Derepression of inflammation-related genes link to microglia activation and neural maturation defect in a mouse model of Kleefstra syndrome

• Published in: iScience 2021-07, Vol.24 (7), p.102741-102741, Article 102741
• Main Authors: Yamada, Ayumi, Hirasawa, Takae, Nishimura, Kayako, Shimura, Chikako, Kogo, Naomi, Fukuda, Kei, Kato, Madoka, Yokomori, Masaki, Hayashi, Tetsutaro, Umeda, Mana, Yoshimura, Mika, Iwakura, Yoichiro, Nikaido, Itoshi, Itohara, Shigeyoshi, Shinkai, Yoichi
• Format: Article
• Language: English
• Subjects: Behavioral neuroscience; Developmental neuroscience; Molecular neuroscience; Pathophysiology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.102741

Haploinsufficiency of EHMT1, which encodes histone H3 lysine 9 (H3K9) methyltransferase G9a-like protein (GLP), causes Kleefstra syndrome (KS), a complex disorder of developmental delay and intellectual disability. Here, we examined whether postnatal supply of GLP can reverse the neurological phenotypes seen in Ehmt1Δ/+ mice as a KS model. Ubiquitous GLP supply from the juvenile stage ameliorated behavioral abnormalities in Ehmt1Δ/+ mice. Postnatal neuron-specific GLP supply was not sufficient for the improvement of abnormal behaviors but still reversed the reduction of H3K9me2 and spine number in Ehmt1Δ/+ mice. Interestingly, some inflammatory genes, including IL-1β (Il1b), were upregulated and activated microglial cells increased in the Ehmt1Δ/+ brain, and such phenotypes were also reversed by neuron-specific postnatal GLP supply. Il1b inactivation canceled the microglial and spine number phenotypes in the Ehmt1Δ/+ mice. Thus, H3K9me2 and some neurological phenotypes are reversible, but behavioral abnormalities are more difficult to improve depending on the timing of GLP supply. [Display omitted] •Activated microglias increase in a Ehmt1Δ/+ mouse model of Kleefstra syndrome•Diminished H3K9me2 in Ehmt1Δ/+ mouse neurons is reversed by post-natal GLP supply•GLP supply from the juvenile stage can improve abnormal behaviors of Ehmt1Δ/+ mice•Il1b KO cancelles the microglial and spine number phenotypes in the Ehmt1Δ/+ mice Pathophysiology; Behavioral neuroscience; Molecular neuroscience; Developmental neuroscience