Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression

Abstract

Stress during pregnancy has a wide variety of negative effects in both human [1] and animal offspring [2]. These effects are especially apparent in various forms of learning and memory such as object recognition [3] and spatial memory [4]. The cognitive effects of prenatal stress (PNS) may be mediated through epigenetic changes such as histone acetylation and DNA methylation [5]. As such, the present study investigated the effects of chronic unpredictable PNS on memory and epigenetic measures in adult offspring. Mice that underwent PNS exhibited impaired spatial memory in the Morris water maze, as well as sex-specific changes in levels of DNA methyltransferase (DNMT) 1 protein, and acetylated histone H3 (AcH3) in the hippocampus, and serum corticosterone. Male mice exposed to PNS exhibited decreased hippocampal AcH3, whereas female PNS mice displayed a further reduction in AcH3, as well as heightened hippocampal DNMT1 protein levels and corticosterone levels. These data suggest that PNS may epigenetically reduce transcription in the hippocampus, particularly in females in whom this effect may be related to increased baseline stress hormone levels, and which may underlie the sexual dimorphism in rates of mental illness in humans.

Keywords: Chronic unpredictable stress; DNA methyltransferase; Histone acetylation; Morris water maze; Mouse; Sex differences.

Fig. 1

A) Number of platform crossings per 10-s interval in the probe trial of each day of spatial Morris water maze testing. PNS mice made significantly fewer platform crossings than controls, but no other main effects or interactions were significant. B) Main effect of PNS on platform crossings, collapsed across days and sexes. Control mice made significantly more platform crossings than prenatally stressed mice (p < 0.05). Each symbol in (A) and bar in (B) represents the mean ± standard error of the mean (SEM).

Fig. 2

A) AcH3Lys14 levels were decreased by PNS in both sexes. AcH3Lys14 levels were significantly higher in male controls than in male and female PNS groups. The female PNS group also had lower AcH3Lys14 levels than the male PNS and female control groups. B) DNMT1 levels were significantly increased by PNS in females. The female PNS group had significantly higher DNMT1 levels than all other groups. PNS did not significantly affect DNMT1 levels in males * indicates p < 0.05, ** indicates p < 0.0001. Each bar represents the mean ± SEM.

Fig. 3

Serum corticosterone concentrations in each group. Corticosterone concentrations were higher in female PNS mice relative to male PNS mice. * indicates p < 0.05 (t-test). Each bar represents the mean ± SEM.