Doszyn Olga, Kedra Magdalena, Zmorzynska Justyna
Laboratory of Molecular and Cellular Neurobiology, International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland.
Laboratory of Developmental Neurobiology, International Institute of Molecular Mechanisms and Machines, 02-247 Warsaw, Poland.
iScience. 2024 May 28;27(6):110149. doi: 10.1016/j.isci.2024.110149. eCollection 2024 Jun 21.
Mechanistic target of rapamycin complex 1 (mTORC1) is an integration hub for extracellular and intracellular signals necessary for brain development. Hyperactive mTORC1 is found in autism spectrum disorder (ASD) characterized by atypical reactivity to sensory stimuli, among other symptoms. In Tuberous sclerosis complex (TSC) inactivating mutations in the or genes result in hyperactivation of the mTORC1 pathway and ASD. Here, we show that lack of light preference of the TSC zebrafish model, is caused by aberrant processing of light stimuli in the left dorsal habenula and fish have impaired function of the left dorsal habenula, in which neurons exhibited higher activity and lacked habituation to the light stimuli. These characteristics were rescued by rapamycin. We thus discovered that hyperactive mTorC1 caused aberrant habenula function resulting in lack of light preference. Our results suggest that mTORC1 hyperactivity contributes to atypical reactivity to sensory stimuli in ASD.
雷帕霉素复合物1的机制性靶点（mTORC1）是大脑发育所需的细胞外和细胞内信号的整合枢纽。在自闭症谱系障碍（ASD）中发现mTORC1过度活跃，其特征包括对感觉刺激的非典型反应等症状。在结节性硬化症（TSC）中，TSC1或TSC2基因的失活突变导致mTORC1通路过度激活和ASD。在这里，我们表明TSC斑马鱼模型缺乏光偏好是由左背侧缰核中光刺激的异常处理引起的，并且TSC斑马鱼左背侧缰核功能受损，其中的神经元表现出更高的活性并且对光刺激缺乏习惯化。这些特征可通过雷帕霉素挽救。因此，我们发现mTorC1过度活跃导致缰核功能异常，从而导致缺乏光偏好。我们的结果表明，mTORC1过度活跃导致ASD中对感觉刺激的非典型反应。
