Abstract

Lead (Pb) can cause a significant neurotoxicity in both adults and children, leading to the impairment to brain function. Pb exposure plays a key role in the impairment of learning and memory through synaptic neurotoxicity, resulting in the cognitive function. Researches have demonstrated that Pb exposure plays an important role in the etiology and pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease. However, the underlying mechanisms remain unclear. In the current study, a gestational Pb exposure (GLE) rat model was established to investigate the underlying mechanisms of Pb-induced cognitive impairment. We demonstrated that low-level gestational Pb exposure impaired spatial learning and memory as well as hippocampal synaptic plasticity at postnatal day 30 (PND 30) when the blood concentration of Pb had already recovered to normal levels. Pb exposure induced a decrease in hippocampal glucose metabolism by reducing glucose transporter 4 (GLUT4) levels in the cell membrane through the phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) pathway. In vivo and in vitro GLUT4 over-expression increased the membrane translocation of GLUT4 and glucose uptake, and reversed the Pb-induced impairment to synaptic plasticity and cognition. These findings indicate that Pb exposure impairs synaptic plasticity by reducing the level of GLUT4 in the cell membrane as well as glucose uptake via the PI3K-Akt signaling pathway, demonstrating a novel mechanism for Pb exposure-induced neurotoxicity.

Highlights

  • The developing brain is vulnerable to lead (Pb) exposure, which causes persistent behavioral and emotional disturbances, such as cognitive dysfunction, including deficits in executive functioning, attention, and memory (Mills et al, 2011)

  • We demonstrated that low-level gestational particularly vulnerable to lead (Pb) exposure impaired spatial learning and memory as well as hippocampal synaptic plasticity at postnatal day 30 (PND 30) when the blood concentration of Pb had already recovered to normal levels

  • Through morphological analysis (Golgi-Cox staining) and long-term potentiation (LTP) recording in the hippocampal cornu ammonis 1 (CA1) region of the offspring, we investigated the effect of low-level gestational Pb exposure on hippocampal synaptic plasticity and examined how the offspring’s spatial learning and memory functions were affected at PND 30 using Morris water maze (MWM) experiments

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Summary

Introduction

The developing brain is vulnerable to lead (Pb) exposure, which causes persistent behavioral and emotional disturbances, such as cognitive dysfunction, including deficits in executive functioning, attention, and memory (Mills et al, 2011). Regardless of the exposure time window, these studies and ours collectively revealed that developmental Pb exposure significantly impairs spatial learning and memory (Hu et al, 2014, 2016; Wang et al, 2016). As the hippocampus is sensitive to Pb exposure and plays a critical role in spatial learning and memory, which is the basis of cognitive ability (Barha and Galea, 2013), the hippocampus has become a research focus for Pb exposure-induced neurotoxicity (Anderson et al, 2013). Pb exposure during development impairs hippocampus-dependent spatial learning and memory via modifying the levels of N-methyl-D-aspartate (NMDA) receptor-dependent brain-derived neurotrophic factors (BDNFs)

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