SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

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

Perez-Sisques, L; Bhatt, S; Matuleviciute, R; Gileadi, T; Kramar, E; Graham, A; Garcia, FG; Keiser, A; Matheos, DP; Cain, JA; et al. Perez-Sisques, L; Bhatt, S; Matuleviciute, R; Gileadi, T; Kramar, E; Graham, A; Garcia, FG; Keiser, A; Matheos, DP; Cain, JA; Pittman, AM; Andreae, LC; Fernandes, C; Wood, MA; Giese, KP; Basson, MA (2024) The intellectual disability risk gene Kdm5b regulates long term memory consolidation in the hippocampus. The Journal of Neuroscience, 44 (19). e1544232024. ISSN 0270-6474 https://doi.org/10.1523/jneurosci.1544-23.2024
SGUL Authors: Pittman, Alan Michael

[img]
Preview
PDF Accepted Version
Available under License Creative Commons Attribution.

Download (7MB) | Preview

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 Kdm5bΔARID allele that lacks demethylase activity. Kdm5bΔARID/ΔARID 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 Kdm5bΔARID/ΔARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, wildtype 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. Significance statement 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.

Item Type: Article
Additional Information: Copyright © 2024 Perez-Sisques et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, Neurology & Neurosurgery
Journal or Publication Title: The Journal of Neuroscience
ISSN: 0270-6474
Language: en
Dates:
DateEvent
8 May 2024Published
4 April 2024Published Online
30 March 2024Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
MR/V013173/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
DTPMedical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/X010481/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
NIIHDWellcome Trusthttp://dx.doi.org/10.13039/100004440
AG057558National Institute on Aginghttp://dx.doi.org/10.13039/100000049
K99AG078501National Institute on AgingUNSPECIFIED
AG077872National Institute on Aginghttp://dx.doi.org/10.13039/100000049
URI: https://openaccess.sgul.ac.uk/id/eprint/116449
Publisher's version: https://doi.org/10.1523/jneurosci.1544-23.2024

Actions (login required)

Edit Item Edit Item