Research Papers:

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

Yanan Li, Xinran Li, Cen Guo, Lina Li, Yuxin Wang, Yiming Zhang, Yu Chen, Wenhan Liu and Li Gao _

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Oncotarget. 2017; 8:30956-30970. https://doi.org/10.18632/oncotarget.16042

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Yanan Li1, Xinran Li1, Cen Guo1, Lina Li1, Yuxin Wang1, Yiming Zhang1, Yu Chen1, Wenhan Liu1, Li Gao1

1College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China

Correspondence to:

Li Gao, email: [email protected]

Keywords: ketamine, pregnancy, long-term neurocognitive dysfunction, ERK, synapse

Received: January 16, 2017     Accepted: March 01, 2017     Published: March 09, 2017


Early life exposure to ketamine caused neurohistopathologic changes and persistent cognitive dysfunction. For this study, a pregnant rat model was developed to investigate neurocognitive effects in the offspring, following ketamine exposure during the second trimester. Pregnant rats on gestational day 14 (equal to midtrimester pregnancy in humans), intravenously received 200 mg/kg ketamine for 3 h. Their behavior was tested (Morris water maze, odor recognition test, and fear conditioning) at postnatal days (P25–30). Furthermore, hippocampal morphology of the offspring (P30) was examined via Nissl staining and hippocampal dendritic spine density was determined via Golgi staining. The hippocampal protein levels of nerve growth factor (NGF), extracellular signal-regulated kinase (ERK), phosphorylated-ERK (p-ERK), cyclic adenosine monophosphate response element-binding (CREB), p-CREB, synaptophysin (SYP), synapsin (SYN), and postsynaptic density-95 (PSD95) were measured via western blot. Additionally, SCH772984 (an ERK inhibitor) was used to evaluate both role and underlying mechanism of the ERK pathway in PC12 cells. We found that ketamine caused long-term neurocognitive dysfunction, reduced the density of the dendritic spin, caused neuronal loss, and down-regulated the expression of NGF, ERK, p-ERK, mitogen, and stress-activated protein kinase (MSK), CREB, p-CREB, SYP, SYN, and PSD95 in the hippocampus. These results suggest that ketamine induced maternal anesthesia during period of the fetal brain development can cause long-term neurocognitive dysfunction in the offspring, which likely happens via inhibition of the NGF-ERK-CREB pathway in the hippocampus. Our results highlight the central role of ERK in neurocognition.

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