Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
eNeuro. 2023 May 16;10(5). doi: 10.1523/ENEURO.0461-22.2023. Print 2023 May.
Autism spectrum disorder (ASD) is a common neurodevelopmental condition for which there are no pharmacological therapies that effectively target its core symptomatology. Animal models of syndromic forms of ASD, such as neurofibromatosis type 1, may be of use in screening for such treatments. larvae lacking expression exhibit tactile hypersensitivity following mechanical stimulation, proposed to mirror the sensory sensitivity issues comprising part of the ASD diagnostic criteria. Such behavior is associated with synaptic dysfunction at the neuromuscular junction (NMJ). Both phenotypes may thus provide tractable outputs with which to screen for potential ASD therapies. In this study, we demonstrate that, while loss of expression within the embryo is sufficient to impair NMJ synaptic transmission in the larva, constitutive knock-down is required to induce tactile hypersensitivity, suggesting that a compound must be administered throughout development to rescue this behavior. With such a feeding regime, we identify two compounds from a targeted, low-throughput screen that significantly and consistently reduce, but do not fully rescue, tactile hypersensitivity in larvae. These are the HMG CoA-reductase inhibitor simvastatin, and the BK channel activator BMS-204352. At the NMJ, both compounds induce a significant reduction in the enhanced spontaneous transmission frequency of larvae, though again not to the level of vehicle-treated controls. However, both compounds fully rescue the increased quantal size of mutants, with simvastatin also fully rescuing their reduced quantal content. Thus, the further study of both compounds as potential ASD interventions is warranted.
自闭症谱系障碍（ASD）是一种常见的神经发育障碍，目前尚无有效的药物治疗方法能够有效针对其核心症状。神经纤维瘤病 1 型等综合征形式的 ASD 动物模型可能有助于筛选此类治疗方法。缺失表达的幼虫在受到机械刺激后表现出触觉过敏，这被认为反映了构成 ASD 诊断标准一部分的感觉敏感性问题。这种行为与神经肌肉接头（NMJ）的突触功能障碍有关。因此，这两种表型都可能提供可处理的输出，用于筛选潜在的 ASD 治疗方法。在这项研究中，我们证明了尽管胚胎中缺失表达足以损害幼虫 NMJ 的突触传递，但必须进行组成型敲低才能诱导触觉过敏，这表明必须在整个发育过程中给予一种化合物才能挽救这种行为。通过这种喂养方案，我们从靶向、低通量筛选中确定了两种化合物，它们可显著且一致地降低但不能完全挽救缺失表达幼虫的触觉过敏。这两种化合物是 HMG CoA 还原酶抑制剂辛伐他汀和 BK 通道激活剂 BMS-204352。在 NMJ 处，这两种化合物均诱导缺失表达幼虫的增强自发性传递频率显著降低，但仍未达到对照的水平。然而，这两种化合物都完全挽救了缺失表达突变体增加的量子大小，辛伐他汀还完全挽救了它们减少的量子含量。因此，有必要进一步研究这两种化合物作为潜在的 ASD 干预措施。
