Control of Synaptic Plasticity and Memory via Suppression of Poly(A)-Binding Protein

• Published in: Neuron (Cambridge, Mass.) Vol. 78; no. 2; pp. 298 - 311
• Main Authors: Khoutorsky, Arkady, Yanagiya, Akiko, Gkogkas, Christos G., Fabian, Marc R., Prager-Khoutorsky, Masha, Cao, Ruifeng, Gamache, Karine, Bouthiette, Frederic, Parsyan, Armen, Sorge, Robert E., Mogil, Jeffrey S., Nader, Karim, Lacaille, Jean-Claude, Sonenberg, Nahum
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.04.2013; Elsevier Limited
• Subjects: Adenosine Triphosphatases - pharmacology; Animals; Brain research; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calpain - pharmacology; Cells, Cultured; Conditioning (Psychology) - drug effects; Conditioning (Psychology) - physiology; Dactinomycin - pharmacology; Enzyme Inhibitors - pharmacology; Fear - drug effects; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Hippocampus - cytology; Long-Term Potentiation - drug effects; Long-Term Potentiation - genetics; Male; Mammals; Medical research; Memory - drug effects; Memory - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; N-Methylaspartate - pharmacology; Neurons - drug effects; Neurons - physiology; Oligodeoxyribonucleotides - pharmacology; Poly(A)-Binding Proteins; Protein synthesis; Protein Synthesis Inhibitors - pharmacology; Proteins; Reaction Time - drug effects; Reaction Time - genetics; RNA, Messenger - metabolism; Synapses - physiology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2013.02.025

Control of protein synthesis is critical for synaptic plasticity and memory formation. However, the molecular mechanisms linking neuronal activity to activation of mRNA translation are not fully understood. Here, we report that the translational repressor poly(A)-binding protein (PABP)-interacting protein 2A (PAIP2A), an inhibitor of PABP, is rapidly proteolyzed by calpains in stimulated neurons and following training for contextual memory. Paip2a knockout mice exhibit a lowered threshold for the induction of sustained long-term potentiation and an enhancement of long-term memory after weak training. Translation of CaMKIIα mRNA is enhanced in Paip2a−/− slices upon tetanic stimulation and in the hippocampus of Paip2a−/− mice following contextual fear learning. We demonstrate that activity-dependent degradation of PAIP2A relieves translational inhibition of memory-related genes through PABP reactivation and conclude that PAIP2A is a pivotal translational regulator of synaptic plasticity and memory. •PAIP2A impairs protein synthesis via inhibiting PABP activity•PAIP2A is rapidly proteolyzed following neuronal activity and contextual learning•Paip2a−/− mice exhibit a lowered threshold for L-LTP induction and enhanced memory•The translation of CaMKIIα mRNA is augmented in Paip2a−/− mice The study by Khoutorsky et al. reveals a new pathway to stimulate protein synthesis in neurons via proteolysis of PAIP2A, a poly(A)-binding protein (PABP) repressor. This mechanism plays a role in synaptic plasticity and memory.