Format

Send to

Choose Destination
EMBO J. 2017 Jun 14;36(12):1770-1787. doi: 10.15252/embj.201695748. Epub 2017 May 9.

A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses.

Author information

1
Biochemisch-Pharmakologisches Centrum, Institut für Physiologische Chemie, Philipps-Universität Marburg, Marburg, Germany.
2
Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology, Department of Internal Medicine III, German Center for Cardiovascular Research (DZHK), University Hospital Heidelberg, Heidelberg, Germany.
3
Physiology & Medical Physics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
4
Beaumont Hospital, Dublin, Ireland.
5
Epilepsiezentrum Frankfurt Rhein-Main, Neurozentrum, Goethe-Universität Frankfurt, Frankfurt, Germany.
6
Epilepsiezentrum Hessen - Marburg, Philipps-Universität Marburg, Marburg, Germany.
7
Department of Molecular Biology and Genetics and Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark.
8
Institute for Genetics, University of Cologne, Cologne, Germany.
9
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
10
Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
11
Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
12
Biochemisch-Pharmakologisches Centrum, Institut für Physiologische Chemie, Philipps-Universität Marburg, Marburg, Germany schratt@staff.uni-marburg.de.

Abstract

Synaptic downscaling is a homeostatic mechanism that allows neurons to reduce firing rates during chronically elevated network activity. Although synaptic downscaling is important in neural circuit development and epilepsy, the underlying mechanisms are poorly described. We performed small RNA profiling in picrotoxin (PTX)-treated hippocampal neurons, a model of synaptic downscaling. Thereby, we identified eight microRNAs (miRNAs) that were increased in response to PTX, including miR-129-5p, whose inhibition blocked synaptic downscaling in vitro and reduced epileptic seizure severity in vivo Using transcriptome, proteome, and bioinformatic analysis, we identified the calcium pump Atp2b4 and doublecortin (Dcx) as miR-129-5p targets. Restoring Atp2b4 and Dcx expression was sufficient to prevent synaptic downscaling in PTX-treated neurons. Furthermore, we characterized a functional crosstalk between miR-129-5p and the RNA-binding protein (RBP) Rbfox1. In the absence of PTX, Rbfox1 promoted the expression of Atp2b4 and Dcx. Upon PTX treatment, Rbfox1 expression was downregulated by miR-129-5p, thereby allowing the repression of Atp2b4 and Dcx. We therefore identified a novel activity-dependent miRNA/RBP crosstalk during synaptic scaling, with potential implications for neural network homeostasis and epileptogenesis.

KEYWORDS:

RNA‐binding protein; epilepsy; homeostatic plasticity; microRNA; synaptic scaling

PMID:
28487411
PMCID:
PMC5470041
DOI:
10.15252/embj.201695748
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center