Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa 3200003, Israel.
Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 3498838, Israel.
Int J Mol Sci. 2023 Feb 15;24(4):3924. doi: 10.3390/ijms24043924.
Purposeful induction of fever for healing, including the treatment of epilepsy, was used over 2000 years ago by Hippocrates. More recently, fever has been demonstrated to rescue behavioral abnormalities in children with autism. However, the mechanism of fever benefit has remained elusive due in large part to the lack of appropriate human disease models recapitulating the fever effect. Pathological mutations in the IQSEC2 gene are frequently seen in children presenting with intellectual disability, autism and epilepsy. We recently described a murine A350V IQSEC2 disease model, which recapitulates important aspects of the human A350V IQSEC2 disease phenotype and the favorable response to a prolonged and sustained rise in body core temperature in a child with the mutation. Our goal has been to use this system to understand the mechanism of fever benefit and then develop drugs that can mimic this effect and reduce IQSEC2-associated morbidity. In this study, we first demonstrate a reduction in seizures in the mouse model following brief periods of heat therapy, similar to what was observed in a child with the mutation. We then show that brief heat therapy is associated with the correction of synaptic dysfunction in neuronal cultures of A350V mice, likely mediated by Arf6-GTP.
目的明确地诱导发热以达到治疗效果，包括治疗癫痫，这一方法在 2000 多年前就由希波克拉底提出。最近，人们发现发热可以改善自闭症儿童的行为异常。然而，由于缺乏能够重现发热效应的合适人类疾病模型，发热有益的机制仍然难以捉摸。IQSEC2 基因的病理性突变在伴有智力障碍、自闭症和癫痫的儿童中经常出现。我们最近描述了一个携带 A350V IQSEC2 基因突变的小鼠疾病模型，该模型重现了人类 A350V IQSEC2 疾病表型的重要方面，以及对突变患儿长时间持续升高核心体温的有利反应。我们的目标一直是利用该系统来了解发热有益的机制，然后开发能够模拟这种效果并降低与 IQSEC2 相关发病率的药物。在这项研究中，我们首先证明了在小鼠模型中，短暂的热疗可以减少癫痫发作，这与携带该突变的患儿的观察结果相似。然后我们表明，短暂的热疗与 A350V 小鼠神经元培养物中突触功能障碍的纠正有关，这可能是由 Arf6-GTP 介导的。
