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

Ayumi Yamada; Takae Hirasawa; Kayako Nishimura; Chikako Shimura; Naomi Kogo; Kei Fukuda; Madoka Kato; Masaki Yokomori; Tetsutaro Hayashi; Mana Umeda; Mika Yoshimura; Yoichiro Iwakura; Itoshi Nikaido; Shigeyoshi Itohara; Yoichi Shinkai

doi:10.1016/j.isci.2021.102741

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

iScience. 2021 Jun 17;24(7):102741. doi: 10.1016/j.isci.2021.102741. eCollection 2021 Jul 23.

Authors

Ayumi Yamada¹, Takae Hirasawa², Kayako Nishimura¹, Chikako Shimura¹, Naomi Kogo³, Kei Fukuda¹, Madoka Kato², Masaki Yokomori², Tetsutaro Hayashi⁴, Mana Umeda⁴, Mika Yoshimura⁴, Yoichiro Iwakura⁵, Itoshi Nikaido^{4

6

7}, Shigeyoshi Itohara³, Yoichi Shinkai¹

Affiliations

¹ Cellular Memory Laboratory, Cluster for Pioneering Research, RIKEN, Wako, Saitama, Japan.
² Department of Biosciences, School of Science and Engineering, Teikyo University, 1-1 Toyosatodai, Utsunomiya, Tochigi, Japan.
³ Laboratory for Behavioral Genetics, RIKEN Center for Brain Science, Wako, Saitama, Japan.
⁴ Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Wako, Saitama, Japan.
⁵ Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
⁶ Functional Genome Informatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
⁷ Bioinformatics Course, Master's/Doctoral Program in Life Science Innovation (T-LSI), School of Integrative and Global Majors (SIGMA), University of Tsukuba, Wako, Saitama 351-0198, Japan.

Abstract

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 Ehmt1 ^Δ/+ mice as a KS model. Ubiquitous GLP supply from the juvenile stage ameliorated behavioral abnormalities in Ehmt1 ^Δ/+ 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 Ehmt1 ^Δ/+ mice. Interestingly, some inflammatory genes, including IL-1β (Il1b), were upregulated and activated microglial cells increased in the Ehmt1 ^Δ/+ brain, and such phenotypes were also reversed by neuron-specific postnatal GLP supply. Il1b inactivation canceled the microglial and spine number phenotypes in the Ehmt1 ^Δ/+ mice. Thus, H3K9me2 and some neurological phenotypes are reversible, but behavioral abnormalities are more difficult to improve depending on the timing of GLP supply.

Keywords: Behavioral neuroscience; Developmental neuroscience; Molecular neuroscience; Pathophysiology.