The intellectual disability risk gene Kdm5b regulates long term memory consolidation in the hippocampus
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ABSTRACT:
PROVIDER: PRJNA1005646 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25648300_1.fastq.gz | Fastqsanger.gz | |||
| SRR25648300_2.fastq.gz | Fastqsanger.gz | |||
| SRR25648301_1.fastq.gz | Fastqsanger.gz | |||
| SRR25648301_2.fastq.gz | Fastqsanger.gz | |||
| SRR25648302_1.fastq.gz | Fastqsanger.gz |
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Project description:The histone lysine demethylase KDM5B has been implicated in recessive intellectual disability disorders and heterozygous, protein truncating variants in KDM5B are associated with reduced cognitive function in the normal adult population. To help distinguish between developmental and demethylase-dependent functions of KDM5B in hippocampus-dependent learning and memory, we studied mice homozygous for a Kdm5bDARID allele that lacks demethylase activity. Demethylase-deficient Kdm5bDARID/DARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in mice in the home cage (baseline) and hyperactivated upon learning stimulus compared to wildtype mice. The expression of other learning-associated genes was also significantly altered in the Kdm5bDARID/DARID hippocampus. 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 learning and memory mechanisms.
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Project description:Sleep has been strongly implicated in learning and especially in the reprocessing of recently acquired memory. Children with intellectual disability (ID) tend to have sleep-wake disturbances, which may contribute to the pathophysiology of the disease. As far as sleep is, in part, a circadian process, we decided to study rhythmic gene expression in hippocampus, a brain structure, which plays a key role in memory in human and rodents. By investigating the transcriptome of mouse adult hippocampus, we report here the identification of 663 circadian rhythm (CR)-regulated genes, which have been clustered in four categories, based on their temporal pattern of expression. In addition to the standard core-clock genes, enrichment analysis of the hippocampal CR-regulated genes revealed the presence of several transcription factors, underlying the existence of an inter-regulation of genes' expression between clusters. Interestingly, these hippocampal circadian rhythm-regulated genes are very enriched in sleep/wakefulness related genes. We show here that glucocorticoid signaling, already shown to be involved in memory regulation, is a circadian regulated pathway in hippocampus. Furthermore, we identified a list of 30 CR-regulated ID genes. Our results demonstrate that hippocampus can be considered as a peripheral oscillator and illustrate the link between circadian rhythm, sleep, intellectual disability and memory consolidation. In order to identify circadian rhythm-regulated genes in mouse hippocampus, we realized a study in dark-dark conditions, thus allowing to overcome the effects induced by light changes. To systematically identify genes with circadian regulated expression, RNA samples from the hippocampus of three mice at four Circadian Time (CT) points were used for expression profiling using Agilent microarray technology. The dark/dark period started at 7 p.m. The Circadian Time (CT) 18 samples were taken after 30 h of continuous dark; the other circadian times followed at 6-h intervals: CT0, CT6 and CT12 after 36, 42 and 48 h of continuous darkness, respectively.
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Project description:Sleep has been strongly implicated in learning and especially in the reprocessing of recently acquired memory. Children with intellectual disability (ID) tend to have sleep-wake disturbances, which may contribute to the pathophysiology of the disease. As far as sleep is, in part, a circadian process, we decided to study rhythmic gene expression in hippocampus, a brain structure, which plays a key role in memory in human and rodents. By investigating the transcriptome of mouse adult hippocampus, we report here the identification of 663 circadian rhythm (CR)-regulated genes, which have been clustered in four categories, based on their temporal pattern of expression. In addition to the standard core-clock genes, enrichment analysis of the hippocampal CR-regulated genes revealed the presence of several transcription factors, underlying the existence of an inter-regulation of genes' expression between clusters. Interestingly, these hippocampal circadian rhythm-regulated genes are very enriched in sleep/wakefulness related genes. We show here that glucocorticoid signaling, already shown to be involved in memory regulation, is a circadian regulated pathway in hippocampus. Furthermore, we identified a list of 30 CR-regulated ID genes. Our results demonstrate that hippocampus can be considered as a peripheral oscillator and illustrate the link between circadian rhythm, sleep, intellectual disability and memory consolidation.
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