Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency

Loss-of-function mutations in genes encoding lysine demethylases specific for trimethylated lysine 4 of histone 3 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder (ASD) and intellectual disability (ID). To study the role of KDM5B (lysine demethylase 5B)–mediated H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviors and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex. Increased H3K4me3 levels at the promoter and associated expression of the Grin2d gene were associated with increased levels of N -methyl- d -aspartate receptor subunit 2D (NMDAR2D) protein in synaptosomes isolated from the early postnatal Kdm5b -deficient neocortex. Treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalizations. These findings suggest that increased H3K4me3 levels and associated Grin2d gene up-regulation disrupt brain development and function, leading to socio-communication deficits and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency.