Atoh1 mediated disturbance of neuronal maturation by perinatal hypoxia induces cognitive deficits

• Published in: Communications biology Vol. 7; no. 1; pp. 1121 - 14
• Main Authors: Cai, Xin-Yu, Ma, Si-Yu, Tang, Ming-Hui, Hu, Liang, Wu, Ke-de, Zhang, Zhen, Zhang, Ya-Qi, Lin, Ye, Patel, Nishant, Yang, Zhao-Cong, Mo, Xu-Ming
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.09.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Brain injury; Cell adhesion & migration; Cell migration; Cell Movement; Cognition & reasoning; Cognitive ability; Cognitive Dysfunction - etiology; Cognitive Dysfunction - metabolism; Dendritic branching; Female; Heart diseases; Hypoxia; Hypoxia - metabolism; Male; Math1 protein; Maturation; Mice; Mice, Inbred C57BL; Neonates; Neurodevelopmental disorders; Neurogenesis; Neurological complications; Neurological diseases; Neurons - metabolism; Synaptogenesis; Tubulin
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06846-7

Neurodevelopmental disorders are currently one of the major complications faced by patients with congenital heart disease (CHD). Chronic hypoxia in the prenatal and postnatal preoperative brain may be associated with neurological damage and impaired long-term cognitive function, but the exact mechanisms are unknown. In this study, we find that delayed neuronal migration and impaired synaptic development are attributed to altered Atoh1 under chronic hypoxia. This is due to the fact that excessive Atoh1 facilitates expression of Kif21b, which causes excess in free-state α-tubulin, leading to disrupted microtubule dynamic stability. Furthermore, the delay in neonatal brain maturation induces cognitive disabilities in adult mice. Then, by down-regulating Atoh1 we alleviate the impairment of cell migration and synaptic development, improving the cognitive behavior of mice to some extent. Taken together, our work unveil that Atoh1 may be one of the targets to ameliorate hypoxia-induced neurodevelopmental disabilities and cognitive impairment in CHD.