Abstract
Spina bifida aperta is a congenital malformation characterized by the failure of neural tube closure resulting in an unprotected fetal spinal cord. The spinal cord then undergoes progressive damage, likely due to chemical and mechanical factors related to exposure to the intrauterine environment. Astrogliosis in exposed spinal cords has been described in animal models of spina bifida during embryonic life but its relationship with neuroinflammatory processes are completely unknown. Using a retinoic acid-induced rat model of spina bifida we demonstrated that, when exposed to amniotic fluid, fetal spinal cords showed progressive astrogliosis with neuronal loss at mid-gestation (E15) compared to unexposed spinal cords. The number of microglial cells with a reactive phenotype and activation marker expression increased during gestation and exhibited progressive disruption in the inhibitory immune ligand-receptor system. Specifically we demonstrate down-regulation of CD200 expression and up-regulation of CD200R. Exposed spinal cords demonstrated neuroinflammation with increased tissue water content and cytokine production by the end of gestation (E20), which correlated with active Caspase3 expression in the exposed layers. Our findings provide new evidence that microglia activation, including the disruption of the endogenous inhibitory system (CD200-CD200R), may participate in the pathogenesis of spina bifida through late gestation.
Highlights
Neural tube defects, the most prevalent and disabling of all the congenital malformations, occur with an incidence of 1 per 1,000 births[1]
Variations were observed in the shape of the open spinal cord and the extent of neural tissue loss
In analyzing the expression of CD200-CD200R, we demonstrated that disruption of this inhibitory immune ligand-receptor system in the lesion led to microglial activation at E20
Summary
The most prevalent and disabling of all the congenital malformations, occur with an incidence of 1 per 1,000 births[1] These serious malformations of the central nervous system (CNS) develop when the canal of the brain or spinal cord remains persistently open to the environment. This process during gastrulation, occurs during the fourth week of human gestation, and the lack of closure result in anencephaly and/or spina bifida. Knowing the exhisting neural tissue damage in utero in spina bifida and given the importance of this immune ligand-receptor system in regulating microglial expression during brain development and microglial priming; we hypothezised that spina bifida suffer a progressive astrroglial and microglial activation during gestation and the microglia priming may be related to the alteration of the CD200-CD200R system. This study examines progression during gestation of astrogliosis and neuroinflammation analyzing the effect of CD200-CD200R on microglia reactivity during gestation in the rat fetal model of retinoic acid-induced spina bifida aperta
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