Prenatal stress-induced impairments of cognitive flexibility and bidirectional synaptic plasticity are possibly associated with autophagy in adolescent male-offspring

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Prenatal stress (PS) brings numerous outcomes on offspring, including anxiety, depression-like behavior and other cognitive disorder. In this study, a rat model of PS was established by using restraint stress for 45 min three times per day from the 15th to 21st day of pregnancy. Behavioral tests, including open field test (OPT), elevated plus-maze (EPM) and Morris water-maze (MWM), were performed in adolescent male-offspring. The bidirectional synaptic plasticity, including long-term potential (LTP) and depotentiation (DEP), from the hippocampal Schaffer collaterals to CA1 region was subsequently measured. Furthermore, Western blot assay, immunofluorescence staining and hematoxylin-eosin (HE) staining were employed. The MWM test showed that the cognitive flexibility was remarkably damaged in PS offspring. Meanwhile, PS considerably aggravated the anxiety and depression-like behavior in OPT and EPM. Both LTP and DEP were significantly inhibited by PS. Furthermore, PS considerably altered the expression of synaptic-related proteins NR2A, NR2B and PSD-95 in adolescent male-offspring. Interestingly, PS significantly elevated the autophagy level in the hippocampus of male-offspring. In order to investigate the role of autophagy on the negative impacts of PS in adolescent male-offspring, both in vitro and in vivo studies were performed. It was found that autophagy inhibitors significantly eliminated the alterations in gene expression induced by corticosterone. The results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by PS in adolescent male-offspring.HighlightsPS impairs cognitive flexibility in adolescent offspring.PS reduces in vivo hippocampal LTP and DEP capacities in adolescent offspring.Hippocampal expressions of NR2A, NR2B and PSD-95 were significantly altered by PS.Level of hippocampal cell death and autophagy was effectively elevated by PS.Autophagy may be involved in the effect of PS on the offspring.

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