DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation.

Shaghayegh Navabpour,Timothy J Jarome,Jessie Rogers,Taylor Mcfadden

doi:10.3390/ijms21238995

Shaghayegh Navabpour, Timothy J Jarome + Show 2 more

Open Access

https://doi.org/10.3390/ijms21238995

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Abstract

Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Furthermore, though recent evidence suggests that neuronal activity triggers DNA double-strand breaks (DSBs) in some early-response genes, it is currently unknown if DSBs contribute to the reconsolidation of a memory following retrieval. Here, using chromatin immunoprecipitation (ChIP) analyses, we report a significant overlap between DSBs and H3K4me3 in area CA1 of the hippocampus during the reconsolidation process. We found an increase in phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker of DSB, in the Npas4, but not c-fos, promoter region 5 min after retrieval, which correlated with increased H3K4me3 levels, suggesting that the two epigenetic marks may work in concert during the reconsolidation process. Consistent with this, in vivo siRNA-mediated knockdown of topoisomerase II β, the enzyme responsible for DSB, prior to retrieval, reduced Npas4 promoter-specific H2A.XpS139 and H3K4me3 levels and impaired long-term memory, indicating an indispensable role of DSBs in the memory reconsolidation process. Collectively, our data propose a novel mechanism for memory reconsolidation through increases in epigenetic-mediated transcriptional control via DNA double-strand breaks.

Highlights

The traditional view of memory storage is that once a memory for a task or learned association is stored or “consolidated,” it becomes stable and no longer susceptible to disruption [1]
These findings propose a novel mechanism for memory reconsolidation through the increase of gene transcription via double-strand breaks (DSBs) early on after memory retrieval
Since H2A.XpS139 levels could be changing in a gene-specific manner, which may not be detected in bulk histone extracts, we examined levels of this histone modification at the Npas4 and c-fos genes (Figure 1F), two well-described regulators of memory reconsolidation that undergo extensive epigenetic editing following retrieval [10,35]

Summary

Introduction

The traditional view of memory storage is that once a memory for a task or learned association is stored or “consolidated,” it becomes stable and no longer susceptible to disruption [1] This notion has been challenged by various studies showing that previously consolidated memories are susceptible to disruption or modification after retrieval and are re-stabilized through a process called reconsolidation [2,3,4]. This reconsolidation process is controlled by increased transcriptional and translational regulation [4,5,6,7]. It is not clear how the transcription of Npas is regulated during the reconsolidation process

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