摘要：SummaryHaploinsufficiency ofEHMT1, 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 inEhmt1Δ/+mice as a KS model. Ubiquitous GLP supply from the juvenile stage ameliorated behavioral abnormalities inEhmt1Δ/+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 inEhmt1Δ/+mice. Interestingly, some inflammatory genes, includingIL-1β (Il1b), were upregulated and activated microglial cells increased in theEhmt1Δ/+brain, and such phenotypes were also reversed by neuron-specific postnatal GLP supply.Il1binactivation canceled the microglial and spine number phenotypes in theEhmt1Δ/+mice. Thus, H3K9me2 and some neurological phenotypes are reversible, but behavioral abnormalities are more difficult to improve depending on the timing of GLP supply.Graphical abstractDisplay OmittedHighlights•Activated microglias increase in aEhmt1Δ/+mouse model of Kleefstra syndrome•Diminished H3K9me2 inEhmt1Δ/+mouse neurons is reversed by post-natal GLP supply•GLP supply from the juvenile stage can improve abnormal behaviors ofEhmt1Δ/+mice•Il1bKO cancelles the microglial and spine number phenotypes in theEhmt1Δ/+micePathophysiology; Behavioral neuroscience; Molecular neuroscience; Developmental neuroscience
