Environmental exposure to pesticides at levels deemed safe by regulatory agencies has been linked to increased risk for neurodevelopmental disorders. Yet, the mechanisms linking exposure to these disorders remain unclear. Here, we show that maternal exposure to the pesticide deltamethrin (DM) at the no observed adverse effect level (NOAEL) disrupts long-term potentiation (LTP) in the hippocampus of adult male offspring three months after exposure, a phenotype absent in female offspring. Clonazepam, a GABAa receptor agonist, rescued this deficit, indicating impaired hippocampal GABAergic signaling. Recordings from CA1 pyramidal neurons, complemented by MALDI mass spectrometry imaging, showed an imbalance in excitatory/inhibitory tone. Using a combination of parvalbumin (PV)-Cre transgenic mice and hippocampal injection of designer receptors exclusively activated by designer drugs (DREADDs), we show that developmental DM exposure reduces hippocampal PV interneuron intrinsic firing. DREADD activation rescued both PV interneuron firing and LTP deficits. Complementary behavioral experiments revealed a deficit in social memory, a behavior relevant to autism spectrum disorder (ASD) symptomatology, which was restored by DREADD activation. Overall, these results establish a novel mechanistic link between maternal exposure to DM at the NOAEL and known cellular, circuital, and behavioral vulnerabilities, indicating it is a potential driver in the exposome of ASD.

中文翻译：

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常见农药的环境暴露会诱导海马细小白蛋白中间神经元神经发育脆弱性驱动的突触缺陷和社会记忆障碍


监管机构认为安全水平的杀虫剂环境暴露与神经发育障碍的风险增加有关。然而，将暴露与这些疾病联系起来的机制仍不清楚。在这里，我们表明，母体暴露于未观察到的不良反应水平 （NOAEL） 的农药溴氰菊酯 （DM） 会破坏暴露三个月后成年雄性后代海马体的长期增强 （LTP），这种表型在雌性后代中不存在。氯硝西泮是一种 GABAa 受体激动剂，挽救了这种缺陷，表明海马 GABA 能信号传导受损。来自 CA1 锥体神经元的记录，辅以 MALDI 质谱成像，显示兴奋性/抑制性张力不平衡。使用小白蛋白 （PV）-Cre 转基因小鼠和海马注射仅由设计药物 （DREADD） 激活的设计受体的组合，我们表明发育性 DM 暴露减少了海马 PV 中间神经元的内在放电。DREADD 激活挽救了 PV 中间神经元放电和 LTP 缺陷。互补行为实验揭示了社交记忆缺陷，这是一种与自闭症谱系障碍 （ASD） 症状相关的行为，通过 DREADD 激活恢复了这种缺陷。总体而言，这些结果在母体在 NOAEL 暴露于 DM 与已知的细胞、回路和行为脆弱性之间建立了新的机制联系，表明它是 ASD 暴露组的潜在驱动因素。