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MicroRNA-34a Acutely Regulates Synaptic Efficacy in the Adult Dentate Gyrus In Vivo

  • Birgitte Berentsen
  • Sudarshan Patil
  • Kine Rønnestad
  • Kevin M. Goff
  • Maciej Pajak
  • T. Ian Simpson
  • Karin Wibrand
  • Clive R. BramhamEmail author
Article

Abstract

Activity-dependent synaptic plasticity involves rapid regulation of neuronal protein synthesis on a time-scale of minutes. miRNA function in synaptic plasticity and memory formation has been elucidated by stable experimental manipulation of miRNA expression and activity using transgenic approaches and viral vectors. However, the impact of rapid miRNA modulation on synaptic efficacy is unknown. Here, we examined the effect of acute (12 min), intrahippocampal infusion of a miR-34a antagonist (antimiR) on medial perforant path-evoked synaptic transmission in the dentate gyrus of adult anesthetised rats. AntimiR-34a infusion acutely depressed medial perforant path-evoked field excitatory post-synaptic potentials (fEPSPs). The fEPSP decrease was detected within 9 min of infusion, lasted for hours, and was associated with knockdown of antimiR-34a levels. AntimiR-34a-induced synaptic depression was sequence-specific; no changes were elicited by infusion of scrambled or mismatch control. The rapid modulation suggests that a target, or set of targets, is regulated by miR-34a. Western blot analysis of dentate gyrus lysates revealed enhanced expression of Arc, a known miR-34a target, and four novel predicted targets (Ctip2, PKI-1α, TCF4 and Ube2g1). Remarkably, antimiR-34a had no effect when infused during the maintenance phase of long-term potentiation. We conclude that miR-34a regulates basal synaptic efficacy in the adult dentate gyrus in vivo. To our knowledge, these in vivo findings are the first to demonstrate acute (< 9 min) regulation of synaptic efficacy in the adult brain by a miRNA.

Keywords

microRNA miR-34a Gene expression Hippocampus Protein synthesis Synaptic plasticity Synaptic efficacy 

Notes

Funding Information

This work was supported by Research Council of Norway (grants 204861 and 249951) to CB. Karin Wibrand was supported by a grant from Bergen Medical Research Foundation (BMFS). Sudarshan Patil was supported by the University of Bergen. Maciej Pajak was funded by grants EP/F500385/1 and BB/F529254/1

Supplementary material

12035_2019_1816_MOESM1_ESM.xlsx (41 kb)
ESM 1 (XLSX 41.3 kb)

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Authors and Affiliations

  1. 1.Department of BiomedicineUniversity of BergenBergenNorway
  2. 2.KG Jebsen Centre for Neuropsychiatric DisordersUniversity of BergenBergenNorway
  3. 3.Institute for Adaptive and Neural Computation, School of InformaticsUniversity of EdinburghEdinburghUK

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