Zhang Qing, Xu Lu, Bai Yang, Chen Peiye, Xing Mengen, Cai Fang, Wu Yili, Song Weihong
Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research Center for Mental Disorders, School of Mental Health and Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, BC, Canada.
Front Mol Neurosci. 2023 Apr 6;16:1155047. doi: 10.3389/fnmol.2023.1155047. eCollection 2023.
Hypoxia is an environmental risk factor for many disorders throughout life. Perinatal hypoxia contributes to autism spectrum disorder (ASD), while hypoxic conditions in the elderly facilitate memory deficits. However, the effects of hypoxia on adolescence remains elusive. CNTNAP2 is a critical molecule in ASD pathogenesis with undefined mechanisms. We investigate hypoxia's impact on adolescence and the underlying mechanism related to CNTNAP2.
Three-chamber social approach test, Y maze, Morris Water Maze and Open Field Test were applied to evaluate behavioral alterations. Immunoblotting, 5'- RACE and dual-luciferase reporter assay were performed to examine CNTNAP2 protein expression, transcription start site (TSS) of human CNTNAP2 gene and CNTNAP2 promoter activity, respectively.
Intermittent hypoxia treatment improved social behaviors and working memory in adolescent mice. CNTNAP2 was increased in the brains of hypoxia-treated mice. The sequencing results identified the TSS at 518 bp upstream of the translation start site ATG. Hypoxia upregulated CNTNAP2 by interacting with functional hypoxia response elements in CNTNAP2 promoter.
Intermittent hypoxia enhanced sociability and working memory associated with CNTNAP2 upregulation. Our study provides novel insights into intermittent hypoxia's impact on development and the interaction between genetic and environmental risk factors in ASD pathogenesis.
缺氧是一生中许多疾病的环境风险因素。围产期缺氧会导致自闭症谱系障碍（ASD），而老年人的缺氧状况会促使记忆缺陷。然而，缺氧对青春期的影响仍不明确。接触蛋白相关蛋白2（CNTNAP2）是ASD发病机制中的关键分子，其机制尚不清楚。我们研究了缺氧对青春期的影响以及与CNTNAP2相关的潜在机制。
采用三室社交接近试验、Y迷宫试验、莫里斯水迷宫试验和旷场试验来评估行为改变。分别进行免疫印迹、5'-RACE和双荧光素酶报告基因检测，以检测CNTNAP2蛋白表达、人CNTNAP2基因的转录起始位点（TSS）和CNTNAP2启动子活性。
间歇性缺氧处理改善了青春期小鼠的社交行为和工作记忆。缺氧处理小鼠的大脑中CNTNAP2增加。测序结果确定TSS位于翻译起始位点ATG上游518 bp处。缺氧通过与CNTNAP2启动子中的功能性缺氧反应元件相互作用上调CNTNAP2。
间歇性缺氧增强了社交能力和工作记忆，与CNTNAP2上调有关。我们的研究为间歇性缺氧对发育的影响以及ASD发病机制中遗传和环境风险因素之间的相互作用提供了新的见解。
