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

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 behaviours 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 was associated with increased levels of NMDAR2D protein in synaptosomes isolated from the early postnatal Kdm5b-deficient neocortex. Treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalizations.