Role of immature choroid plexus in the pathology of model mice and human iPSC-derived organoids with autism spectrum disorder

• Published in: Cell reports (Cambridge) 2025-01, Vol.44 (1), p.115133, Article 115133
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: ASD; autism spectrum disorder; blood-CSF barrier; CAMDI; choroid plexus; ChP; cilia; CP: Neuroscience; critical period; maturation; metformin; organoid; social behavior; tight junction
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.115133

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. [Display omitted] •ChP-specific CAMDI-KO mice exhibit immature ChP development and ASD-like behaviors•ChP-specific CAMDI-KO mice exhibit a delayed social critical period•Early postnatal metformin treatment improves immature ChP and behavior in ASD model mice•Immature ChP development is reproduced in organoids derived from patients with ASD Tanabe et al. demonstrate the presence of an immature ChP in organoids derived from patients with ASD, finding that mice models with an immature ChP exhibit ASD-like symptoms. A treatment strategy is suggested to ensure the maturation of the ChP without a delayed critical period, possibly preventing the development of ASD-like symptoms.