Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling

Abstract

AbstractLoss-of-function mutations in genes encoding lysine methyltransferases (KMTs) and demethylases (KDMs) responsible for regulating the trimethylation of histone 3 on lysine 4 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder and intellectual disability. To study the specific role of H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developingKdm5bmutant neocortex. These included elevated expression ofGrin2d. TheGrin2dgene product NMDAR2D was increased in synaptosomes isolated from theKdm5b-deficient neocortex and treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalisations and reduced repetitive digging behaviours. These findings suggest that increased H3K4me3 levels and associatedGrin2dgene upregulation disrupt brain development and function, leading to socio-communication deficits and repetitive behaviours, and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency.