Pb exposure induces an imbalance of excitatory and inhibitory synaptic transmission in cultured rat hippocampal neurons

Zou, Rong-Xin; Gu, Xiaozhen; Ding, Jin-Jun; Wang, Tiandong; Bi, Nanxi; Niu, Kang; Ge, Ming; Chen, Xiangtao; Wang, Huili

doi:10.1016/j.tiv.2019.104742

Cited by 16 publications

(12 citation statements)

References 55 publications

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“…The present study's findings corroborate with the current evidence that suggests that the KCC 2 expression when altered, places the brain at increased risk for developing neuropathies (Kahle et al, 2005(Kahle et al, , 2008. Supporting the present study's find-ings, Zou et al (2020) have shown that in rat hippocampal cultured neurons Pb 2ϩ -exposure alters both the excitatory and inhibitory synaptic transmission in a dose-dependent manner, but had the most perturbing effects at 1 mol/L. Further, Zou et al (2020) reported that 1 mol/L Pb 2ϩ -exposure increased glutamic acid decarboxylase expression, increased GABA-AR surface expression, and shifted the E/I synaptic balance by promoting GABA synthesis as a compensatory mechanism in response to Pb 2ϩ -induced brain excitability.…”

Section: Discussionsupporting

confidence: 90%

“…Supporting the present study’s findings, Zou et al (2020) have shown that in rat hippocampal cultured neurons Pb 2+ -exposure alters both the excitatory and inhibitory synaptic transmission in a dose-dependent manner, but had the most perturbing effects at 1 μmol/L. Further, Zou et al (2020) reported that 1 μmol/L Pb 2+ -exposure increased glutamic acid decarboxylase expression, increased GABA- AR surface expression, and shifted the E/I synaptic balance by promoting GABA synthesis as a compensatory mechanism in response to Pb 2+ -induced brain excitability. Consistent with these reports, such neuropathies in the E/I balancing may make the brain susceptible to epilepsy or epileptogenic events due to increased brain excitability and altered GDP activity (Ben-Ari, 2002; Ben-Ari et al, 2012) and such abnormalities in the establishment of the GABAergic shift may be in part responsible for causing autism spectrum disorders (ASDs; Ben-Ari, 2018).…”

Section: Discussionsupporting

confidence: 90%

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Developmental Pb2+-exposure alters KCC₂ and VSCC-β3 subunit expression patterns in the postnatal rat brain and cerebellar granule cell cultures: Implications for disrupted GABA-shifts resulting from neurotoxicant exposures.

Neuwirth¹,

Idrissi²

2021

Psychology & Neuroscience

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The neurotoxicant lead (Pb2+) has been studied extensively regarding neurodevelopmental impacts altering the glutamatergic system that persists across the life span. Recently, research has been redirected toward revisiting Pb2+-impacts on the neurodevelopment of the GABAergic system because it precedes the functional expression and activation of the glutamatergic system. Because the potassium chloride cotransporter (KCC2) drives the developmental regulatory shift from GABA-excitation-to-inhibition, and that the GABAA receptors activation can alter gene expression via excitation-dependent coupling of voltage sensitive calcium channels (VSCC), it is important to investigate how Pb2+-exposure might also alter the development, function, and activation of the GABAergic system. Here the relationship between control and 1,000 ppm perinatal Pb2+-exposed rats (i.e., from gestation to postnatal day [PND-22]) on the KCC2 spatiotemporal expression in the ventro-medial prefrontal cortex (vmPFC) and hippocampus (i.e., DG and CA-3) at PND 2, 7, 14, and 22 was examined. Additionally, the KCC2, the VSCC-β3 subunit of the L-type calcium channel and the GABA-AR-β3 subunit expression were examined in primary neuronal cerebellar granule cell cultures (CGC) 3-DIV to assess the impacts of Pb2+-exposure on the VSCC-β3 excitation-dependent coupling in altering the GABA-shift. The results showed that developmental Pb2+-exposure elevated the KCC2 expression in vmPFC at PND 2 and reduced at PND 14 and 22; whereas in the DG, the KCC2 expression was elevated at PND 2 and 7, and reduced at PND 14. In the CA-3, the KCC2 expression was elevated at PND 2 and 7. In the PNC, Pb2+ did not affect cell viability or confluence, but it reduced the expression of KCC2 irrespective of Pb2+-dosage and dose-dependently for VSCC-β3. Notably, in the CGCs the GABA-AR-β3 expression showed a curvilinear relationship with the most impacts at low- (0.05–0.1 μmol/L) and high-Pb2+ doses (1.5 μmol/L) in-vitro. The data suggest that lower levels of Pb2+-exposure, at the cellular level, reduced VSCC-β3 and KCC2 expression, thereby delaying the GABA-shift. As a result, the altered GABA-AR-β3 expression, dependent upon its ability to compensate during development, can cause differential patterns of mature KCC2 expression across brain regions at PND 22. Thus, developmental Pb2+-exposure can alter the development of the GABAergic system prior to the functional expression and activation of the glutamatergic system.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Developmental Pb2+-exposure alters KCC₂ and VSCC-β3 subunit expression patterns in the postnatal rat brain and cerebellar granule cell cultures: Implications for disrupted GABA-shifts resulting from neurotoxicant exposures.

Neuwirth¹,

Idrissi²

2021

Psychology & Neuroscience

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“…However, the production of cultures at a reasonable price, time effort and robustness has proven challenging. Under such conditions, the presence of both, excitatory and inhibitory neurons is important to obtain stable networks (Tukker et al 2018 ; Zou et al 2020 ). We have shown for MCC that they may be used for such MEA analysis.…”

Section: Discussionmentioning

confidence: 99%

A human stem cell-derived test system for agents modifying neuronal N-methyl-d-aspartate-type glutamate receptor Ca2+-signalling

et al. 2021

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Methods to assess neuronal receptor functions are needed in toxicology and for drug development. Human-based test systems that allow studies on glutamate signalling are still scarce. To address this issue, we developed and characterized pluripotent stem cell (PSC)-based neural cultures capable of forming a functional network. Starting from a stably proliferating neuroepithelial stem cell (NESC) population, we generate “mixed cortical cultures” (MCC) within 24 days. Characterization by immunocytochemistry, gene expression profiling and functional tests (multi-electrode arrays) showed that MCC contain various functional neurotransmitter receptors, and in particular, the N-methyl-d-aspartate subtype of ionotropic glutamate receptors (NMDA-R). As this important receptor is found neither on conventional neural cell lines nor on most stem cell-derived neurons, we focused here on the characterization of rapid glutamate-triggered Ca2+ signalling. Changes of the intracellular free calcium ion concentration ([Ca2+]i) were measured by fluorescent imaging as the main endpoint, and a method to evaluate and quantify signals in hundreds of cells at the same time was developed. We observed responses to glutamate in the low µM range. MCC responded to kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and a subpopulation of 50% had functional NMDA-R. The receptor was modulated by Mg2+, Zn2+ and Pb2+ in the expected ways, and various toxicologically relevant agonists (quinolinic acid, ibotenic acid, domoic acid) triggered [Ca2+]i responses in MCC. Antagonists, such as phencyclidine, ketamine and dextromethorphan, were also readily identified. Thus, the MCC developed here may fill an important gap in the panel of test systems available to characterize the effects of chemicals on neurotransmitter receptors.

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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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Pb exposure induces an imbalance of excitatory and inhibitory synaptic transmission in cultured rat hippocampal neurons

Cited by 16 publications

References 55 publications

Developmental Pb2+-exposure alters KCC₂ and VSCC-β3 subunit expression patterns in the postnatal rat brain and cerebellar granule cell cultures: Implications for disrupted GABA-shifts resulting from neurotoxicant exposures.

Developmental Pb2+-exposure alters KCC₂ and VSCC-β3 subunit expression patterns in the postnatal rat brain and cerebellar granule cell cultures: Implications for disrupted GABA-shifts resulting from neurotoxicant exposures.

A human stem cell-derived test system for agents modifying neuronal N-methyl-d-aspartate-type glutamate receptor Ca2+-signalling

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

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