Neuronal Dendrite Spine Remodeling Regulated By Histone Acetylation Mediates Offspring's Cognition Impairment Induced By Abdominal Surgery Under Ketamine Anesthesia During Middle Pregnancy

Background and object:Histone acetylation regulates cognitive function by regulating dendritic spine remodeling in hippocampal neurons.Previous studies have shown that maternal ketamine anesthesia during pregnancy can cause learning and memory impairment in offspring,but the role of histone acetylation in it is unclear.There are some pregnant women have to undergo non-obstetric surgery in the second trimester.Therefore the study was investigated the role of neuronal dendrite spine remodeling regulated by histone acetylation in offspring's cognition impairment induced by abdominal surgery under ketamine anesthesia during middle pregnancy.Methods:Thirty pregnant Sprague–Dawley(SD) rats were randomly assigned to three groups: Ketamine anaesthesia(Ket group),abdominal surgery under ketamine anaesthesia(Surg group) and Control(C group).On the 14 th day of gestation,pregnant rats in the Ket group received ketamine anaesthesia for 2 h,while those in Surg group underwent abdominal surgery under ketamine anaesthesia,the total time of anaesthesia and operation was 2 h.Equal volumes of saline were given to the control group.The offspring rats of each group were then assigned to three subgroup,Suberoylanilide Hydroxamic Acid(SAHA),Senegenin(SEN) and dimethyl sulfoxide(DMSO).Offspring were intraperitoneally injected with traditional Chinese medicine(SEN),histone deacetylase 2(HDAC2) inhibitor SAHA or DMSO once per day from the first day after birth,for 14 consecutive days.The cliff avoidance,open field and Morris Water Maze(MWM) test were used to evaluate spatial perception,anxiety-like behavior and spatial learning and memory function on the 7th,22 th and30th days respectively.The day after MWM test(P 36),the hippocampus was collected for the detection of the activity of histone deacetylases(HDACs) and histone acetyltransferases(HAT),the expression levels of developmentally down-regulated 9(NEDD9) and postsynaptic density 95(PSD-95) mRNA andprotein and the density and type of dendritic spines with ultraviolet spectrophotometry,Q-PCR,western blot and Golgi stain respectively.Results:Cliff avoidance test showed that the scores in Surg group were decreased significantly when compared to control group(1.56 ± 0.21 vs.1.27 ± 0.24).The results of open field test showed no significant changes among three groups.Compared with control group,the escape latency increased,while platform crossing times(5.26 ± 1.29 vs.3.90 ± 1.17) and target quadrant traveling time(30.07 ± 5.42 vs.22.93 ± 7.32) decreased in Surg group.Surgery under ketamine anaesthesia enhanced the activity of HDACs(203.57 ± 39.24 vs.266.21 ± 73.01),decreased the protein levels of NEDD9(1.04 ± 0.09 vs.0.55 ± 0.16) and PSD-95(1.00 ± 0.17 vs.0.53 ±0.12) and the density of dendritic spine,while did not change the mRNA levels of NEDD9,PSD-95,the type of dendritic spine and the activity of HAT.All these indexes in Ket group showed no significant changes.SEN decreased escape latency,while increased platform crossing times,target quadrant traveling time,the protein levels of NEDD9(0.55± 0.16 vs.0.98 ± 0.29) and PSD-95(0.53± 0.12 vs.0.98 ±0.20) and the density of dendritic spine in surgery exposure rat offspring.SAHA showed no obvious effect on these indexes.Conclusion:Ketamine anaesthesia in the middle stage of pregnancy has no effect on cognition,but abdominal surgery under ketamine anaesthesia impairs spatial perception and spatial learning and memory in offspring;this is associated with up-regulation of HDACs activity,down-regulation of the protein levels of NEDD9 and PSD-95 and the density of dendritic spine.Traditional Chinese medicine SEN can mitigate the spatial learning and memory impairments caused by abdominal surgery under ketamine anaesthesia.