Bidirectional Control of mRNA Translation and Synaptic Plasticity by the Cytoplasmic Polyadenylation Complex

• Published in: Molecular cell 2012-07, Vol.47 (2), p.253-266
• Main Authors: Udagawa, Tsuyoshi, Swanger, Sharon A., Takeuchi, Koichi, Kim, Jong Heon, Nalavadi, Vijayalaxmi, Shin, Jihae, Lorenz, Lori J., Zukin, R. Suzanne, Bassell, Gary J., Richter, Joel D.
• Format: Article
• Language: English
• Subjects: Animals; Cytoplasm - metabolism; dendrites; Dendrites - metabolism; Hippocampus - metabolism; Humans; Male; memory; messenger RNA; Mice; Mice, Inbred C57BL; mRNA Cleavage and Polyadenylation Factors - metabolism; Neuronal Plasticity; Nuclear Proteins - metabolism; phosphorylation; Polyadenylation; Polynucleotide Adenylyltransferase - metabolism; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Repressor Proteins - metabolism; ribonucleoproteins; Ribonucleoproteins - metabolism; RNA-binding proteins; RNA-Binding Proteins - metabolism; Synaptic Transmission; Transcription Factors - metabolism; translation (genetics)
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2012.05.016

Translational control of mRNAs in dendrites is essential for certain forms of synaptic plasticity and learning and memory. CPEB is an RNA-binding protein that regulates local translation in dendrites. Here, we identify poly(A) polymerase Gld2, deadenylase PARN, and translation inhibitory factor neuroguidin (Ngd) as components of a dendritic CPEB-associated polyadenylation apparatus. Synaptic stimulation induces phosphorylation of CPEB, PARN expulsion from the ribonucleoprotein complex, and polyadenylation in dendrites. A screen for mRNAs whose polyadenylation is altered by Gld2 depletion identified >100 transcripts including one encoding NR2A, an NMDA receptor subunit. shRNA depletion studies demonstrate that Gld2 promotes and Ngd inhibits dendritic NR2A expression. Finally, shRNA-mediated depletion of Gld2 in vivo attenuates protein synthesis-dependent long-term potentiation (LTP) at hippocampal dentate gyrus synapses; conversely, Ngd depletion enhances LTP. These results identify a pivotal role for polyadenylation and the opposing effects of Gld2 and Ngd in hippocampal synaptic plasticity. [Display omitted] ► CPEB and the cytoplasmic polyadenylation complex are regulated by synaptic activity ► Synaptic stimulation induces polyadenylation in dendrites ► Two CPEB partners, Gld2 and Neuroguidin, enhance and repress synaptic plasticity ► Gld2 controls the polyadenylation of >100 mRNAs in neurons including NR2A and HuD