Ketamine administered pregnant rats impair learning and memory in offspring via the CREB pathway

Abstract

Ketamine has been reported to impair the capacity for learning and memory. This study examined whether these capacities were also altered in the offspring and investigated the role of the CREB signaling pathway in pregnant rats, subjected to ketamine-induced anesthesia. On the 14th day of gestation (P14), female rats were anesthetized for 3 h via intravenous ketamine injection (200 mg/Kg). Morris water maze task, contextual and cued fear conditioning, and olfactory tasks were executed between the 25th to 30th day after birth (B25-30) on rat pups, and rats were sacrificed on B30. Nerve density and dendritic spine density were examined via Nissl’s and Golgi staining. Simultaneously, the contents of Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII), p-CaMKII, CaMKIV, p-CaMKIV, Extracellular Regulated Protein Kinases (ERK), p-ERK, Protein Kinase A (PKA), p-PKA, cAMP-Response Element Binding Protein (CREB), p-CREB, and Brain Derived Neurotrophic Factor (BDNF) were detected in the hippocampus. We pretreated PC12 cells with both PKA inhibitor (H89) and ERK inhibitor (SCH772984), thus detecting levels of ERK, p-ERK, PKA, p-PKA, p-CREB, and BDNF. The results revealed that ketamine impaired the learning ability and spatial as well as conditioned memory in the offspring, and significantly decreased the protein levels of ERK, p-ERK, PKA, p-PKA, p-CREB, and BDNF. We found that ERK and PKA (but not CaMKII or CaMKIV) have the ability to regulate the CREB-BDNF pathway during ketamine-induced anesthesia in pregnant rats. Furthermore, ERK and PKA are mutually compensatory for the regulation of the CREB-BDNF pathway.

Administration of Ketamine Causes Autophagy and Apoptosis in the Rat Fetal Hippocampus and in PC12 Cells

“…Previous studies have reported that ketamine damages nerve cells (Li X. et al, 2017 ). Using 1 mg/kg of ketamine in young male monkeys led to permanent and irreversible damage to brain function (Sun et al, 2014 ).…”

Long-term neurocognitive dysfunction in offspring via NGF/ ERK/CREB signaling pathway caused by ketamine exposure during the second trimester of pregnancy in rats

“…There is considerable body of evidence to show that activation of ERK (p-ERK) in the hippocampus enhances memory via phosphorylation of the downstream transcription factor CREB on Ser residue 133 [ 32 ]. Low expression of CREB can lead to significant damage to the memory [ 33 , 34 ], while high expression of CREB can result in significant enhancement of memory and an improvement on social cognitive function [ 35 ]. Results from Figure 8 have shown that ketamine injection significantly reduced the level of the ERK, p-ERK, MSK, CREB, and p-CREB proteins in the hippocampus.…”

Osteopontin contributes to effective neutrophil recruitment, IL‐1β production and apoptosis in Aspergillus fumigatus keratitis

“…Neutralizing antibodies included a goat LOX-1 neutralizing antibody (R&D, Minneapolis, MN, USA) at a final concentration of 10 lg mL À1 , 38 a goat dectin-1 neutralizing antibody (R&D) at a final concentration of 30 lg mL À1 , a goat OPN neutralizing antibody (R&D) at a final concentration of 10 lg mL À1 39 and a control goat IgG (R&D). Inhibitors included the JNK inhibitor SP600125 (SelleckChem, Houston, TX, USA) (40 lmol L À1 ), 40 the Erk1/2 inhibitor SCH772984 (SelleckChem) (10 lmol L À1 ) 41 and the 4E-BP1/eIF4E interaction inhibitor 4E1RCat (SelleckChem) (50 lmol L À1 ). 42 HCECs were treated with human osteopontin recombinant protein (rhOPN; R&D Systems) at a final concentration of 180 ng mL À1 ) 43 or 4E1RC at 1 h after treatment with the OPN neutralizing antibody.…”