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

• Published in: Neuron (Cambridge, Mass.) Mass.), 2015-06, Vol.86 (6), p.1433-1448
• Main Authors: Fioriti, Luana, Myers, Cory, Huang, Yan-You, Li, Xiang, Stephan, Joseph S., Trifilieff, Pierre, Colnaghi, Luca, Kosmidis, Stylianos, Drisaldi, Bettina, Pavlopoulos, Elias, Kandel, Eric R.
• Format: Article
• Language: English
• Subjects: Aggregates; Animals; Anxiety - genetics; Behavior; Conditioning (Psychology) - physiology; Exploratory Behavior - physiology; Fear - drug effects; Fear - physiology; Gene expression; Glutamic Acid - pharmacology; Hippocampus - cytology; Hippocampus - physiology; Hippocampus - ultrastructure; In Vitro Techniques; Insects; Life Sciences; Locomotion - genetics; Long-Term Potentiation - drug effects; Long-Term Potentiation - genetics; Male; Mammals; Maze Learning - drug effects; Maze Learning - physiology; Memory - drug effects; Memory - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular weight; Mutation - genetics; Neurons; Neurons - physiology; Phosphopyruvate Hydratase - metabolism; Protein synthesis; Proteins; Reaction Time - genetics; Reaction Time - physiology; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2015.05.021

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. •CPEB3 forms aggregates after synaptic activity in the hippocampus•After aggregation, CPEB3 promotes the translation of AMPA receptors•CPEB3 conditional knockout mice have impaired long-term memory and LTP•CPEB3 mediates the persistence of memory through a prion-like mechanism Fioriti et al. found that the translational regulator CPEB3 is a prion-like molecule that aggregates to form an amyloid-like structure in the brain of mice. CPEB3 aggregates mediate the maintenance of hippocampal-based long-term memories.