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

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