Tanabe Motoi, Saito Yuga, Takasaki Ayaka, Nakano Keita, Yamamoto Shunta, Suzuki Chikako, Kawamura Nao, Hattori Aki, Oikawa Mami, Nagashima Shun, Yanagi Shigeru, Yamaguchi Tomoyuki, Fukuda Toshifumi
Laboratory of Regenerative Medicine, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
Department of Life Science, Faculty of Science, Gakushuin University, Toshima-ku, Tokyo, Japan.
Cell Rep. 2025 Jan 28;44(1):115133. doi: 10.1016/j.celrep.2024.115133. Epub 2024 Dec 27.
During gestation, the choroid plexus (ChP) produces protein-rich cerebrospinal fluid and matures prior to brain development. It is assumed that ChP dysfunction has a profound effect on developmental neuropsychiatric disorders, such as autism spectrum disorder (ASD). However, the mechanisms linking immature ChP to the onset of ASD remain unclear. Here, we find that ChP-specific CAMDI-knockout mice develop an immature ChP alongside decreased multiciliogenesis and expression of differentiation marker genes following disruption of the cerebrospinal fluid barrier. These mice exhibit ASD-like behaviors, including anxiety and impaired socialization. Additionally, the administration of metformin, an FDA-approved drug, before the social critical period achieves ChP maturation and restores social behaviors. Furthermore, both the ASD model mice and organoids derived from patients with ASD developed an immature ChP. These results propose the involvement of an immature ChP in the pathogenesis of ASD and suggest the targeting of functional maturation of the ChP as a therapeutic strategy for ASD.
在妊娠期，脉络丛（ChP）产生富含蛋白质的脑脊液，并在脑发育之前成熟。据推测，脉络丛功能障碍对发育性神经精神疾病，如自闭症谱系障碍（ASD）有深远影响。然而，将未成熟脉络丛与自闭症谱系障碍发病联系起来的机制仍不清楚。在这里，我们发现脉络丛特异性CAMDI基因敲除小鼠在脑脊液屏障破坏后，脉络丛发育不成熟，同时多纤毛形成减少和分化标记基因表达降低。这些小鼠表现出自闭症谱系障碍样行为，包括焦虑和社交障碍。此外，在社交关键期之前给予美国食品药品监督管理局（FDA）批准的药物二甲双胍，可使脉络丛成熟并恢复社交行为。此外，自闭症谱系障碍模型小鼠和来自自闭症谱系障碍患者的类器官都出现了脉络丛发育不成熟的情况。这些结果表明未成熟脉络丛参与了自闭症谱系障碍的发病机制，并提示将脉络丛的功能成熟作为自闭症谱系障碍的治疗策略。
