Bridging Synaptic and Epigenetic Maintenance Mechanisms of the Engram

Abstract

How memories are maintained, and how memories are lost during aging or disease, are intensely investigated issues. Arguably, the reigning theory is that synaptic modifications allow for the formation of engrams during learning, and sustaining engrams sustains memory. Activity-regulated gene expression profiles have been shown to be critical to these processes, and their control by the epigenome has begun to be investigated in earnest. Here, we propose a novel theory as to how engrams are sustained. We propose that many of the genes that are currently believed to underlie long-term memory are actually part of a “plasticity transcriptome” that underpins structural and functional modifications to neuronal connectivity during the hours to days following learning. Further, we hypothesize that a “maintenance transcriptome” is subsequently induced that includes epigenetic negative regulators of gene expression, particularly histone deacetylases. The maintenance transcriptome negatively regulates the plasticity transcriptome, and thus the plastic capability of a neuron, after learning. In this way, the maintenance transcriptome would act as a metaplasticity mechanism that raises the threshold for change in neurons within an engram, helping to ensure the connectivity is stabilized and memory is maintained.

Is plasticity of synapses the mechanism of long-term memory storage?

“…According to this idea, the transcriptional repression maintains memory by preventing learning-induced neuronal plasticity from being readily overwritten by new experience-related plasticity. 125…”

Hippocampal Subgranular Zone FosB Expression Is Critical for Neurogenesis and Learning

“…creation and expression of memories (Liu X et al, 2014;Minatohara K et al, 2015;Ramirez S, 2018;Tonegawa S et al, 2015), including IEG transcription factors that orchestrate the sweeping changes in gene expression underlying the formation of stable engrams central to learning. As the process of learning and memory consolidation can take place over timescales of up to days or weeks, mechanisms controlling gene expression over these timescales, including epigenetics (Duke CG et al, 2017;Kyrke-Smith M and Williams JM, 2018;Leighton LJ et al, 2018), have become a key area of study in the learning field. The IEG ΔFosB, a transcription factor produced by the FosB gene, is unique in its stability, with a half-life in vivo of around eight days (Carle TL et al, 2007;Nishijima T et al, 2013;Ulery-Reynolds PG et al, 2009), allowing it to accumulate in neurons and regulate gene expression after repeated stimulation (Nestler EJ, 2012).…”

Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to successive stimulus

“…N = 8 for DMSO condition, N = 4 for all PMA conditions. 2-way interaction (F(6,48) = 1.242, P = 0.302); main effect of KCL (F(2,48) = 1.505, P = 0.232); main effect of PMA (F(3, 48) = 125.2, P < 0.0001). All three PMA concentrations induced Arc pre-mRNA compared to DMSO: 1µM PMA ( P < 0.0001), 0.1 µM PMA ( P < 0.0001), and 0.01 µM PMA ( P = 0.0005).…”

“…Enhancer histone acetylation (17, 47–49) and RNA Pol pausing (29, 50) modulate the dynamics of neuronal-activity inducible genes, and could respond to previous experience. However, histone deacetylases, which negatively regulate transcription, are upregulated five or more hours after LTP induction (48). These effects are far too late to explain the short-term depressive effects described in our findings.…”