Neurotoxicology of deltamethrin in the developing brain

摘要 流行病学研究发现，早期接触拟除虫菊酯是一个值得关注的威胁风险因素- 缺陷多动障碍(ADHD)。因为报告的暴露风险在未观察到的范围内--不利的-- 影响水平(NOAEL)指南，环境中暴露于拟除虫菊酯可能是被低估的主要因素 一般人群中ADHD和其他神经发育障碍的原因。早期生命的动物模型 暴露在拟除虫菊酯杀虫剂溴氰菊酯(DM)中，这是一种作用于昆虫电压的强大神经毒素- 门控Na+(Nav)通道，通过干扰多巴胺信号通路重现ADHD样行为 伏隔核(NAC)，与人类疾病有关的大脑区域。然而，其毒性机制 发育中的大脑中的糖尿病还没有确定。我们小组最近的研究提供了证据 糖尿病与哺乳动物Nav1.1通道的交叉反应，该通道是一种表达在快速尖峰小白蛋白中的异构体 (Pv)发育中的抑制性中间神经元。这些细胞对输出施加了强大的抑制控制 NAC，如果中断，会导致多巴胺功能障碍，影响运动活动、注意力和 冲动，多动症的内在表型。支持在早期糖尿病患者中进行的研究 暴露动物模型显示DM在NAc/纹状体内局部积聚和GABA丢失。 显示同一脑区PV中间神经元放电中断，并伴有ADHD样行为。 基于这一前提，我们提出了分子(目标1)、功能(目标2)和行为(目标3)研究 验证一种假设，即DM对发育中的大脑的毒性主要机制是破坏PV 导致NAC局部抑制控制丧失的神经元间功能和常见的行为表型 多动症。这项研究的结果将为基于分子的风险因素理解提供新的见解 为神经发育障碍提供针对暴露的治疗发展的指导。

ABSTRACT Epidemiological studies identify early life exposure to pyrethroids as a threatening risk factor for attention- deficit hyperactivity disorder (ADHD). Because the reported risk of exposure is within no-observed-adverse- effect level (NOAEL) guidelines, environmental exposure to pyrethroids could be an underestimated leading cause of ADHD and other neurodevelopmental disorders in the general population. Animal models of early-life exposure to the pyrethroid pesticide deltamethrin (DM), a potent neurotoxin that acts on the insect voltage- gated Na+ (Nav) channel, recapitulates ADHD-like behavior through disruption of dopamine signaling in the nucleus accumbens (NAc), the brain region implicated in the human disease. Yet, the mechanism of toxicity of DM in the developing brain has not yet been determined. Recent studies from our group provide evidence for cross reactivity of DM with the mammalian Nav1.1 channel, an isoform expressed in fast-spiking parvalbumin (PV) inhibitory interneurons during development. These cells exert a powerful inhibitory control over the output of the NAc, which, if disrupted, leads to dopamine dysfunction with effects on locomotor activity, attention, and impulsivity, endophenotypes that characterize ADHD. In supporting studies conducted in an early-life DM exposure animal model we show regional accumulation of DM and loss in GABA in the NAc/striatum and demonstrate disruption of PV interneuron firing in the same brain region accompanied by ADHD-like behaviors. Building on this premise, we propose molecular (Aim 1), functional (Aim 2) and behavioral (Aim 3) studies to test the hypothesis that the primary mechanism of DM toxicity in the developing brain is to disrupt PV interneuron function leading to loss of local inhibitory control in the NAc and behavioral phenotypes common to ADHD. Outcomes of this study will provide new insights into the molecular-based understanding of risk factors for neurodevelopmental disorders providing guidance for therapeutic development against exposure.