Abstract
Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning. However, the molecular mechanisms that drive engram stabilization during consolidation and consequently ensure its reactivation by memory recall are not fully understood. In this study we manipulate, during memory consolidation, the levels of the de novo DNA methyltransferase 3a2 (Dnmt3a2) selectively within dentate gyrus neurons activated by fear conditioning. We found that Dnmt3a2 upregulation enhances memory performance in mice and improves the fidelity of reconstitution of the original neuronal ensemble upon memory retrieval. Moreover, similar manipulation in a sparse, non-engram subset of neurons does not bias engram allocation or modulate memory strength. We further show that neuronal Dnmt3a2 overexpression changes the DNA methylation profile of synaptic plasticity-related genes. Our data implicates DNA methylation selectively within neuronal ensembles as a mechanism of stabilizing engrams during consolidation that supports successful memory retrieval.
Highlights
Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning
We aimed at manipulating the molecular composition of neurons within behaviorally-allocated neuronal ensembles to investigate whether DNA methylation within these cells serves as a mechanism regulating engram stability and long-term memory storage
We found that after induction of synaptic activity, levels of HADnmt3a2 expression and DNA methylation per cell were positively correlated in hippocampal cultures (Fig. 1b)
Summary
Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning. We have a surprisingly limited understanding of the molecular mechanisms within behaviorallyallocated neurons that ensure the stabilization of the engram during memory consolidation required for successful reactivation at memory retrieval, which drives efficient memory recall. Epigenetic mechanisms such as DNA methylation have emerged as important regulators of memory consolidation[8]. We showed that reinforcing DNA methylation-related mechanisms through Dnmt3a2 overexpression within memory-encoding neuronal ensembles during consolidation was sufficient to strengthen contextual fear memory and the stability of the engram. While we focus here on hippocampal engrams, we suggest that epigenetic mechanisms are likely to be preserved across different regions of the central nervous system and during diverse adaptive processes
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