Mimicking Age-Associated Gadd45γ Dysregulation Results in Memory Impairments in Young Adult Mice

Abstract

Age-related memory loss is observed across multiple mammalian species and preferentially affects hippocampus-dependent memory. Memory impairments are characterized by accelerated decay of spatial memories. Nevertheless, the molecular mechanisms underlying these deficits are still largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage (Gadd45) family during aging and cognition, respectively. We report that aging impairs the expression of Gadd45␥ in the hippocampus of cognitively impaired male mice. Mimicking this decrease in young adult male mice led to age-like memory deficits in hippocampus-dependent memory tasks. Gadd45␥ reduction impaired the activity of key components of the mitogen-activated protein kinase (MAPK) pathway (p38 and JNK) in mouse hippocampal cultures. Furthermore, we found that activation of downstream targets, such as ATF-2, c-Jun, and CREB (cAMP response element-binding protein), was disrupted. Finally, we showed that Gadd45␥ is required for induction of key earlyand late-response genes that have been associated with aging. Together, these findings indicate that Gadd45␥ expression regulates cognitive abilities and synapse-to-nucleus communication and suggest Gadd45␥ dysfunction as a potential mechanism contributing to age-related cognitive impairments.

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

“…The similar consequences of bidirectional dysregulation of Gadd45γ expression levels suggest that this approach may neglect functionally relevant and seemingly disparate age-associated transcription changes. Using in vivo and in vitro models we show that hippocampal levels of Gadd45γ are tightly regulated and that either a decrease (Brito et al, 2020) or an increase in Gadd45γ can dysregulate plasticity-associated gene expression and cause cognitive impairments. Notably, previous studies that performed transcriptomic analysis of human hippocampal tissue throughout adulthood also suggested an age-associated increase in Gadd45γ expression (Kang et al, 2011;Pletikos et al, 2014).…”

“…However, no overall correlation between age-associated gene expression in mice and humans has been detected (Zahn et al, 2007). We asked whether Gadd45γ expression in human aged hippocampus would be compromised as observed in mice (Brito et al, 2020).…”

“…and gene expression. Considering that Gadd45γ regulates CREB activity (Brito et al, 2020), we next investigated whether Gadd45γ overexpression would impact CREB regulation. First, we assessed whether Gadd45γ overexpression in the hippocampus of young adult mice (Figure 2A) affects the levels of phosphorylated CREB in baseline conditions.…”

MeCP2 gates spatial learning-induced alternative splicing events in the mouse hippocampus

“…A total volume of 1.5 μl (2:1 mixture of rAAV solution and 20% mannitol) was injected into the dorsal hippocampus (relative to Bregma: − 2 mm anteroposterior, ± 1.5 mm mediolateral, − 1.7, − 1.9 and − 2.1 mm dorsoventral) at the speed of 200 nl/min as previously described [ 21 , 30 ].…”

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

“…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.…”