Analysis of sleep disorder phenotypes in mouse models of Rett Syndrome for drug discovery

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08198
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kurume University
• Principal Investigator: Takahashi Tomoyuki 久留米大学, 高次脳疾患研究所, 教授 (20332687)
• Co-Investigator(Kenkyū-buntansha): 河原 幸江 久留米大学, 医学部, 准教授 (10279135) ; 佐藤 貴弘 久留米大学, 付置研究所, 准教授 (50368883)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: レット症候群

Outline of Final Research Achievements

Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2), located on the X chromosome. Many RTT patients have sleep problems, such as insomnia characterized by difficulties initiating and maintaining sleep, prolonged night awakenings, and circadian sleep disorders. However, little is known about neural mechanisms underlying the sleep-wake problems of RTT. In this study, we found that Mecp2-null mice have sleep problems such as fragmented sleep and abnormal sleep structure. In addition, MeCP2 deficiency affected the expression of several neuromodulator genes in the hypothalamus. Among them, expression of Hcrt/orexin recptors gene was reduced in Mecp2-null brain and hypocretin/orexin signals were attenuated in Mecp2-null mice. These findings suggest that alteration of orexin signal transduction in Mecp2-null mice may be one of the causes of sleep problems in Mecp2-null mice.

Free Research Field

細胞生物学、分子生物学、発生生物学

Academic Significance and Societal Importance of the Research Achievements

レット症候群（RTT）は、主に女児で発症する重度の神経発達症である。一遺伝子の変異によって引き起こされるRTTは、神経発達症の病態メカニズムを解析する上で良いモデルとなるとして注目されている。この事から、本研究課題における RTTの睡眠障害をはじめとする様々な病態メカニズムの研究は、神経発達症をはじめとする様々な神経精神疾患への応用が期待される。