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

Scientists studied mice missing a specific brain protein called KDM5B to understand how it affects development. These mice showed autism-like behaviors and had larger brains. The missing protein caused changes in how genes work in the developing brain, leading to communication problems. When researchers gave the mice a medication called memantine, some of the communication issues improved.

This research helps us understand how certain genetic changes might lead to autism and suggests possible treatments.

This preclinical study investigated mice lacking KDM5B, a histone demethylase enzyme, to understand its role in neurodevelopment. KDM5B-deficient mice displayed autism-like behaviors and increased brain size. The research revealed that loss of KDM5B led to increased H3K4me3 levels and upregulation of neurodevelopmental genes in the developing brain cortex. Specifically, increased expression of the GRIN2D gene resulted in elevated NMDAR2D protein levels in brain synapses.

Treatment with memantine, an NMDAR antagonist, rescued deficits in ultrasonic vocalizations in the mice. The findings suggest that KDM5B deficiency disrupts normal brain development through altered gene expression, leading to social-communication impairments, and identifies NMDAR as a potential therapeutic target for neurodevelopmental disorders associated with KDM5B mutations.

Identifies KDM5B mutations as potential biomarker for autism risk and suggests NMDAR-targeted therapies may benefit individuals with specific genetic variants. However, human studies needed before clinical translation. May inform genetic counseling for families with KDM5B mutations.

Animal model findings may not translate directly to humans. Sample sizes not reported. Limited to specific behavioral and molecular measures. Single intervention tested. Long-term effects of treatment unknown.

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 developingmutant neocortex.

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