Adult hippocampal MeCP2 preserves the genomic responsiveness to learning required for long-term memory formation

Karaca, Kübra Gülmez; Brito, David V.C.; Zeuch, Benjamin; Oliveira, Ana M.M.

doi:10.1016/j.nlm.2018.02.010

Cited by 34 publications

(50 citation statements)

References 85 publications

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“…Habituation was performed in the first week of rAAV delivery, when the rAAV expression is almost undetectable 14,20 , to minimize the habituation-induced expression of Dnmt3a2. Two weeks after the last handling day, CFC or spatial object learning was performed 57 . Briefly, for CFC, mice were placed into the conditioning-chamber (23 × 23 × 35 cm, TSE, Bad Homburg, Germany) and 148 s later, received a 2 s foot shock (0.5 mA).…”

Section: Methodsmentioning

confidence: 99%

Neuronal ensemble-specific DNA methylation strengthens engram stability

et al. 2020

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Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning. However, the molecular mechanisms that drive engram stabilization during consolidation and consequently ensure its reactivation by memory recall are not fully understood. In this study we manipulate, during memory consolidation, the levels of the de novo DNA methyltransferase 3a2 (Dnmt3a2) selectively within dentate gyrus neurons activated by fear conditioning. We found that Dnmt3a2 upregulation enhances memory performance in mice and improves the fidelity of reconstitution of the original neuronal ensemble upon memory retrieval. Moreover, similar manipulation in a sparse, non-engram subset of neurons does not bias engram allocation or modulate memory strength. We further show that neuronal Dnmt3a2 overexpression changes the DNA methylation profile of synaptic plasticity-related genes. Our data implicates DNA methylation selectively within neuronal ensembles as a mechanism of stabilizing engrams during consolidation that supports successful memory retrieval.

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Section: Methodsmentioning

confidence: 99%

Neuronal ensemble-specific DNA methylation strengthens engram stability

et al. 2020

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“…Three weeks after stereotaxic surgeries, following 5 days of handling, the spatial object recognition (SOR) was performed. The open field test was performed in the first session of the SOR training as described previously (Gulmez Karaca et al, 2018; Brito et al, in press). The Smart Video Tracking Software (Panlab, Harvard Apparatus) was used to score the time spent in the central zone (32% of the arena), number of center entries and total distance travelled in the open field test.…”

Section: Methodsmentioning

confidence: 99%

“…2 h after the start of the SOR test, mice were perfused intracardially with 4% paraformaldehyde (PFA) (Sigma, Munich, Germany) and free-floating brain slices (at a thickness of 20 µ m) were immunostained as previously described (Gulmez Karaca et al, 2018; Oliveira et al, 2012). Primary antibodies were used at the following concentrations: anti-HA tag (Covance MMS-101R (1:1000)), anti-Fos (Cell Signaling #2250, 1:1000)).…”

Section: Methodsmentioning

confidence: 99%

Engram reactivation during memory retrieval predicts long-term memory performance in aged mice

Karaca

Brito

Zeuch

et al. 2020

Preprint

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Age-related cognitive decline preferentially targets long-lasting episodic memories that require intact hippocampal function. Memory traces (or engrams) are believed to be encoded within the neurons activated during learning (neuronal ensembles), and recalled by reactivation of the same population. However, whether engram reactivation dictates memory performance in late life is not known. Here, we labelled neuronal ensembles formed during object location recognition learning in the dentate gyrus, and analyzed the reactivation of this population by long-term memory recall in young adult, cognitively impaired- and unimpaired-aged mice. We found that reactivation of memory-encoding neuronal ensembles at long-term memory recall was disrupted in impaired- but not unimpaired-aged mice. Furthermore, we showed that the memory performance in the aged population correlated with the degree of engram reactivation at long-term memory recall. Overall, our data implicates recall-induced engram reactivation as a prediction factor of memory performance throughout aging. Moreover, our findings suggest impairments in neuronal ensemble stabilization and/or reactivation as an underlying mechanism in age-dependent cognitive decline.

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“…C57Bl/6N mice (Charles River, Sulzfeld, Germany) were prepared and maintained as previously described (Gulmez Karaca et al, 2020) (Oliveira et al, 2012;Oliveira et al, 2016). The open field test was carried out within the first session of the object-place recognition training as previously described (Gulmez Karaca et al, 2018).…”

Section: Primary Hippocampal Cultures Hippocampal Cultures From Newbornmentioning

confidence: 99%

Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice

Brito

Karaca

Kupke

et al. 2020

Preprint

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AbstractAging is associated with the progressive decay of cognitive function. Hippocampus-dependent processes, such as the formation of spatial memory, are particularly vulnerable to aging. Currently, the molecular mechanisms responsible for age-dependent cognitive decline are largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage gamma (Gadd45γ) during aging and cognition. We report that Gadd45γ expression is increased in the hippocampus of aged humans and that Gadd45γ overexpression in the young adult mouse hippocampus compromises cognition. Moreover, Gadd45γ overexpression in hippocampal neurons disrupted CREB signaling and the expression of well-established activity-regulated genes. This work shows that Gadd45γ expression is tightly controlled in the hippocampus and its disruption may be a mechanism contributing to age-related cognitive impairments observed in humans.

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Adult hippocampal MeCP2 preserves the genomic responsiveness to learning required for long-term memory formation

Cited by 34 publications

References 85 publications

Neuronal ensemble-specific DNA methylation strengthens engram stability

Neuronal ensemble-specific DNA methylation strengthens engram stability

Engram reactivation during memory retrieval predicts long-term memory performance in aged mice

Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice

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