The intellectual disability risk gene Kdm5b regulates long term memory consolidation in the hippocampus

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders and heterozygous, protein truncating variants in are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in t...

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Veröffentlicht in:The Journal of neuroscience 2024-05, Vol.44 (19), p.e1544232024
Hauptverfasser: Perez-Sisques, Leticia, Bhatt, Shail, Matuleviciute, Rugile, Gileadi, Talia, 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
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Sprache:eng
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Zusammenfassung:The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders and heterozygous, protein truncating variants in 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 allele that lacks demethylase activity. 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 learning stimulus compared to wildtype mice. A number of other learning-associated genes was also significantly dysregulated in the hippocampus. Next, we knocked down specifically in the adult, wildtype mouse hippocampus with shRNA. 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 gene variants are caused by direct effects on memory consolidation mechanisms. The histone lysine demethylase KDM5B has been implicated in cognitive performance and intellectual disability conditions in the human population. In the present manuscript we show that mice expressing a demethylase-deficient KDM5B and mice with a specific knockdown of KDM5B in the adult hippocampus exhibit hippocampus-dependent learning and memory phenotypes. Molecular analyses suggest a key role for KDM5B in regulating the dynamic expression of activity-regulated genes during memory consolidation. Deficits in LTP are present in mice with KDM5B knockdown. Together, these findings provide the first evidence for a direct function for KDM5B in memory consolidation in the hippocampus.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.1544-23.2024