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dc.contributor.authorPerez-Sisques, L
dc.contributor.authorBhatt, S
dc.contributor.authorMatuleviciute, R
dc.contributor.authorGileadi, T
dc.contributor.authorKramar, E
dc.contributor.authorGraham, A
dc.contributor.authorGarcia, FG
dc.contributor.authorKeiser, A
dc.contributor.authorMatheos, DP
dc.contributor.authorCain, JA
dc.contributor.authorPittman, AM
dc.contributor.authorAndreae, LC
dc.contributor.authorFernandes, C
dc.contributor.authorWood, MA
dc.contributor.authorGiese, KP
dc.contributor.authorBasson, MA
dc.date.accessioned2024-05-07T08:57:22Z
dc.date.issued2024-04-04
dc.date.updated2024-05-03T16:04:43Z
dc.description.abstractThe 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 ΔARID allele that lacks demethylase activity. Kdm5b ΔARID/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 Kdm5b ΔARID/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.en_GB
dc.description.sponsorshipMedical Research Council (MRC)en_GB
dc.description.sponsorshipNational Institute of Agingen_GB
dc.description.sponsorshipWellcome Trusten_GB
dc.format.extente1544232024-
dc.format.mediumPrint-Electronic
dc.identifier.citationArticle e1544232024en_GB
dc.identifier.doihttps://doi.org/10.1523/JNEUROSCI.1544-23.2024
dc.identifier.grantnumberMR/V013173/1en_GB
dc.identifier.grantnumberMR/X010481/1en_GB
dc.identifier.grantnumberAG057558en_GB
dc.identifier.grantnumberAG076835en_GB
dc.identifier.grantnumberK99AG078501en_GB
dc.identifier.grantnumberAG077872en_GB
dc.identifier.urihttp://hdl.handle.net/10871/135878
dc.language.isoenen_GB
dc.publisherSociety for Neuroscienceen_GB
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pubmed/38575342en_GB
dc.rights© 2024 Perez-Sisques et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.en_GB
dc.subjectKDM5Ben_GB
dc.subjecthistone lysine demethylaseen_GB
dc.subjecthippocampusen_GB
dc.subjectlearningen_GB
dc.subjectmemoryen_GB
dc.subjectmouseen_GB
dc.subjectchromatinen_GB
dc.titleThe intellectual disability risk gene Kdm5b regulates long term memory consolidation in the hippocampusen_GB
dc.typeArticleen_GB
dc.date.available2024-05-07T08:57:22Z
dc.identifier.issn0270-6474
exeter.place-of-publicationUnited States
dc.descriptionThis is the author accepted manuscript. the final version is available from the Society for Neuroscience via the DOI in this recorden_GB
dc.descriptionData availability: RNAseq data (fastq files) were deposited at the Gene Expression Omnibus (GEO) archive under the accession number GSE240887 and made freely available upon publicationen_GB
dc.identifier.eissn1529-2401
dc.identifier.journalThe Journal of Neuroscienceen_GB
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_GB
dcterms.dateAccepted2024-03-30
rioxxterms.versionAMen_GB
rioxxterms.licenseref.startdate2024-04-04
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2024-05-07T08:52:46Z
refterms.versionFCDAM
refterms.dateFOA2024-05-07T08:57:28Z
refterms.panelAen_GB
refterms.dateFirstOnline2024-04-04


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© 2024 Perez-Sisques et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Except where otherwise noted, this item's licence is described as © 2024 Perez-Sisques et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.