The brain‐derived neurotrophic factor (BDNF)‐tyrosine kinase B (TrkB) (BDNF‐TrkB) signalling pathway plays a crucial role in regulating learning and memory. Synaptophysin provides the structural basis for synaptic plasticity and depends on BDNF processing and subsequent TrkB signalling. Our previous studies demonstrated that maternal exposure to propofol during late stages of pregnancy impaired learning and memory in rat offspring. The purpose of this study is to investigate whether the BDNF‐TrkB signalling pathway is involved in propofol‐induced learning and memory impairments. Propofol was intravenously infused into pregnant rats for 4 hrs on gestational day 18 (E18). Thirty days after birth, learning and memory of offspring was assessed by the Morris water maze (MWM) test. After the MWM test, BDNF and TrkB transcript and protein levels were measured in rat offspring hippocampus tissues using real‐time PCR (RT‐PCR) and immunohistochemistry (IHC), respectively. The levels of phosphorylated‐TrkB (phospho‐TrkB) and synaptophysin were measured by western blot. It was discovered that maternal exposure to propofol on day E18 impaired spatial learning and memory of rat offspring, decreased mRNA and protein levels of BDNF and TrkB, and decreased the levels of both phospho‐TrkB and synaptophysin in the hippocampus. Furthermore, the TrkB agonist 7,8‐dihydroxyflavone (7,8‐DHF) reversed all of the observed changes. Treatment with 7,8‐DHF had no significant effects on the offspring that were not exposed to propofol. The results herein indicate that maternal exposure to propofol during the late stages of pregnancy impairs spatial learning and memory of offspring by disturbing the BDNF‐TrkB signalling pathway. The TrkB agonist 7,8‐DHF might be a potential therapy for learning and memory impairments induced by maternal propofol exposure.

Increasing evidence indicates that most general anesthetics can harm developing neurons and induce cognitive dysfunction in a dose- and time-dependent manner. Histone deacetylase 2 (HDAC2) has been implicated in synaptic plasticity and learning and memory. Our previous results showed that maternal exposure to general anesthetics during late pregnancy impaired the offspring’s learning and memory, but the role of HDAC2 in it is not known yet. In the present study, pregnant rats were exposed to 1.5% isoflurane in 100% oxygen for 2, 4 or 8 hours or to 100% oxygen only for 8 hours on gestation day 18 (E18). The offspring born to each rat were randomly subdivided into 2 subgroups. Thirty days after birth, the Morris water maze (MWM) was used to assess learning and memory in the offspring. Two hours before each MWM trial, an HDAC inhibitor (SAHA) was given to the offspring in one subgroup, whereas a control solvent was given to those in the other subgroup. The results showed that maternal exposure to isoflurane impaired learning and memory of the offspring, impaired the structure of the hippocampus, increased HDAC2 mRNA and downregulated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) mRNA, N-methyl-D-aspartate receptor 2 subunit B (NR2B) mRNA and NR2B protein in the hippocampus. These changes were proportional to the duration of the maternal exposure to isoflurane and were reversed by SAHA. These results suggest that exposure to isoflurane during late pregnancy can damage the learning and memory of the offspring rats via the HDAC2-CREB -NR2B pathway. This effect can be reversed by HDAC2 inhibition.

Propofol is widely used in clinical practice, including non‐obstetric surgery in pregnant women. Previously, we found that propofol anaesthesia in maternal rats during the third trimester (E18) caused learning and memory impairment to the offspring rats, but how about the exposure during early pregnancy and the underlying mechanisms? Histone acetylation plays an important role in synaptic plasticity. In this study, propofol was administered to the pregnant rats in the early pregnancy (E7). The learning and memory function of the offspring were tested by Morris water maze (MWM) test on post‐natal day 30. Two hours before each MWM trial, histone deacetylase 2 (HDAC2) inhibitor, suberoylanilide hydroxamic acid (SAHA), Senegenin (SEN, traditional Chinese medicine), hippyragranin (HGN) antisense oligonucleotide (HGNA) or vehicle were given to the offspring. The protein levels of HDAC2, acetylated histone 3 (H3) and 4 (H4), cyclic adenosine monophosphate (cAMP) response element‐binding protein (CREB), N‐methyl‐D‐aspartate receptor (NMDAR) 2 subunit B (NR2B), HGN and synaptophysin in offspring's hippocampus were determined by Western blot or immunofluorescence test. It was discovered that infusion with propofol in maternal rats on E7 leads to impairment of learning and memory in offspring, increased the protein levels of HDAC2 and HGN, decreased the levels of acetylated H3 and H4 and phosphorylated CREB, NR2B and synaptophysin. HDAC2 inhibitor SAHA, Senegenin or HGN antisense oligonucleotide reversed all the changes. Thus, present results indicate exposure to propofol during the early gestation impairs offspring's learning and memory via inhibiting histone acetylation. SAHA, Senegenin and HGN antisense oligonucleotide might have therapeutic value for the adverse effect of propofol.

Preclinical studies suggest that propofol may cause neuronal injury to the developing brain. A previous study demonstrated that, in a rat model, maternal exposure to propofol during early or late pregnancy caused learning and memory impairment in the offspring. However, whether propofol exposure during middle pregnancy can cause long‑term behavioral deficits in the offspring remains to be elucidated. N‑methyl‑D‑aspartate receptor 2B subunit (NR2B) serves a critical role in memory modulation. To exert its function, NR2B must be transported to the neuronal membrane by kinesin family member 17 (KIF17). The aim of the present study was to investigate the role of KIF17 in learning and memory impairment in rat offspring caused by propofol exposure during middle pregnancy. Pregnant rats were exposed to propofol on gestational day 14 (G14) for 4 and 8 h, with control pregnant rats receiving an equal volume of normal saline. The learning and memory of the offspring was assessed using Morris water maze tests from postnatal day 30 (P30) to P36. The levels of KIF17 protein, total NR2B (T‑NR2B) and membrane NR2B (M‑NR2B) in the hippocampus were detected using western blotting. The results demonstrated that propofol exposure caused learning and memory deficits and decreased KIF17 and M‑NR2B protein levels in the hippocampus; however, no but changes in the expression of T‑NR2B were observed. These results indicate that maternal propofol exposure during middle pregnancy impairs learning and memory in offspring rats by suppressing the expression of KIF17 and inhibiting the translocation of NR2B to the neuronal membrane.