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The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2024 May 08; Vol. 44 (19). Date of Electronic Publication: 2024 May 08. - Publication Year :
- 2024
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Abstract
- The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b <superscript> Δ ARID </superscript> allele that lacks demethylase activity. Kdm5b <superscript> Δ ARID/ Δ ARID </superscript> mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b <superscript> Δ ARID/ Δ ARID </superscript> hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.<br />Competing Interests: The authors declare no competing financial interests.<br /> (Copyright © 2024 Perez-Sisques et al.)
- Subjects :
- Animals
Mice
Male
Female
Long-Term Potentiation genetics
Long-Term Potentiation physiology
Mice, Inbred C57BL
DNA-Binding Proteins
Hippocampus metabolism
Intellectual Disability genetics
Jumonji Domain-Containing Histone Demethylases genetics
Jumonji Domain-Containing Histone Demethylases metabolism
Memory Consolidation physiology
Memory, Long-Term physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 44
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 38575342
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.1544-23.2024