Effects of duration and timing of prenatal stress on hippocampal myelination and synaptophysin expression

The relationship between prenatal stress (PS) exposure and neurodevelopmental deficits remains inconclusive, especially when assessing the role of PS duration and timing and sex-dependent effects. This study explored a sex-specific association between the duration and timing of exposure and the outcomes of PS-induced neurotoxicity in hippocampal microstructure, synaptophysin expression, and neurobehavioral performance in rats. Pregnant rats were randomly assigned to control, PS-ML (exposed to prenatal restraint stress in the mid-to-late period of pregnancy), or PS-L (exposed in the late period of pregnancy) groups, and offspring in each group were divided into two subgroups by sex. Surface-righting reflex test, cliff avoidance test and Morris water maze test showed that neurodevelopmental levels were reduced in PS-treated pups but without significant sex differences. On postnatal day 22, hippocampal microstructure was examined by electron microscopy, and the expression of hippocampal synaptophysin was assessed by western blot. Abnormal ultrastructural appearance of hippocampal neurons and myelin sheaths, more degenerating neurons and higher G-ratios were found in young PS-ML and PS-L rats as well as reduced expression of hippocampal synaptophysin, although PS-ML pups were more greatly affected than PS-L, with males showing slightly greater impairments than females. These findings suggest that hippocampal hypo-myelination and decreased synaptophysin expression in neurodevelopment may be a duration and time-dependent effect of prenatal stress exposure, modified slightly by sex.