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Differential regulation of local mRNA dynamics and translation following long-term potentiation and depression.

ABSTRACT: Decades of work have demonstrated that messenger RNAs (mRNAs) are localized and translated within neuronal dendrites and axons to provide proteins for remodeling and maintaining growth cones or synapses. It remains unknown, however, whether specific forms of plasticity differentially regulate the dynamics and translation of individual mRNA species. To address this, we targeted three individual synaptically localized mRNAs, CamkIIa, β-actin, Psd95, and used molecular beacons to track endogenous mRNA movements. We used reporters and CRISPR/Cas9 gene editing to track mRNA translation in cultured neurons. We found alterations in mRNA dynamic properties occurred during two forms of synaptic plasticity, long-term potentiation (cLTP) and depression (mGluR-LTD). Changes in mRNA dynamics following either form of plasticity resulted in an enrichment of mRNA in the vicinity of dendritic spines. Both the reporters and tagging of endogenous proteins revealed the transcript-specific stimulation of protein synthesis following cLTP or mGluR-LTD. As such, the plasticity-induced enrichment of mRNA near synapses could be uncoupled from its translational status. The enrichment of mRNA in the proximity of spines allows for localized signaling pathways to decode plasticity milieus and stimulate a specific translational profile, resulting in a customized remodeling of the synaptic proteome.

SUBMITTER: Donlin-Asp PG

PROVIDER: S-EPMC8020670 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Differential regulation of local mRNA dynamics and translation following long-term potentiation and depression.

Donlin-Asp Paul G PG Polisseni Claudio C Klimek Robin R Heckel Alexander A Schuman Erin M EM

Proceedings of the National Academy of Sciences of the United States of America 20210301 13

Decades of work have demonstrated that messenger RNAs (mRNAs) are localized and translated within neuronal dendrites and axons to provide proteins for remodeling and maintaining growth cones or synapses. It remains unknown, however, whether specific forms of plasticity differentially regulate the dynamics and translation of individual mRNA species. To address this, we targeted three individual synaptically localized mRNAs, CamkIIa, β-actin, Psd95, and used molecular beacons ...[more]

PMID: 33771924

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Project description:Coordinated regulation of gene expression is essential for consolidation of the memory mechanism, long-term potentiation (LTP). Triggering of LTP by N-methyl-D-aspartate receptor (NMDAR) activation rapidly activates constitutive and inducible transcription factors, which promote expression of genes responsible for LTP maintenance. As microRNA (miRNA) coordinate expression of genes related through seed sites, we hypothesize that miRNA contribute to the regulation of the LTP-induced gene response. MiRNA function primarily as negative regulators of gene expression. As LTP induction promotes a generalized rapid up-regulation of gene expression, we predicted a complementary rapid down-regulation of miRNA levels. Accordingly, we carried out global miRNA expression profiling in the rat dentate gyrus 20 min post-LTP induction in vivo. Consistent with our hypothesis, we found a large number of differentially expressed miRNA, the majority down-regulated. Detailed analysis of miR-34a-5p and miR-132-3p revealed this down-regulation was transient and NMDAR-dependent, whereby block of NMDARs released an activity-associated inhibitory mechanism. Furthermore, down-regulation of mature miR-34a-5p and miR-132-3p occurred solely by post-transcriptional mechanisms, occurring despite an associated up-regulation of the pri-miR-132 transcript. To understand how down-regulation of miR-34a-5p and miR-132-3p intersects with the molecular events occurring following LTP, we used bioinformatics to identify potential targets. Previously validated targets included the key LTP-regulated genes Arc and glutamate receptor subunits. Predicted targets included the LTP-linked kinase, Mapk1, and neuropil-associated transcripts Hn1 and Klhl11, which were validated using luciferase reporter assays. Furthermore, we found that the level of p42-Mapk1, the protein encoded by the Mapk1 transcript, was up-regulated following LTP. Together, these data support the interpretation that miRNA, in particular miR-34a-5p and miR-132-3p, make a surprisingly rapid contribution to synaptic plasticity via dis-inhibition of translation of key plasticity-related molecules.

Project description:Ethnopharmacological relevanceRFAP is a compound extraction complex of four Traditional Chinese Medicine (TCM), including the dry bark of Paeonia lactiflora Pall. (Radix Paeoniae Alba), Gardenia jasminoides J. Ellis (Fructus Gardeniae), Albizia julibrissin Durazz. (Albizia julibrissin Durazz), and Paeonia × suffruticosa Andrews (Peony bark). Not only RFAP but also the individual ingredients have been commonly used for the treatment of depression in the clinic. However, the underlying mechanism of pharmacology is difficult to interpret since its holistic and multidrug nature.Aim of the studyThis study aimed to elucidate the potential antidepressant mechanism of RFAP in the treatment of chronic unpredictable mild stress (CUMS) rats' model via the quantitative proteomics approach.Materials and methodsWe established the CUMS rats' model and evaluated the efficacy of RFAP using multiple behavior assays, including the sugar preference test, open field test, and forced swimming test. Then label-free quantitative proteomics analyses were performed to evaluate the integrated changes of proteome profiling in control, CUMS, RFAP low dose, and RFAP high dose groups. Finally, we validated the critical changed proteins in the pathways of long-term depression and potentiation via RT-PCR and Western blotting assays.ResultsWe successfully established the CUMS rats' model. The behavior assays indicated that the rats demonstrated a tendency to behavioral despair after four weeks. Label-free quantitative proteomics showed that 107 proteins were significantly upregulated and 163 proteins were downregulated in the CUMS group compared to the control group. These differentially expressed proteins were involved in long-term potentiation, long-term depression, nervous system development, neuronal synaptic structural constituent of ribosome, ATP metabolic process, learning or memory, and cellular lipid metabolic process. RFAP treatment partially restored the differentially expressed protein profile. The protective effect of RFAP on behavioral assessment were consistent with the results of proteomics.ConclusionsThe results indicated that RFAP exerted a synergistic effect on CUMS by regulating long-term inhibition and potentiation-related proteins.

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Differential regulation of local mRNA dynamics and translation following long-term potentiation and depression.

Publications

Differential regulation of local mRNA dynamics and translation following long-term potentiation and depression.

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