Abstract
Lead (Pb) is known to impair children’s cognitive function. It has been previously shown that developmental Pb exposure alters dendritic spine formation in hippocampal pyramidal neurons. However, the underlying mechanism has not yet been defined. In this study, a low-level gestational Pb exposure (GLE) rat model was employed to investigate the impact of Pb on the spine density of the hippocampal pyramidal neurons and its regulatory mechanism. Pb exposure resulted in impaired performance of the rats in the Morris water maze tasks, and in decreased EPSC amplitudes in hippocampal CA3-CA1 regions. With a 3D reconstruction by the Imaris software, the results from Golgi staining showed that the spine density in the CA1 region was reduced in the Pb-exposed rats in a dose-dependent manner. Decreased spine density was also observed in cultured hippocampal neurons following the Pb treatment. Furthermore, the expression level of NLGN1, a postsynaptic protein that mediates synaptogenesis, was significantly decreased following the Pb exposure both in vivo and in vitro. Up-regulation of NLGN1 in cultured primary neurons partially attenuated the impact of Pb on the spine density. Taken together, our resultssuggest that Pb exposure alters spine plasticity in the developing hippocampus by down-regulating NLGN1 protein levels.
Highlights
Early postnatal exposures[15] and late postnatal exposures[16]
Considering the important roles of Neuroligin 1 (NLGN1) in the formation and regulation of the spines in the hippocampus, we examined whether the Pb-induced decrease in spine density in the CA1 region was accompanied by a reduction in NLGN1 expression
This study investigated the impact of low-level gestational Pb exposure on learning and memory and the role of NLGN1 in this process
Summary
Early postnatal exposures[15] and late postnatal exposures[16]. To date, it has been shown that Pb exposure impairs hippocampal-dependent spatial learning and memory by altering N-methyl-D-aspartate (NMDA) receptor-dependent brain derived neurotrophic factors (BDNF)[17], by impairing hippocampal LTP, possibly via microglia-neuron cross-talk[18], and by introducing epigenetic changes through manipulating the expression of DNA methyltransferases and methyl cytosine-binding proteins[19]. Changes in dendritic spine density and structure are crucial for post-synaptic plasticity and contribute to the morphological bases of learning and memory function[22,23]. Neuroligin 1 (NLGN1), a postsynaptic adhesion protein, is located predominantly in excitatory synapses and is involved in diverse forms of excitatory synaptic plasticity across species[29,30]. NLGN proteins, especially NLGN1, are required for synaptogenesis, dendritic spine maturation and stability. Taken together, these observations have led us to postulate that developmental Pb exposure disrupts NLGN1, leading to altered dendritic spine formation in hippocampal neurons, which, in turn, results in learning and memory impairment. Given that gestational brain development in humans is analogous to the prenatal through PND10 period in rats[33,34,35], we established a low-level human-equivalent gestational Pb exposure (GLE) rat model to explore this issue
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