Bidirectional control of dendritic mRNA translation, glutamate receptor expression, and synapse structure by the CPEB-associated polyadenylation machinery

Neurons are highly polarized cells that extend elaborate dendritic arbors and have thousands of synaptic inputs. The post-transcriptional control of gene expression through dendritic mRNA localization and local protein synthesis is an important means for regulating postsynaptic protein expression. Moreover, translational control of dendritic mRNAs is essential for certain forms of synaptic plasticity, learning, and memory. CPEB (cytoplasmic polyadenylation element binding protein) is one RNA binding protein that regulates local translation in dendrites as well as synaptic structure and function. However, the mechanism by which it regulates these processes is unknown. Herein, we identify a poly(A) polymerase, a deadenylase, and the translation inhibitory factor neuroguidin as components of a dendritic CPEB-associated polyadenylation complex. Synaptic stimulation induces phosphorylation of CPEB, expulsion of the deadenylase from the ribonucleoprotein complex, and mRNA polyadenylation in dendrites. Furthermore, these CPEB-associated translation factors bidirectionally regulate dendritic spine morphology as well as AMPA receptor surface expression in cultured hippocampal neurons. One CPEB target mRNA is that encoding GluN2A, which is an NMDA receptor subunit and a critical regulator of synapse function and plasticity. We found that GluN2A mRNA is localized to dendrites and associates with CPEB. The dendritic transport and local translation of GluN2A mRNA is regulated target sequence within GluN2A mRNA. The CPEB-associated poly(A) polymerase promotes dendritic GluN2A protein expression and surface expression of GluN2A-containing NMDA receptors; whereas, the negative translation factor neuroguidin inhibits GluN2A expression in dendrites and at the cell surface. Moreover, protein synthesis and this poly(A) polymerase are required for activity-induced translation of GluN2A and membrane insertion of GluN2A-containing NMDA receptors. These results identify a pivotal role for dendritic mRNA polyadenylation and the opposing effects of CPEB-associated translation factors in regulating receptor expression and synapse structure at glutamatergic synapses as well as activity-induced membrane insertion of NMDA receptors during synaptic plasticity.