Retardation of neurobehavioral development and reelin down-regulation regulated by further DNA methylation in the hippocampus of the rat pups are associated with maternal deprivation

It is known that early life stress has profound effects in early developing hippocampus. Reelin is a large protein that regulates neuronal migration during embryonic development. The expression of reelin persists in brain, but its function is little known. The aim of the present study was to investigate the effects of maternal deprivation (MD) on early neurobehavioral development of rats, and the role of reelin and the potential mechanism underlying regulation of its expression in hippocampus. Rat pups were removed from mothers during the postnatal day (PND) 2–15 for 3 h a day. Reflex developments including grasping, gait, righting, cliff avoidance, auditory startle, hot-plate test and negative geotaxis, were tested during the first 3 weeks. The level of reelin mRNA and reelin gene methylation in the hippocampal formation were determined using real-time PCR analysis. As expected, some differences appeared in the measure of neurobehavior and expression of reelin in rat pups. Several significant deficiencies were observed in bodyweight, auditory startle and grasping reflex while a great enhancement in hot-plate test in rat pups suffering from MD. On PND 22, the expression of reelin mRNA reduced in the hippocampus followed by MD. Meanwhile, the changes of DNA methylation showed an opposite trend compared with the reelin expression. The results suggest that MD in early life has harmful effects on neurobehavioral development, and causes the down-regulation of reelin mRNA by further DNA methylation in postnatal hippocampus.

Research highlights▶ We focus on the relationship between the early neurobehavioral development and MD. ▶ We focus on the relationship between reelin mRNA and early-life stress. ▶ The hippocampal reelin mRNA were decreased by repeated MD over the early development. ▶ We investigated whether and how DNA methylation regulates reelin mRNA in hippocampus.