Acute neurotoxicant exposure induces hyperexcitability in mouse lumbar spinal motor neurons.
Acute neurotoxicant exposure induces hyperexcitability in mouse lumbar spinal motor neurons.
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急性神经毒物暴露会导致小鼠腰椎运动神经元过度兴奋。
DOI：
10.1152/jn.00775.2019
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发表时间：
2020
影响因子：
2.5
通讯作者：
Atchison,WilliamD
中科院分区：
文献类型：
--
作者：
Sceniak,MichaelP;Spitsbergen,JakeB;Sabo,ShastaL;Yuan,Yukun;Atchison,WilliamD
脊髓运动神经元（MNs）易受谷氨酸能兴奋性毒性的影响，这种作用与肌萎缩侧索硬化症（ALS）的腰椎MN变性有关。MN对环境毒物暴露的易感性是散发性ALS的一个潜在因素，但尚未系统研究。本研究的目的是测试一种众所周知的环境神经毒物在小鼠腰椎MNs中诱导高兴奋性的能力。甲基汞（MeHg）通过细胞内Ca2+浓度（[Ca2+]i）升高的机制引起神经毒性，这是兴奋性毒性的标志。我们使用体外腰椎MNs的全细胞膜片钳记录，测试急性暴露于MeHg是否通过改变突触传递诱导MNs的高兴奋性。急性MeHg暴露（20 μM）导致自发性兴奋性突触后电流（EPSCs）和微型EPSCs的频率增加。MeHg也增加了抑制性突触后电流（IPSCs）的频率。尽管EPSCs和IPSCs均增加，但MeHg增加了自发和诱发的动作电位放电率，表明向高兴奋性转变。同样与高兴奋性一致的是，氟4-AM微荧光法显示MeHg暴露诱导[Ca2+]i增加。脊髓高兴奋性部分由Ca2+渗透性AMPA受体介导，因为1-萘基精胺阻断了EPSCs中mehg依赖性的增加。因此，脊髓MNs似乎对MeHg暴露高度敏感，导致自发网络兴奋性显著增加和正常功能的破坏。体内MeHg暴露后，脊髓中观察到的长时间的高兴奋性可导致最终的神经退行性和运动功能丧失，并可能导致MeHg诱导的ALS症状加速。脊髓运动神经元（MN）易受谷氨酸能兴奋性毒性的影响，这种作用与肌萎缩侧索硬化症（ALS）患者腰椎MN变性有关。这项研究调查了MN对环境毒物暴露的易感性，这是散发性ALS的一个潜在因素。脊髓MNs似乎对甲基汞暴露高度敏感，导致自发网络兴奋性显著增加和正常功能的破坏。在ALS脊髓症状中观察到，长时间的高兴奋性可导致神经退行性和运动功能丧失。
Spinal motor neurons (MNs) are susceptible to glutamatergic excitotoxicity, an effect associated with lumbar MN degeneration in amyotrophic lateral sclerosis (ALS). MN susceptibility to environmental toxicant exposure, one prospective contributor to sporadic ALS, has not been systematically studied. The goal of this study was to test the ability of a well-known environmental neurotoxicant to induce hyperexcitability in mouse lumbar MNs. Methylmercury (MeHg) causes neurotoxicity through mechanisms involving elevated intracellular Ca2+concentration ([Ca2+]i), a hallmark of excitotoxicity. We tested whether acute exposure to MeHg induces hyperexcitability in MNs by altering synaptic transmission, using whole cell patch-clamp recordings of lumbar spinal MNs in vitro. Acute MeHg exposure (20 μM) led to an increase in the frequency of both spontaneous excitatory postsynaptic currents (EPSCs) and miniature EPSCs. The frequency of inhibitory postsynaptic currents (IPSCs) was also increased by MeHg. Action potential firing rates, both spontaneous and evoked, were increased by MeHg, despite increases in both EPSCs and IPSCs, indicating a shift toward hyperexcitability. Also consistent with hyperexcitability, fluo 4-AM microfluorimetry indicated that MeHg exposure induced an increase in [Ca2+]i. Spinal cord hyperexcitability is partially mediated by Ca2+-permeable AMPA receptors, as MeHg-dependent increases in EPSCs were blocked by 1-napthyl spermine. Therefore, spinal MNs appear highly susceptible to MeHg exposure, leading to significant increases in spontaneous network excitability and disruption of normal function. Prolonged hyperexcitability could lead to eventual neurodegeneration and loss of motor function as observed in spinal cord after MeHg exposure in vivo and may contribute to MeHg-induced acceleration of ALS symptoms.NEW & NOTEWORTHYSpinal motor neurons (MN) are susceptible to glutamatergic excitotoxicity, an effect associated with lumbar MN degeneration in amyotrophic lateral sclerosis (ALS). This study investigated MN susceptibility to environmental toxicant exposure, one prospective contributor to sporadic ALS. Spinal MNs appear highly susceptible to methylmercury exposure, leading to significant increases in spontaneous network excitability and disruption of normal function. Prolonged hyperexcitability could lead to neurodegeneration and loss of motor function as observed in ALS spinal cord symptoms.
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影响因子：
10.4
作者：
Clarkson TW
通讯作者：
Clarkson TW
影响因子：
3.8
作者：
Edwards, JR;Marty, MS;Atchison, WD
通讯作者：
Atchison, WD
甲基汞在多个部位发挥作用，阻断海马突触传递。
DOI：
--
发表时间：
1995
期刊：
The Journal of pharmacology and experimental therapeutics.
影响因子：
--
作者：
Yuan,Y;Atchison,WD
通讯作者：
Atchison,WD
omega-agatoxin-IVA 和 omega-conotoxin-MVIIC 对小鼠运动神经末梢神经周 Ca 和 Ca( ) 激活的 K 电流的影响。
DOI：
--
发表时间：
1996
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Xu,YF;Atchison,WD
通讯作者：
Atchison,WD
Lambert-Eaton肌无力综合征的被动转移诱导小鼠运动神经末梢ICa的二氢吡啶敏感性。
影响因子：
2.5
作者：
Y. F. Xu;S. Hewett;W. Atchison
通讯作者：
W. Atchison