Effect Of Prenatal Administration Of Dexamethasone On Learning And Memory In Rat Offspring

Aβis a heterogeneous 39-43-amino acid peptide generated by sequential cleavage of amyloid precursor protein byβ-secretase andγ-secretase.The hippocampus is a brain region important for memory and contains a high density of glucocorticoids receptors(GR).Glucocorticoids(GCs) are important adrenal steroids that affect numerous physiological processes in the brain,and widely used in medicine.Previous studies showed that increased plasma levels of Dexamethasone (DEX) can potentiate the loss of hippocampal synapsis and aggravate the apotosis of the dentate gyrus,accompanied with atrophy of hippocampus.Because prenatal administration of DEX could impair the regulation of hypothalamic-pituitary-adrenal (HPA) axis and increase the level of GCs in fetus and adult offsprings.Therefore,in this study we investigate whether prenatal administration of DEX could lead to learning and memory impairment in rat offspring in vivo,and,if so,what is the underlying mechanism.Additionally,in vitro,we focused on assessing whether pre-incubation of neurons with DEX could increase the Aβ_25-35-triggered elevation in phospho-tau protein,p25 protein and cdk5 mRNA.We also wanted to investigate whether DEX could up-regulate the increased level of nuclear p53 induced by Aβ_25-35.Objective The objectives of this experiments were to explore whether prenatal administration of DEX could lead to learning and memory impairment and its relative mechanism in rat offspring.Methods The pregnant rats were treated with DEX(0.5 mg/kg/d or 1.0 mg/kg/d sc×4d) from gestation day 15 to gestation day 18.Morris water maze test was used to investigate whether prenatal administration of DEX(0.5 mg/kg/d or 1.0 mg/kg/d) could lead to learning and memory impairment in rat offspring in vivo,and the histopathologic changes in CA1 field of hippocampus was examined under a light microscope.Primitive hippocampal neurons derived from 18 day embryonic rat were cultuied.Cultured cells were pretreated with DEX(0 or 10μmol/L) for 24 h followed by Aβ_25-35(0 or 5μmol/L) for various time,and then the cell viability,cdk5 mRNA and p53 mRNA,phospho-tau,p25 and nuclear p53 protein were analyzed by LDH release rate assay,RT-PCR and western blot respectly.Results1.Prenatal administration of DEX(0.5 mg/kg/d or 1.0 mg/kg/d,sc×4d) from gestation day 15 to gestation day 18 could increase the escape latency and the swim distances in rat offspring during training session in the Morris water maze test.Severe histological damage was observed in the CA1 cell fields of the hippocampus in DEX(1.0 mg/kg/d)treated group.These neuropathological changes were characterized by decreased cell number,arrangement disorder and condensation.2.Treatment with aggregated Aβ_25-35(5μmol/L) alone could decrease the cell viability.Treatment for 48 h with DEX(10μmol/L) alone did not cause a significant increase in LDH release rate compared with vehicle-treated control cultures.But a 24-h preincubation with DEX(10μmol/L) could further decrease the viability of hippocampal neuron induced by Aβ_25-35(5μmol/L).3.Aβ_25-35(0-20μmol/L)could dose-dependently induce phosphorylation of tau at Thr-231 in primary hippocampal neurons cocultured for 1 h with Aβ_25-35,whereas maximal phosphorylation was obtained with Aβ_25-35(10μmol/L).Treatment of neurons with DEX for 25 h could results in an slight elevation in tau phosphorylation at Thr-231.Pretreated with DEX(10μmol/L) for 24 h could furture promote the increased level of phospho-tau at Thr-231 induced by Aβ_25-35(5μmol/L). 4.Aβ_25-35(5μmol/L) treatment resulted in small but significant increases in the levels of p25 protein and cdk5 mRNA 1 h after Aβwas added to the culture. Treatment with DEX(10μmol/L) alone for 25 h did not increase the levels of p25 protein and cdk5 mRNA.But pretreatment with DEX(10μmol/L) for 24 h could promote the increased levels of p25 protein and cdk5 mRNA induced by Aβ_25-35(5μmol/L).5.Aβ_25-35(5μmol/L) treatment resulted in significant increases in the levels of nuclear protein of p53 and p53 mRNA 18 h after Aβwas added to the culture. Treatment with DEX(10μmol/L) alone for 42 h didn't increase the levels of nuclear protein of p53 and p53 mRNA.Again,pretreatment with DEX(10μmol/L) for 24 h didn't promote the increased levels of nuclear protein of p53 and p53 mRNA induced by Aβ_25-35(5μmol/L) too.Conclusions(1) In vivo,Prenatal administration of DEX(1.0 mg/kg/d,sc×4d)could lead to learning and memory impairment in rat offspring.The neuropathological changes were characterized by decreased cell number,arrangement disorder and condensation.(2) In vitro,DEX(10μmol/L) further decreased the viability of hippocampal neuron induced by Aβ_25-35(5μmol/L).(3) DEX(10μmol/L) could promote the increased level of phospho-tau at Thr-231 induced by Aβ_25-35(5μmol/L).(4) DEX(10μmol/L) could up-regulate the elevated levels of p25 protein and cdk5 mRNA induced by Aβ_25-35(5μmol/L).(5) DEX did not influence Aβ-induced increased levels of p53 mRNA and nuclear p53 protein.