Role of CPEBs in Learning and Memory

Abstract

Memory formation involves a complex interplay of molecular and cellular processes, including synaptic plasticity mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). These processes rely on activity-dependent gene expression and local protein synthesis at synapses. A central unresolved question in neuroscience is how memories can be stably maintained over time, despite the transient nature of the proteins involved in their initial encoding. A key candidate addressing this 'maintenance paradox' is the CPEB (cytoplasmic polyadenylation element-binding protein) family, particularly CPEB3. CPEBs are RNA-binding proteins that regulate the polyadenylation and translation of dormant mRNAs, enabling synaptic tagging and memory consolidation. CPEB3 has been shown to modulate the expression of critical synaptic proteins, including AMPA and NMDA receptor subunits, thereby influencing synaptic strength and long-term memory persistence. Structurally, CPEB3 features a disordered N-terminal domain (NTD) enriched in glutamine and proline residues, which may facilitate reversible aggregation and phase separation and an actin-binding domain, potentially supporting its localisation to ribonucleoprotein granules. The highly conserved C-terminal domain (CTD) contains RNA-recognition motifs essential for mRNA binding. Together, these structural features may enable CPEB3 to function as a molecular switch, linking synaptic activity to enduring changes in protein synthesis and memory encoding. Here, we review the current understanding of the function of CPEB3, highlighting current hypotheses and debates of the role(s) of protein self-assembly in memory formation.

Keywords: AMPA; CPEB; RNA‐binding protein; amyloid; memory; neuroscience.

FIGURE 1

CPEB3 trafficking and regulation of AMPA receptors and possible modes of action of CPEB3 in memory. (A) SUMOylation of CPEB3 and its association with target mRNA can lead to phase separation and localisation to P bodies, where translation of target mRNAs is repressed. (1) Activation of AMPA and NMDA receptors leads to (2) LTP. Increased cellular Ca²⁺ concentration leads to activation of calpain‐2 and proteolysis of CPEB3 into its NTD and CTD halves. (3) LTP leads to deSUMOylation of CPEB3 and translocation out of P bodies. (4) Subsequent oligomerisation of CPEB3 and its mono‐ubiquitination by Neurl1 leads to CPEB3 association with polysomes and translation of target mRNAs, including GluA2. (5) This results in increased AMPA subunit trafficking to the cell surface and membrane insertion of functional AMPA receptors. In addition, CPEB3 is able to modulate GluA2 indirectly through STAT5b. Created in BioRender. Hicks, D. (2025) https://BioRender.com/tbnros4. (B) Possible structures into which CPEB3 (represented in blue) might self‐assemble. Oligomers (represented using blue beads), condensates (LLPS), aggregates (represented using blue beads) or amyloid‐like fibrils (represented using beads (light blue representing the core and dark blue representing the ‘fuzzy coat’) and also in detail using the PDB 6VPS model of Orb2 fibril structures (light blue) with additional ‘fuzzy coat’ regions (dark blue)). Each structure may actively facilitate translation of target mRNAs or result in their release. Which, if any, or all, of these is involved in long‐term formation of memory remains to be resolved and is a key question for future research. Created in BioRender. Aubrey, L. (2025) https://BioRender.com/nl6c5uk.

FIGURE 2

Domain organisation in CPEB family members. (A) Domain organisation in CPEBs 1–4, showing NTD and CTD with RNA Recognition Motifs (RRM) and zinc finger (ZnF) sub‐domains. (B–D) Percentage sequence identity (black) and similarity (blue) between CPEB family members. Similarity is defined as GAVLI/FYW/CM/ST/KRH/DENQ/P.

FIGURE 3

Domain organisation in human CPEB3. Top: The main functional domains of CPEB3. Middle: Residues 160–325 (the Actin binding domain). Lower: Regions with repetitive sequences (AAR (amino acid repeat) regions) and those able to form transient secondary structural elements of different types (2°).