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AUTISM-LIKE PHENOTYPES AND INCREASED NMDAR2D EXPRESSION IN MICE WITH KDM5B HISTONE LYSINE DEMETHYLASE DEFICIENCY
Leticia Perez-Sisquesand 23 co-authors
King's College London
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS07-10AM-241
Presentation
Date TBA
Board: PS07-10AM-241
Event Information
Poster Board
PS07-10AM-241
Poster
View posterAbstract
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. To study the role of KDM5B (Lysine DeMethylase-5B), we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased relative brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex. Increased H3K4me3 levels at the promoter of the Grin2d gene was associated with increased Grin2d gene expression and elevated levels of NMDAR2D protein in synaptosomes isolated from the early postnatal Kdm5b-deficient neocortex. Accordingly, treating Kdm5b-deficient mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalizations. These findings suggest that increased H3K4me3 levels and associated Grin2d gene upregulation disrupt brain development and function, leading to socio-communicative deficits. Our experiments identify the developmentally regulated NMDAR2D subunit as a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency.
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