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

Abstract

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 <i>Kdm5b</i> mutant neocortex. Increased H3K4me3 levels at the promoter and associated expression of the <i>Grin2d</i> gene were associated with increased levels of <i>N</i>-methyl-d-aspartate receptor subunit 2D (NMDAR2D) protein in synaptosomes isolated from the early postnatal <i>Kdm5b</i>-deficient neocortex. Treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalizations. These findings suggest that increased H3K4me3 levels and associated <i>Grin2d</i> 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.