Epigenetic mechanisms of memory formation and reconsolidation

Abstract

Memory consolidation involves transcriptional control of genes in neurons to stabilize a newly formed memory. Following retrieval, a once consolidated memory destabilizes and again requires gene transcription changes in order to restabilize, a process referred to as reconsolidation. Understanding the molecular mechanisms of gene transcription during the consolidation and reconsolidation processes could provide crucial insights into normal memory formation and memory dysfunction associated with psychiatric disorders. In the past decade, modifications of epigenetic markers such as DNA methylation and posttranslational modifications of histone proteins have emerged as critical transcriptional regulators of gene expression during initial memory formation and after retrieval. In light of the rapidly growing literature in this exciting area of research, we here examine the most recent and latest evidence demonstrating how memory acquisition and retrieval trigger epigenetic changes during the consolidation and reconsolidation phases to impact behavior. In particular we focus on the reconsolidation process, where we discuss the already identified epigenetic regulators of gene transcription during memory reconsolidation, while exploring other potential epigenetic modifications that may also be involved, and expand on how these epigenetic modifications may be precisely and temporally controlled by important signaling cascades critical to the reconsolidation process. Finally, we explore the possibility that epigenetic mechanisms may serve to regulate a system or circuit level reconsolidation process and may be involved in retrieval-dependent memory updating. Hence, we propose that epigenetic mechanisms coordinate changes in neuronal gene transcription, not only during the initial memory consolidation phase, but are triggered by retrieval to regulate molecular and cellular processes during memory reconsolidation.

Keywords: Acetylation; Chromtain; Epigenetics; Hippocampus; Histones; Methylation; Reconsolidation; Transcription.

Figure 1. Hypothetical epigenetic regulation of memory reconsolidation

Memory retrieval could lead to dynamic changes in the chromatin structure, resulting in increased (histone acetylation, methylation and ubiquitination) and decreased (histone methylation, ubiquitination and DNA methylation) gene transcription that is necessary for the reconsolidation process. Manipulation of the enzymes that regulate these histone and DNA modifications can have opposing effects on the reconsolidation process, resulting in impaired or enhanced memory. Red arrows indicate impaired memory following retrieval. Blue arrows indicate enhanced memory following retrieval. HAT: histone acetyltransferase; HDAC: histone deacetylase; HDM: histone demethylase; HMT: histone methyltransferase; DNMT: DNA methyltransferase.