NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation

Abstract

It is well established that fear memory formation requires de novo gene transcription in the amygdala. We provide evidence that epigenetic mechanisms in the form of histone lysine methylation in the lateral amygdala (LA) are regulated by NMDA receptor (NMDAR) signaling and involved in gene transcription changes necessary for fear memory consolidation. Here we found increases in histone H3 lysine 9 dimethylation (H3K9me2) levels in the LA at 1 h following auditory fear conditioning, which continued to be temporally regulated up to 25 h following behavioral training. Additionally, we demonstrate that inhibiting the H3K9me2 histone lysine methyltransferase G9a (H/KMTs-G9a) in the LA impaired fear memory, while blocking the H3K9me2 histone lysine demethylase LSD1 (H/KDM-LSD1) enhanced fear memory, suggesting that H3K9me2 in the LA can bidirectionally regulate fear memory formation. Furthermore, we show that NMDAR activity differentially regulated the recruitment of H/KMT-G9a, H/KDM-LSD1, and subsequent H3K9me2 levels at a target gene promoter. This was largely regulated by GluN2B-but not GluN2A-containing NMDARs via ERK activation. Moreover, fear memory deficits associated with NMDAR or ERK blockade were successfully rescued through pharmacologically inhibiting LSD1, suggesting that enhancements of H3K9me2 levels within the LA can rescue fear memory impairments that result from hypofunctioning NMDARs or loss of ERK signaling. Together, the present study suggests that histone lysine methylation regulation in the LA via NMDAR-ERK-dependent signaling is involved in fear memory formation.

Environmental Enrichment Improves Behavior, Cognition, and Brain Functional Markers in Young Senescence-Accelerated Prone Mice (SAMP8)

“…DNA methylation generally decreases transcriptional access to DNA, although the functional effects of this gene silencing depend on the genes that are altered. As indicated previously, NMDAR activity drives regulation of LSD1, and its activation reduces LSD1 [18] transcription, indicating a greater extent of DNA methylation and correlation with its cofactor CoREST, which participates in the activation complex of histone methylation by LSD1.…”

Importance of the GluN2B carboxy-terminal domain for enhancement of social memories

“…Additionally, transgenic mice overexpressing the chimeric subunit with the GluN2B aminoterminal domain and the GluN2A carboxy-terminal domain demonstrated impaired long-term social recognition and olfactory recognition memory, similar to what was previously described in the transgenic GluN2A overexpression mice . The NMDA receptor is highly expressed in the forebrain areas (Hestrin 1992b;Monyer et al 1994;Sheng et al 1994) and has been shown to be necessary in the formation of memory Gao et al 2010;Gupta-Agarwal et al 2014) and the consolidation of long-term memory (Shimizu et al 2000;Santini et al 2001;Roesler et al 2005;Wu et al 2007;Liu et al 2014). While social memory is a different form of memory involving different mechanisms than olfactory memory, several of the same brain areas are involved in both types of memory.…”

The role of chromatin repressive marks in cognition and disease: A focus on the repressive complex GLP/G9a

“…In the LA, H3K9me2 levels were increased one hour following auditory fear conditioning and this increase persisted until twenty-five hours following behavioral training. In contrast, H3K4me3 remained unchanged in the LA following training (Gupta-Agarwal et al, 2014).…”