Genome sequencing studies have implicated genes encoding chromatin-modifying factors in intellectual disability (ID) and autism spectrum disorders (ASD). One such gene is KDM5B, a histone lysine demethylase. Recessive mutations in KDM5B are linked to rare ID syndromes, and protein-truncating variants in KDM5B are associated with cognitive deficits. This study investigates the role of KDM5B in hippocampus-dependent learning and memory, focusing on how KDM5B loss-of-function mutations affect memory consolidation.
Contents
Methods
Animals
Experiments were conducted on mice carrying the Kdm5btm1Jtpu allele, referred to as Kdm5bΔARID. These mice were housed in controlled conditions and genotyped using PCR. Homozygous Kdm5bΔ/Δ mice were used for the experiments, derived from intercrossing heterozygous F1 mice.
Behavioral Tests
Behavioral assessments included open field tests, object location memory (OLM) tests, elevated plus maze (EPM), spontaneous alternation in a Y-maze, Morris water maze (MWM), fear-conditioning tests, and grip strength measurements. These tests were conducted to evaluate hippocampus-dependent learning and memory, anxiety-like behavior, and motor function.
Molecular Analyses
Molecular analyses included Western blotting, immunofluorescence, Golgi staining, RNA extraction, qRT-PCR, and RNA sequencing (RNAseq). These techniques were used to assess the expression of KDM5B, histone modifications, and activity-regulated genes in the hippocampus.
Results
KDM5B Deficiency and Hippocampal Histology
Homozygous Kdm5bΔ/Δ mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. These mice showed an increased number of H3K4me3-positive cells in the hippocampus, indicating elevated histone methylation levels due to the lack of KDM5B demethylase activity.
Behavioral Findings
Kdm5bΔ/Δ mice exhibited hyperactivity in the open field test and spent less time in the inner area, suggesting an anxiety-like phenotype. In the OLM test, these mice showed significant deficits in long-term spatial memory, although short-term memory remained intact. In the MWM test, mutant mice displayed impaired spatial learning and reference memory, with increased escape latency and reduced platform crossings during the probe trial. Additionally, Kdm5bΔ/Δ mice showed reduced freezing behavior in the contextual fear-conditioning test, indicating associative long-term memory deficits.
Molecular Findings
RNAseq analyses revealed altered baseline and learning-induced gene expression in the hippocampus of Kdm5bΔ/Δ mice. Immediate early genes, such as Egr1 and Npas4, were downregulated at baseline but showed exaggerated induction following a learning stimulus. Four distinct clusters of differentially expressed genes were identified, highlighting the dysregulation of transcriptional and signaling pathways associated with learning and memory.
Discussion
Role of KDM5B in Synaptic Plasticity
The findings demonstrate that KDM5B is crucial for the regulation of gene expression and synaptic plasticity in the hippocampus. The increased histone methylation and altered gene expression profiles in Kdm5bΔ/Δ mice suggest that KDM5B-mediated demethylation is essential for the dynamic regulation of activity-dependent genes during memory consolidation.
Implications for Intellectual Disability
The study provides insights into how mutations in KDM5B contribute to cognitive deficits observed in ID syndromes. The hyperactivity and learning deficits in Kdm5bΔ/Δ mice mirror some of the behavioral phenotypes seen in humans with KDM5B mutations, suggesting that these mice can serve as a model for studying the molecular mechanisms underlying cognitive impairments in ID and ASD.
Future Directions
Future research should explore the specific mechanisms by which KDM5B regulates the expression of activity-dependent genes and synaptic plasticity. Investigating the interactions between KDM5B and other chromatin-modifying enzymes could provide a more comprehensive understanding of the epigenetic regulation of memory consolidation. Additionally, studying the potential compensatory mechanisms in KDM5B-deficient mice may reveal new targets for therapeutic interventions in ID and ASD.
Conclusion
This study identifies KDM5B as a critical regulator of gene expression and synaptic plasticity in the hippocampus. The findings highlight the importance of KDM5B in memory consolidation and provide a potential link between KDM5B mutations and cognitive deficits in ID syndromes. Understanding the role of KDM5B in memory processes may pave the way for developing targeted therapies for cognitive impairments associated with genetic disorders.
References
For further details, you can access the full study here.
