Effects Of Exposure To Lipopolysaccharides During Pregnancy On Age-related Spatial Learning And Memory And Levels Of Hippocampal Histone Phosphorylation And Methylation Of Offspring In The CD-1 Mice

Background: Learning and memory impairment caused by aging seriously affects the life of the elderly,and the population aging has becoming more seriously.However,the mechanism underlying the age-related memory impairment remains unknown.Studies found that the age-related memory impairment was closely correlated with intrauterine developmental disorders.Infection is the most common exposure during pregnancy.Maternal infection affects fetal development and neurological behavior of offspring adulthood,especially age-related memory impairment.In recent years,a large number of studies have been conducted in the field of histone post-translational modification of epigenetic modifications.Some histone PTMs,such as phosphorylation and methylation,have been demonstrated that played an important role in the development and progression of various neurological and psychiatric diseases,and involved in age-related learning and memory dysfunction.Our study investigated whether exposure to adverse factors during pregnancy could accelerate cognitive impairment in the offspring,and explored whether histone phosphorylation and methylation modifications are involved in this damage Objective: In our study,we investigated the effects of LPS during pregnancy on the spatial learning and memory of offspring in CD-1 mice,and assessd the age-related changes of phosphorylation of H3S10 and trimethylation of H3K9 levels.We also studied the effects of maternal inflammation on the levels of H3S10 p and H3K9me3 in different subareas of hippocampus,and explored the correlation between the spatial learning and memory of offspring and the H3S10 p and H3K9me3 Methods: In our study,the pregnant mice received intraperitoneal injection of lipopolysaccharide(LPS,50 or 25 μg/kg)and normal saline during gestational days 15-17,respectively.After normal parturition,the offspring was separated into higher doses group(50μg / kg,H-LPS),lower doses group(25μg / kg,L-LPS)and control group;Each group was randomly divided into 1-,6-,12-,18-and 22-month-old offspring mice.The six-arm radial water maze(RAWM)was used to assess the spatial learning and memory of offspring,and the expression of H3S10 p and H3K9me3 in different subregions of hippocampus was detected by immunohistochemical method.Finally,we explored the correlation brtween the immunohistochemical results and the consequences from the RAWM task Results: 1)The spatial learning and memory(SLM)impairment began in 12-month-old CD-1 mice,i.e.,the 22-、18-and 12-month-old mice had more errors and longer latency in both the learning and memory phases compared to the 1-and 6-month-old mice,with worsened performances during the aging;2)Age significantly affected the levels of H3S10 phosphorylation(H3S10p)and H3K9 trimethylation(H3K9me3),i.e.,the levels of H3S10 p in DG、CA1 and CA3 areas of hippocampus significantly decreased with aging in H-LPS and L-LPS groups,so did the H3S10 p levels in DG and CA1 areas in the control group.The levels of H3K9me3 increased with aging in DG and CA1 areas;3)Prenatal exposure to inflammation could dose-dependently accelerate the SLM impairment and histone PTMs change(H3S10p decrease and H3K9me3 increase)from 12-month-old mice;4)The changes of neurobiological indicators significantly correlated with SLM impairment.The hippocampal H3S10 p level negatively and H3K9me3 level positively correlated with the SLM ability from 12-month-old mice.Conclusions: 1)LPS exposure during pregnancy could dose-dependent accelerate age-related SLM impairment and the levels of H3S10 p and H3K9me3 change from midlife onwards;2)Impairment of SLM abilities might correlate with the levels of H3S10 p decreased and H3K9me3 increased.