文章基本信息

标题：Influence of Nanomolar Deltamethrin on the Hallmarks of Primary Cultured Cortical Neuronal Network and the Role of Ryanodine Receptors
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作者：Jing Zheng ; Yiyi Yu ; Wei Feng 等
期刊名称：Environmental Health Perspectives
印刷版ISSN：0091-6765
电子版ISSN：1552-9924
出版年度：2019
卷号：127
期号：6
页码：1-16
DOI：10.1289/EHP4583
出版社：OCR Subscription Services Inc
摘要：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 Ca 2 + oscillations (SCOs), and electrical spike activity (ESA) functions critical to neuronal network formation. Methods: Measurements of SCOs using Ca 2 + 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 ( RyR 1 T 4826 I / T 4826 I ) mice between 5 and 14 d in vitro (DIV). [ H 3 ] 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 RyR 1 T 4826 I / T 4826 I were more responsive to DM than WT. RyR 1 T 4826 I / T 4826 I 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 .