Neurite-Enriched MicroRNA-218 Stimulates Translation of the GluA2 Subunit and Increases Excitatory Synaptic Strength

  • Anna RocchiEmail author
  • Daniela Moretti
  • Gabriele Lignani
  • Elisabetta Colombo
  • Joachim Scholz-Starke
  • Pietro Baldelli
  • Tatiana Tkatch
  • Fabio Benfenati


Local control of protein translation is a fundamental process for the regulation of synaptic plasticity. It has been demonstrated that the local protein synthesis occurring in axons and dendrites can be shaped by numerous mechanisms, including miRNA-mediated regulation. However, several aspects underlying this regulatory process have not been elucidated yet. Here, we analyze the differential miRNA profile in cell bodies and neurites of primary hippocampal neurons and find an enrichment of the precursor and mature forms of miR-218 in the neuritic projections. We show that miR-218 abundance is regulated during hippocampal development and by chronic silencing or activation of neuronal network. Overexpression and knockdown of miR-218 demonstrated that miR-218 targets the mRNA encoding the GluA2 subunit of AMPA receptors and modulates its expression. At the functional level, miR-218 overexpression increases glutamatergic synaptic transmission at both single neuron and network levels. Our data demonstrate that miR-218 may play a key role in the regulation of AMPA-mediated excitatory transmission and in the homeostatic regulation of synaptic plasticity.


GluA2 Homeostatic plasticity Local translation Neurite-specific microRNAs 



We thank Luigi Naldini for kindly providing lentiviral vectors; Monica Morini, Riccardo Navone (Italian Institute of Technology, Genova, Italy), and Michele Cilli (IRCCS San Martino, Genova, Italy) for help in breeding the mice; and Arta Mehilli (Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, Genova, Italy) for assistance in the preparation of primary cultures. This study was supported by research grants from Compagnia di San Paolo (2015.0546 to FB and 2017.0589 to PB), EU FP7 Project “Desire” (Grant agreement n. 602531 to FB) and the Italian Ministry of Health Ricerca Finalizzata (GR-2013-02355540 to AR).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1492_Fig5_ESM.png (109 kb)
Fig. S1

Specificity of the effects of miR-218 on GluA2 3′UTR in HEK293T cells. (A) Luciferase expression was used to monitor the dose-dependent effect of miR-218 mimic on GluA2 3’UTR in HEK293T cells that do not endogenously express GluA2. Scr, scrambled miRNA control. (B) Effect of miR-218 and miR-218 inhibitor (anti-miR-218) on the wild type and mutated forms of Gria2 3′UTR. Data are shown as means ± sem (n = 4). * p < 0.05, ** p < 0.01; unpaired Student’s t test. (PNG 108 kb)

12035_2019_1492_MOESM1_ESM.tif (37.6 mb)
High Resolution Image (TIF 38480 kb)
12035_2019_1492_Fig7_ESM.png (26 kb)
Fig. S2

Luciferase mRNA is not affected by miR-218 overexpression. Real time PCR analysis of luciferase transcript level in hippocampal neurons overexpressing miR-218 mimic as compared to the respective scrambled sequence (Scr). Data are shown as means ± sem (n = 4). (PNG 26 kb)

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High Resolution Image (TIF 4890 kb)
12035_2019_1492_Fig8_ESM.png (153 kb)
Fig. S3

The effects of miR-218 on network activity are mediated by an increase in AMPA transmission. (A) Representative raster plots of the network electrical activity recorded in neurons expressing scrambled sequence (black), miR-218 (red) or miR-218 (green) in presence of the specific AMPA glutamate receptor inhibitor CNQX (20 μM) . (B) The overall activity of the network under the various experimental conditions is expressed as the cumulative firing rates recorded over a period of 200 s (Hz) weighted on the number of active electrodes. Data are means ± sem (n = 3 independent preparations). * p < 0.05; ** p < 0.01; one-way ANOVA/Bonferroni’s multiple comparison test. (PNG 153 kb)

12035_2019_1492_MOESM3_ESM.tif (42 mb)
High Resolution Image (TIF 42968 kb)
12035_2019_1492_MOESM4_ESM.xlsx (11 kb)
ESM 1 (XLSX 11 kb)
12035_2019_1492_MOESM5_ESM.xlsx (11 kb)
ESM 2 (XLSX 10 kb)


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Authors and Affiliations

  1. 1.Center for Synaptic Neuroscience and TechnologyIstituto Italiano di TecnologiaGenoaItaly
  2. 2.IRCSS Ospedale Policlinico San MartinoGenoaItaly
  3. 3.Department of Experimental Medicine, Section of PhysiologyUniversity of GenoaGenoaItaly
  4. 4.Institute of Neurology, Department of Clinical and Experimental EpilepsyUniversity College LondonLondonUK
  5. 5.Consiglio Nazionale delle RicercheInstitute of BiophysicsGenoaItaly

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