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

Abstract

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.

Effect of willed movement training on neurorehabilitation after focal cerebral ischemia and on the neural plasticity-associated signaling pathway

“…Although CR and EM groups also exhibited ERK/CREB pathway activation, this was not as effective as that of the WM group. Notably, BDNF and SYP have been observed to be positively regulated by the ERK pathway (8,9), it is suggested that STAT3 and ERK signaling may exert synergistic or additional effects on the promotion of BDNF and SYP. The ERK/CREB pathway serves as a key signaling pathway for neuroprotection and endogenous neurogenesis.…”

“…The ERK/CREB pathway serves as a key signaling pathway for neuroprotection and endogenous neurogenesis. It was reported that CREB activation serves a critical part in DNA repair and anti-oxidation, thereby protecting neurons from damage induced by cerebral ischemia and reperfusion (9). Neurogenesis mediated by the ERK/CREB pathway is involved in structural and functional neuroplasticity, therefore, it is suggested that ERK/CREB activation triggered by WM training is important to reduce brain damage after stroke, and improves neurobehavioral performance.…”

“…Conditional activation of ERK enhances hippocampus neurogenesis in a rat model of traumatic brain injury, improving the olfactory function under normal conditions and after injury, and inhibition of MEK/ERK abolished the neurogenesis improved by sphingosine-1-phosphate receptor 1 activation (7). The pivotal role of ERK in endogenous neurogenesis is likely mediated through regulating multiple factors, including cyclic adenosine monophosphate response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), nerve growth factor, and synaptophysin (SYP) (8,9). Notably, it has been previously suggested that there is a critical role of CREB activation in plasticity of dendritic spines in central neurons (8,9).…”

“…The pivotal role of ERK in endogenous neurogenesis is likely mediated through regulating multiple factors, including cyclic adenosine monophosphate response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), nerve growth factor, and synaptophysin (SYP) (8,9). Notably, it has been previously suggested that there is a critical role of CREB activation in plasticity of dendritic spines in central neurons (8,9). The CREB-mediated pathway is implicated in enhanced structural plasticity and the behavioral recovery that are promoted by post-stroke forced limb-use in cerebral multi-infarction rats (10).…”

Molecular mechanism of nur77 gene expression and downstream target genes in the early stage of forskolin-induced differentiation in PC12 cells

“…The effect of Nur77 on neuron-specific markers was analyzed in neurite outgrowth induced by forskolin. We first examined if the neuron-specific marker, Synapsin1 as a synaptic marker 45 , β-tubulin III as a neuronal marker of newly generated neurons [46][47][48] or NeuroD as a neuronal marker for the early phase of the neuronal lineage 48 , was upregulated with treatment of 10 µM forskolin for 24 hr. qPCR and immunoblotting detected Synapsin1 and β-tubulin III, but not NeuroD (Fig.…”