Dataset Information

Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex.

ABSTRACT: 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.

SUBMITTER: Udagawa T

PROVIDER: S-EPMC3408552 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex.

Udagawa Tsuyoshi T Swanger Sharon A SA Takeuchi Koichi K Kim Jong Heon JH Nalavadi Vijayalaxmi V Shin Jihae J Lorenz Lori J LJ Zukin R Suzanne RS Bassell Gary J GJ Richter Joel D JD

Molecular cell 20120621 2

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 polya ...[more]

PMID: 22727665

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Project description:We show that a 2-step phospho/dephosphorylation cycle for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor (AMPAR), as used in in vivo learning experiments to assess long-term potentiation (LTP) induction and establishment, exhibits bistability for a wide range of parameters, consistent with values derived from biological literature. The AMPAR model we propose, hence, is a candidate for memory storage and switching behavior at a molecular-microscopic level. Furthermore, the stochastic formulation of the deterministic model leads to a mesoscopic interpretation by considering the effect of enzymatic fluctuations on the Michelis-Menten average dynamics. Under suitable hypotheses, this leads to a stochastic dynamical system with multiplicative noise whose probability density evolves according to a Fokker-Planck equation in the Stratonovich sense. In this approach, the probability density associated with each AMPAR phosphorylation state allows one to compute the probability of any concentration value, whereas the Michaelis-Menten equations consider the average concentration dynamics. We show that bistable dynamics are robust for multiplicative stochastic perturbations and that the presence of both noise and bistability simulates LTP and long-term depression (LTD) behavior. Interestingly, the LTP part of this model has been experimentally verified as a result of in vivo, one-trial inhibitory avoidance learning protocol in rats, that produced the same changes in hippocampal AMPARs phosphorylation state as observed with in vitro induction of LTP with high-frequency stimulation (HFS). A consequence of this model is the possibility of characterizing a molecular switch with a defined biochemical set of reactions showing bistability and bidirectionality. Thus, this 3-enzymes-based biophysical model can predict LTP as well as LTD and their transition rates. The theoretical results can be, in principle, validated by in vitro and in vivo experiments, such as fluorescence measurements and electrophysiological recordings at multiple scales, from molecules to neurons. A further consequence is that the bistable regime occurs only within certain parametric windows, which may simulate a "history-dependent threshold". This effect might be related to the Bienenstock-Cooper-Munro theory of synaptic plasticity.

Dataset Information

Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex.

Publications

Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex.

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