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The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.

The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.

Authors :
Pérez-Sisqués, Leticia
Bhatt, Shail U.
Matuleviciute, Rugile
Gileadi, Talia E.
Kramar, Eniko
Graham, Andrew
Garcia, Franklin G.
Keiser, Ashley
Matheos, Dina P.
Cain, James A.
Pittman, Alan M.
Andreae, Laura C.
Fernandes, Cathy
Wood, Marcelo A.
Giese, K. Peter
Basson, M. Albert
Source :
Journal of Neuroscience; 5/8/2024, Vol. 44 Issue 19, p1-16, 16p
Publication Year :
2024

Abstract

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, proteintruncating 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>ΔARID</superscript> allele that lacks demethylase activity. Kdm5b<superscript>ΔARID/ΔARID</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>ΔARID/ΔARID</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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
02706474
Volume :
44
Issue :
19
Database :
Complementary Index
Journal :
Journal of Neuroscience
Publication Type :
Academic Journal
Accession number :
177206613
Full Text :
https://doi.org/10.1523/JNEUROSCI.1544-23.2024