Influence of Nanomolar Deltamethrin on the Hallmarks of Primary Cultured Cortical Neuronal Network and the Role of Ryanodine Receptors
Influence of Nanomolar Deltamethrin on the Hallmarks of Primary Cultured Cortical Neuronal Network and the Role of Ryanodine Receptors
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纳摩尔溴氰菊酯对原代培养皮质神经元网络特征的影响和兰尼定受体的作用
DOI：
10.1289/ehp4583
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发表时间：
2019-06
影响因子：
10.4
通讯作者：
Cao Zhengyu
中科院分区：
文献类型：
--
作者：
Zheng Jing;Yu Yiyi;Feng Wei;Li Jing;Liu Ju;Zhang Chunlei;Dong Yao;Pessah Isaac N.;Cao Zhengyu
背景：拟除虫菊酯类杀虫剂溴氰菊酯（DM）被广泛用于昆虫防治。虽然DM通过延迟轴突电压依赖性Na+通道的失活来过度刺激神经元网络，但在哺乳动物关键的围产儿时期，这种机制不太可能介导低暴露水平下的神经毒性。目的：我们旨在确定急性和亚慢性DM改变轴突和树突生长的机制，同步Ca2+振荡（SCOs）模式，以及对神经元网络形成至关重要的电尖峰活动（ESA）功能。方法：对野生型（WT）和/或ryanodine受体1 （RyR1T4826I/T4826I）小鼠的原代小鼠皮质神经元进行体外培养5 - 14 d （DIV）的SCOs测量，使用Ca2+成像测量，使用微电极阵列（MEA）技术测量ESA，使用Sholl分析测量树突复杂性。[H3]利用ryanodine结合分析和单通道电压钳来测量RyRs作为DM的直接靶标的参与。结果：神经元网络早在5 DIV时就对DM （30-70 nM）产生反应，降低SCO振幅，降低ESA和burst频率60-70%。DM （10-300 nM）以非单调方式促进轴突生长。DM≥100 nM增强树枝晶复杂性。DM稳定了表达所有三种亚型的RyR1、RyR2和皮质制剂的通道开放状态。DM （30 nM）改变了RyR1通道的门控动力学，增加了平均打开时间，减少了平均关闭时间，从而提高了总体打开概率。表达RyR1T4826I/T4826I的皮层网络的SCO模式对DM的反应比WT更敏感。RyR1T4826I/T4826I神经元的轴突长度比WT神经元长，并且对纳摩尔DM保持较少的促长反应。结论：我们的研究结果表明RyRs是DM的敏感分子靶点，其功能后果可能与体外介导异常神经网络连接有关。https://doi.org/10.1289/EHP4583
Background: The pyrethroid deltamethrin (DM) is broadly used for insect control. Although DM hyperexcites neuronal networks by delaying inactivation of axonal voltage-dependent Na+ channels, this mechanism is unlikely to mediate neurotoxicity at lower exposure levels during critical perinatal periods in mammals. Objectives: We aimed to identify mechanisms by which acute and subchronic DM altered axonal and dendritic growth, patterns of synchronous Ca2+ oscillations (SCOs), and electrical spike activity (ESA) functions critical to neuronal network formation. Methods: Measurements of SCOs using Ca2+ imaging, ESA using microelectrode array (MEA) technology, and dendritic complexity using Sholl analysis were performed in primary murine cortical neurons from wild-type (WT) and/or ryanodine receptor 1 (RyR1T4826I/T4826I) mice between 5 and 14 d in vitro (DIV). [H3]ryanodine binding analysis and a single-channel voltage clamp were utilized to measure engagement of RyRs as a direct target of DM. Results: Neuronal networks responded to DM (30–70 nM) as early as 5 DIV, reducing SCO amplitude and depressing ESA and burst frequencies by 60–70%. DM (10–300 nM) enhanced axonal growth in a nonmonotonic manner. DM≥100 nM enhanced dendritic complexity. DM stabilized channel open states of RyR1, RyR2, and cortical preparations expressing all three isoforms. DM (30 nM) altered gating kinetics of RyR1 channels, increasing mean open time, decreasing mean closed time, and thereby enhancing overall open probability. SCO patterns from cortical networks expressing RyR1T4826I/T4826I were more responsive to DM than WT. RyR1T4826I/T4826I neurons showed inherently longer axonal lengths than WT neurons and maintained less length-promoting responses to nanomolar DM. Conclusions: Our findings suggested that RyRs were sensitive molecular targets of DM with functional consequences likely relevant for mediating abnormal neuronal network connectivity in vitro. https://doi.org/10.1289/EHP4583
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影响因子：
3.7
作者：
Laugeray A;Herzine A;Perche O;Richard O;Montecot-Dubourg C;Menuet A;Mazaud-Guittot S;Lesné L;Jegou B;Mortaud S
通讯作者：
Mortaud S
影响因子：
11.4
作者：
Feng W;Zheng J;Robin G;Dong Y;Ichikawa M;Inoue Y;Mori T;Nakano T;Pessah IN
通讯作者：
Pessah IN
影响因子：
2.9
作者：
Daisuke Ihara;M. Fukuchi;D. Honma;I. Takasaki;A. Tabuchi;M. Tsuda
通讯作者：
Daisuke Ihara;M. Fukuchi;D. Honma;I. Takasaki;A. Tabuchi;M. Tsuda
影响因子：
3.4
作者：
T. Narahashi
通讯作者：
T. Narahashi
影响因子：
4.1
作者：
Clark, J. Marshall;Symington, Steven B.
通讯作者：
Symington, Steven B.