The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3

Abstract

Consolidation of long-term memories depends on de novo protein synthesis. Several translational regulators have been identified, and their contribution to the formation of memory has been assessed in the mouse hippocampus. None of them, however, has been implicated in the persistence of memory. Although persistence is a key feature of long-term memory, how this occurs, despite the rapid turnover of its molecular substrates, is poorly understood. Here we find that both memory storage and its underlying synaptic plasticity are mediated by the increase in level and in the aggregation of the prion-like translational regulator CPEB3 (cytoplasmic polyadenylation element-binding protein). Genetic ablation of CPEB3 impairs the maintenance of both hippocampal long-term potentiation and hippocampus-dependent spatial memory. We propose a model whereby persistence of long-term memory results from the assembly of CPEB3 into aggregates. These aggregates serve as functional prions and regulate local protein synthesis necessary for the maintenance of long-term memory.

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

“…Uba2 is of a specific interest, acting as E1 ligase for SUMO 1-3 version of the protein degradation system (104,105). Strong reduction of Uba2 expression accords well with the recent findings demonstrating reduction of SUMOyation of aggregated CPEB3, a prion-like protein, which promotes protein synthesis leading to maintenance of LTP and consolidation of long-term memory (106,107). The role of CREB SUMOylation has been established in maintenance of long-term spatial memory (108).…”

The Role of Functional Prion-Like Proteins in the Persistence of Memory

“…Fioriti et al (2015) found that in the basal state CPEB3 binds to and represses the translation of its target mRNAs in the brain, such as the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluA1 and GluA2 (Huang . Together, these data suggest that CPEB3 can act as a repressor in the basal state and can be converted to an activator in aggregation by posttranslational modification.…”

Prions, amyloids, and RNA: Pieces of a puzzle

“…169 Finally, three recent manuscripts analyzed aggregation and self-perpetuation of the mouse ortholog of ApCPEB, CPEB3. 59,162,163 Studies of an ectopically expressed purified protein confirmed the ability of CPEB3 to form typical amyloid fibers with a characteristic birefringence upon Congo Red staining. Studies in yeast established that CPEB3 can act as a bona fide prion, i.e.…”

“…Remarkable examples of the translation-coupled functional amyloids in multicellular organisms are neuron-specific forms of the cytoplasmic polyadenylation element binding protein (CPEB), ApCPEB, Orb2, and CPEB3 in the mollusk Aplysia californica, 24,159,160 fruit fly Drosophila melanogaster, 161 and mouse, 59,162,163 correspondingly. CPEB represents a family of RNA-binding proteins that bind U-rich sequences called CPE elements, which are located in the 3 0 untranslated regions of a number of cellular mRNAs.…”

“…Noteworthy, in agreement with the hypothesis that the CPEB3 prion acts as a synaptic tag in the maintenance of long-term memory persistence, CPEB3 aggregation not only self-perpetuates, but also supports the translation of proteins essential for the functioning of the synapse, such as GluR receptors, as well as proteins essential for CPEB3 regulation, such as actin and SUMO. 59,162,163 Overall, CPEB proteins form functional amyloids with prion-like properties that control long-term memory and possess a complex regulatory network consisting of chemical and protein regulators.…”