TAF15 overexpression impairs memory in mice by inhibiting the transcription of Npas4
Ontology highlight
ABSTRACT: TAF15, a DNA and RNA-binding protein primarily localized in the nucleus, has been reported to be associated with the aging process and neurodegenerative diseases accompanied by cognitive decline. However, its role in regulating learning and memory remains unclear. Here, we discovered that TAF15 accumulates in the hippocampus of aged mice, and TAF15 overexpressing in hippocampal neurons led to spatial learning and memory impairments in young mice. These finding are further supported by the significant reduction of dendritic spines density and synaptic proteins level. Further studies revealed that overexpression of TAF15 is likely to reduce the number of dendritic spines by inhibiting the expression of Npas4 (among the most rapidly induced immediate-early genes) and its target gene Nptx2. Notably, the expression of Npas4 and Nptx2 in the hippocampus of aged mice is also downregulated. Additionally, we demonstrated that TAF15 binds to the core promoter of Npas4 gene and inhibits its transcription, and neuronal depolarization induces the dissociation of TAF15 from Npas4 promoter. Together, these findings uncover a direct role of TAF15 in regulating spatial learning and memory formation, which may provide new insights into aging-related cognitive deficits.
Project description:Mice deficient in the glucocorticoid-regenerating enzyme 11β-HSD1 resist age-related spatial memory impairment. To investigate the mechanisms/pathways involved, we used microarrays to identify differentially expressed hippocampal genes that associate with cognitive ageing and 11β-HSD1. Aged wild-type mice were separated into memory-impaired and unimpaired relative to young controls according to their performance in the Y-maze. All individual aged 11β-HSD1-deficient mice showed intact spatial memory. The majority of differentially expressed hippocampal genes were increased with ageing (e.g. immune/inflammatory response genes) with no genotype differences. However, the neuronal-specific transcription factor, Npas4 and immediate early gene, Arc were reduced (relative to young) in the hippocampus of memory-impaired but not unimpaired aged wild-type or aged 11β-HSD1-deficient mice. Quantitative RT-PCR and in situ hybridization confirmed reduced Npas4 and Arc mRNA expression in memory-impaired aged wild-type mice. These findings suggest that 11β-HSD1 may contribute to the decline in Npas4 and Arc mRNA levels associated with memory impairment during ageing, and that decreased activity of synaptic plasticity pathways involving Npas4 and Arc may, in part, underlie the memory deficits seen in cognitively-impaired aged wild-type mice. 20 samples, 5 groups of 4 biological replicates each. Young, Wild Type animals are overall controls
Project description:Mice deficient in the glucocorticoid-regenerating enzyme 11β-HSD1 resist age-related spatial memory impairment. To investigate the mechanisms/pathways involved, we used microarrays to identify differentially expressed hippocampal genes that associate with cognitive ageing and 11β-HSD1. Aged wild-type mice were separated into memory-impaired and unimpaired relative to young controls according to their performance in the Y-maze. All individual aged 11β-HSD1-deficient mice showed intact spatial memory. The majority of differentially expressed hippocampal genes were increased with ageing (e.g. immune/inflammatory response genes) with no genotype differences. However, the neuronal-specific transcription factor, Npas4 and immediate early gene, Arc were reduced (relative to young) in the hippocampus of memory-impaired but not unimpaired aged wild-type or aged 11β-HSD1-deficient mice. Quantitative RT-PCR and in situ hybridization confirmed reduced Npas4 and Arc mRNA expression in memory-impaired aged wild-type mice. These findings suggest that 11β-HSD1 may contribute to the decline in Npas4 and Arc mRNA levels associated with memory impairment during ageing, and that decreased activity of synaptic plasticity pathways involving Npas4 and Arc may, in part, underlie the memory deficits seen in cognitively-impaired aged wild-type mice.
Project description:Aging is often associated with cognitive decline, but many elderly individuals maintain a high level of function throughout life. Here we studied outbred rats, which also exhibit individual differences across a spectrum of outcomes that includes both preserved and impaired spatial memory. Previous work in this model identified the CA3 subfield of the hippocampus as a region critically affected by age and integral to differing cognitive outcomes. Earlier microarray profiling revealed distinct gene expression profiles in the CA3 region, under basal conditions, for aged rats with intact memory and those with impairment. Because prominent age-related deficits within the CA3 occur during neural encoding of new information, here we used microarray analysis to gain a broad perspective of the aged CA3 transcriptome under activated conditions. Behaviorally induced CA3 expression profiles differentiated aged rats with intact memory from those with impaired memory. In the activated profile, we observed substantial numbers of genes (greater than 1000) exhibiting increased expression in aged unimpaired rats relative to aged impaired, including many involved in synaptic plasticity and memory mechanisms. This unimpaired aged profile also overlapped significantly with a learning induced gene profile previously acquired in young adults. Alongside the increased transcripts common to both young learning and aged rats with preserved memory, many transcripts behaviorally-activated in the current study had previously been identified as repressed in the aged unimpaired phenotype in basal expression. A further distinct feature of the activated profile of aged rats with intact memory is the increased expression of an ensemble of genes involved in inhibitory synapse function, which could control the phenotype of neural hyperexcitability found in the CA3 region of aged impaired rats. These data support the conclusion that aged subjects with preserved memory recruit adaptive mechanisms to retain tight control over excitability under both basal and activated conditions. RNA profiles from cognitively unimpaired and impaired aged rats were compared under 2 conditions: spatial learning task and a non-spatial learning task.
Project description:Aging-related microglial activation is associated with dendritic regression and spine loss in the aged brain. However, the microglia-mediated reductions of spine densities by Tonicity-responsive enhancer-binding protein (TonEBP) in the aged brain is yet unknown. We began to address this question by examining the effect of age on microglial activation and the TonEBP expression in mice. by using molecular and morphologic approaches, the roles of TonEBP in microglial activation and dendritic spines were examined in 12-month-old mice and Alzheimer's diseases (AD) mouse models. Here, we found the increased TonEBP in the hippocampus of aged mice and frontal cortex of AD patients. TonEBP haploinsufficiency reduced microglial activation and dendritic spine regression in 12-month aged mice compared to wild-type (WT) mice. We performed electron microscopy to supply interactions with microglial and synapses. We analyzed microglial processes and extracellular space in areas contacting spines and axon terminal, synaptic cleft, among the hippocampus CA1 of 12-month-old TonEBP haploinsufficient mice versus wild-type littermates. Furthermore, in amyloid-ꞵ oligomer (AꞵO)-injected AD mouse model, TonEBP haploinsufficiency inhibited the dendritic spine loss and improved memory deficits in AβO-treated mice compared to WT mice. These findings indicate that TonEBP may play an important role in aging-induced microglial activation and memory deficits.
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.
Project description:We carried out a global survey of age-related changes in mRNA levels in the C57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged mice displayed a mild but specific deficit in spatial memory in the Morris water maze. Experiment Overall Design: No technical replicates; 14 biological replicates for 15-month-old mice, 9 biological replicates for 2-month-old mice. Whole hippocampus.
Project description:The goal is to look at measures of overall metabolic state in relationship to hormonal environment and measures of mood/depression or cognitive function (behavioral and functional MRI images). There are some relationships in this data set between glucose/insulin levels and cognitive function, and we would like to use the untargeted assays to further investigate this relationship. Factors related to visual/spatial memory are included in the design. Factors 1 and 2 (Left Hippocampus, Right Hippocampus) are levels of activation in the hippocampus during a visual memory task, (data missing for some of the samples). Factors 3-5 (BVMT % Retained, BVMT Learning T, BVMT Delay T) are results from a cognitive test of spatial memory function.
Project description:Aging is often associated with cognitive decline, but many elderly individuals maintain a high level of function throughout life. Here we studied outbred rats, which also exhibit individual differences across a spectrum of outcomes that includes both preserved and impaired spatial memory. Previous work in this model identified the CA3 subfield of the hippocampus as a region critically affected by age and integral to differing cognitive outcomes. Earlier microarray profiling revealed distinct gene expression profiles in the CA3 region, under basal conditions, for aged rats with intact memory and those with impairment. Because prominent age-related deficits within the CA3 occur during neural encoding of new information, here we used microarray analysis to gain a broad perspective of the aged CA3 transcriptome under activated conditions. Behaviorally induced CA3 expression profiles differentiated aged rats with intact memory from those with impaired memory. In the activated profile, we observed substantial numbers of genes (greater than 1000) exhibiting increased expression in aged unimpaired rats relative to aged impaired, including many involved in synaptic plasticity and memory mechanisms. This unimpaired aged profile also overlapped significantly with a learning induced gene profile previously acquired in young adults. Alongside the increased transcripts common to both young learning and aged rats with preserved memory, many transcripts behaviorally-activated in the current study had previously been identified as repressed in the aged unimpaired phenotype in basal expression. A further distinct feature of the activated profile of aged rats with intact memory is the increased expression of an ensemble of genes involved in inhibitory synapse function, which could control the phenotype of neural hyperexcitability found in the CA3 region of aged impaired rats. These data support the conclusion that aged subjects with preserved memory recruit adaptive mechanisms to retain tight control over excitability under both basal and activated conditions.
Project description:CTCF is an organizer of higher-order chromatin structure, and regulates gene expression. Genetic studies have implicated mutations in CTCF in intellectual disabilities. However, there is no knowledge of the role of CTCF-mediated chromatin structure in learning and memory. We show that depletion of CTCF in postmitotic neurons, or depletion in the hippocampus of adult mice through viral-mediated knockout, induces deficits in learning and memory. These deficits in learning and memory at the beginning of adulthood are correlated with impaired long term potentiation and reduced spine density, with no changes in basal synaptic transmission and dendritic morphogenesis and arborization. Cognitive disabilities are associated with downregulation of cadherin and learning-related genes. In addition, CTCF knockdown attenuates fear conditioning-induced hippocampal gene expression of key learning genes and loss of long-range interactions at the BDNF and Arc loci. This study identifies CTCF-dependent gene expression regulation and DNA structure as regulators of learning and memory.
Project description:CTCF is an organizer of higher-order chromatin structure, and regulates gene expression. Genetic studies have implicated mutations in CTCF in intellectual disabilities. However, there is no knowledge of the role of CTCF-mediated chromatin structure in learning and memory. We show that depletion of CTCF in postmitotic neurons, or depletion in the hippocampus of adult mice through viral-mediated knockout, induces deficits in learning and memory. These deficits in learning and memory at the beginning of adulthood are correlated with impaired long term potentiation and reduced spine density, with no changes in basal synaptic transmission and dendritic morphogenesis and arborization. Cognitive disabilities are associated with downregulation of cadherin and learning-related genes. In addition, CTCF knockdown attenuates fear conditioning-induced hippocampal gene expression of key learning genes and loss of long-range interactions at the BDNF and Arc loci. This study identifies CTCF-dependent gene expression regulation and DNA structure as regulators of learning and memory.