The regulation of transcription in memory consolidation

Abstract

De novo transcription of DNA is a fundamental requirement for the formation of long-term memory. It is required during both consolidation and reconsolidation, the posttraining and postreactivation phases that change the state of the memory from a fragile into a stable and long-lasting form. Transcription generates both mRNAs that are translated into proteins, which are necessary for the growth of new synaptic connections, as well as noncoding RNA transcripts that have regulatory or effector roles in gene expression. The result is a cascade of events that ultimately leads to structural changes in the neurons that mediate long-term memory storage. The de novo transcription, critical for synaptic plasticity and memory formation, is orchestrated by chromatin and epigenetic modifications. The complexity of transcription regulation, its temporal progression, and the effectors produced all contribute to the flexibility and persistence of long-term memory formation. In this article, we provide an overview of the mechanisms contributing to this transcriptional regulation underlying long-term memory formation.

Figure 1.

How 5-HT and FMRFa bidirectionally regulate chromatin changes leading to c/ebp transcription. (A) At the basal level, CREB1a resides on the C/EBP promoter; some lysine residues of histones are acetylated. (B) 5-HT, through PKA, phosphorylates CREB1 that binds to the C/EBP promoter. Phosphorylated CREB1 then forms a complex with CBP at the promoter. CBP then acetylates lysine residues of the histones (for example, K8 of H4). Acetylation modulates chromatin structure, enabling the transcription machinery to bind and regulate gene expression. (C) FMRFa activates CREB2, which displaces CREB1 from the C/EBP promoter. HDAC5 is then recruited to deacetylate histones. As a result, the gene is repressed. (D) If the neuron is exposed to both FMRFa and 5-HT, CREB1a is replaced by CREB2 at the promoter even though it might still be phosphorylated through the 5-HT-PKA pathway, and HDAC5 is then recruited to deacetylate histones, blocking gene induction (from Guan et al. 2002).

Figure 2.

Two classes of small RNAs in Aplysia central nervous system (CNS). A size histogram of the cloned small RNAs revealed two populations, and further characterization confirmed the new class of sequences (blue) to be piRNAs.

Figure 3.

Epigenetic regulation of the transcriptional switch. 5-HT inhibits miRNA-124 and thus facilitates the activation of CREB-1, which begins the process of memory consolidation, whereas piRNA, also activated by 5-HT but with a delay, methylates and thus represses the promoter of CREB-2, allowing CREB-1 to be active for a longer period of time.