally distributed and densified in stratum S1 and S2. In humans, comparison of a 5-month-old control infant with a 3-month-old alcohol-exposed case revealed a similar mispositioning of calretinin-positive interneurons. This opens new research avenues regarding a neurovascular contribution in the deleterious effects of alcohol in the developing retina and support that ophthalmological examination could become a promising approach for early detection of alcohol-exposed infants presenting with neurovascular brain defects.Significance StatementIn the developing brain, prenatal alcohol exposure (PAE) has been shown to disorganize cortical vasculature leading to defective layering of interneurons which use radial microvessels to enter the neocortex. Using a murine model of FASD, here we show that PAE impairs the retinal microvasculature development and neuronal organization. In particular, migrating calretinin-positive interneurons of the internal nuclear layer are associated with perforating microvessels. PAE reduces the number of vessel-associated calretininergic cells and impairs their positioning. The mispositioning of calretinin-positive interneurons is also observed in a human FAS infant. These findings provide new evidence that PAE-induced cortical impairments are found in retina. They offer promising tools for the early diagnosis of brain impairments in infants in utero exposed to alcohol.