Pb inhibits hippocampal synaptic transmission via cyclin-dependent kinase-5 dependent Synapsin 1 phosphorylation

Ding, Jin-Jun; Zou, Rong-Xin; He, Hui-Ming; Lou, Zhi-Yi; Xu, Yi; Wang, Huili

doi:10.1016/j.toxlet.2018.08.009

Cited by 21 publications

(15 citation statements)

References 27 publications

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“…Given the foundation of ChIP technique, these genes were dynamically occupied by H3K27me3 in the context of lead neurotoxicity, implying that their expression might be regulated by this epigenetic mark. Our recent finding supported this argument, as the transcription of Syn1 was negatively correlated with the Pb-triggered increase of H3K27me3 in the Syn1 locus 45 . While this study demonstrated the regulatory relations of H3K27me3-Wnt9b, this relay should not be regarded as the sole pathway that H3K27me3 governed in regulating memory deficits.…”

Section: Discussionsupporting

confidence: 70%

“…At DIV7, half of the media were renewed with fresh neurobasal media supplemented with Ara-C (2 μL/mL). For Pb exposure, PbAc (5 μM) was added to culture at DIV3 45 . The Pb dosage used in the cell experiment is selected to establish a replicable neuronal deficit model, based on its performance in the previous reports 45,54 and inability to cause excessive cell death (data not shown).…”

Section: Methodsmentioning

confidence: 99%

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Interplay of miR-137 and EZH2 contributes to the genome-wide redistribution of H3K27me3 underlying the Pb-induced memory impairment

Xue

et al. 2019

Cell Death Dis

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Compromised learning and memory is a common feature of multiple neurodegenerative disorders. A paradigm spatial memory impairment could be caused by developmental lead (Pb) exposure. Growing evidence implicates epigenetic modifications in the Pb-mediated memory deficits; however, how histone modifications exemplified by H3K27me3 (H3 Lys27 trimethylation) contribute to this pathogenesis remains poorly understood. Here we found that Pb exposure diminished H3K27me3 levels in vivo by suppressing EZH2 (enhancer of zeste homolog 2) expression at an early stage. EZH2 overexpression in Pb-treated rats rescued the H3K27me3 abundance and partially restored the normal spatial memory, as manifested by the rat performance in a Morris water maze test, and structural analysis of hippocampal spine densities. Furthermore, miR-137 and EZH2 constitute mutually inhibitory loop to regulate the H3K27me3 level, and this feedback regulation could be specifically activated by Pb treatment. Considering genes targeted by H3K27me3, ChIP-chip (chromatin immunoprecipitation on chip) studies revealed that Pb could remodel the genome-wide distribution of H3K27me3, represented by pathways like transcriptional regulation, developmental regulation, cell motion, and apoptosis, as well as a novel Wnt9b locus. As a Wnt isoform associated with canonical and noncanonical signaling, Wnt9b was regulated by the opposite modifications of H3K4me3 (H3 Lys4 trimethylation) and H3K27me3 in Pb-exposed neurons. Rescue trials further validated the contribution of Wnt9b to Pb-induced neuronal impairments, wherein canonical or noncanonical Wnt signaling potentially exhibited destructive or protective roles, respectively. In summary, the study reveals an epigenetic-based molecular change underlying Pb-triggered spatial memory deficits, and provides new potential avenues for our understanding of neurodegenerative diseases with environmental etiology.

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Section: Discussionsupporting

confidence: 70%

Section: Methodsmentioning

confidence: 99%

Interplay of miR-137 and EZH2 contributes to the genome-wide redistribution of H3K27me3 underlying the Pb-induced memory impairment

Xue

et al. 2019

Cell Death Dis

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“…Whole-cell patch-clamp recordings were performed according to the previous study ( 18 , 19 ). The cultured primary hippocampus neurons were treated with Pb acetate (5 μm) and G-CSF (50 ng/ml) for 48 h. Then, cultured primary hippocampus neurons at days in vitro (DIV) 14 were performed using whole-cell patch-clamp recordings.…”

Section: Methodsmentioning

confidence: 99%

Probiotic Lactobacillus rhamnosus GR-1 supplementation attenuates Pb-induced learning and memory deficits by reshaping the gut microbiota

Huang

et al. 2022

Front. Nutr.

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Lead (Pb) exposure during early life has been associated with an increased risk of neurodevelopmental disorders, including learning and memory deficits. The intestinal flora, via the microbiome–gut–brain axis, could play a significant role in the nervous system. However, the effects of probiotics on ameliorating Pb-induced learning and memory deficits are still unclear. In this study, we showed that adolescent Pb exposure (150 ppm) for 2 months impaired spatial learning and memory ability, accompanied by the decreasing diversity of gut microbiota, and the decreasing abundance of Lactobacillus at the genus level. Surprisingly, administration of the Lactobacillus rhamnosus GR-1 (1010 organisms/rat/day), not L. rhamnosus LGG or Lactobacillus reuteri RC-14, reversed learning and memory deficits induced by Pb exposure. Meanwhile, administration of the L. rhamnosus GR-1 increased the diversity of the gut microbiota composition and partially normalized the genus level of Lactobacillus, Parabacteroides, Enterococcus, and Akkermansia in Pb-exposed rats. Notably, supplementation of L. rhamnosus GR-1 decreased the gut permeability of Pb-exposed rats, reduced proinflammatory cytokines [interleukin-1β (IL-1β) and IL-6] expression, and promoted anti-inflammatory cytokines [granulocyte colony-stimulating factor (G-CSF)] expression. Interestingly, neural cell treatment with G-CSF rescued Pb-induced neurotoxicity. In general, L. rhamnosus GR-1 supplementation recovered the Pb-induced loss of intestinal bacteria (Lactobacillus), which may have reversed the damage to learning and memory ability. Collectively, our findings demonstrate an unexpectedly pivotal role of L. rhamnosus GR-1 in Pb-induced cognitive deficits and identify a potential probiotic therapy for cognitive dysfunction during early life.

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“…And in cultured hippocampal neurons, lead exposure was found to impair excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) [27]. Our lab recently published a finding that chronic lead exposure can inhibit the release of neurotransmitters by interfering with its vesicle pool recycling, and the main protein impacted is synapsin 1, which expression and phosphorylation was prone to lead invasion [28]. DOI: http://dx.doi.org/10.5772/intechopen.…”

Section: Molecular Mechanism Of Lead-induced Neurotoxicitymentioning

confidence: 99%

Epigenetics and Lead Neurotoxicity

Xu¹,

Zhang²

2020

Lead Chemistry

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Lead exposure continues to threaten human health in a worldwide perspective. Among the multiple target organs affected by lead, central nervous system (CNS) pervades in the adverse consequences by chronic lead exposure, leading to a variety of neurotoxic manifestations and neurological disorders. The epigenetic machinery plays a vital role in the control of key neural functions, particularly neuronal development. Faulty epigenetic gene regulation can have marked deleterious effect on the developing brain that can last for an entire lifespan. Mounting evidence suggests that lead exposure can pose detrimental effect on CNS through these epigenetic mechanisms. And this chapter reviews the current understandings of concrete epigenetic forms, exemplified by DNA methylation, histone modification, and ncRNAs, responding to lead exposure and moderating the consequent neurotoxicity. In addition, Alzheimer's disease (AD) is presented as a typical instance to explain how environmental lead exposure results in the occurrence of AD in an "early exposure, late onset" fashion. A future perspective, highlighting additional forms of epigenetic elements as well as interactive actions among different molecules, was also proposed. In summary, epigenetics was substantially implicated in regulating lead neurotoxicity.

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Pb inhibits hippocampal synaptic transmission via cyclin-dependent kinase-5 dependent Synapsin 1 phosphorylation

Cited by 21 publications

References 27 publications

Interplay of miR-137 and EZH2 contributes to the genome-wide redistribution of H3K27me3 underlying the Pb-induced memory impairment

Interplay of miR-137 and EZH2 contributes to the genome-wide redistribution of H3K27me3 underlying the Pb-induced memory impairment

Probiotic Lactobacillus rhamnosus GR-1 supplementation attenuates Pb-induced learning and memory deficits by reshaping the gut microbiota

Epigenetics and Lead Neurotoxicity

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