Rajman, Marek ORCID: 0000-0001-9060-2432, Metge, Franziska, Fiore, Roberto, Khudayberdiev, Sharof, Aksoy-Aksel, Ayla, Bicker, Silvia, Reschke, Cristina Ruedell, Raoof, Rana ORCID: 0000-0001-5418-1407, Brennan, Gary P., Delanty, Norman, Farrell, Michael A., O'Brien, Donncha F., Bauer, Sebastian, Norwood, Braxton, Veno, Morten T., Krueger, Marcus, Braun, Thomas ORCID: 0000-0002-6165-4804, Kjems, Jorgen ORCID: 0000-0003-4128-9317, Rosenow, Felix, Henshall, David C., Dieterich, Christoph and Schratt, Gerhard (2017). A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses. Embo J., 36 (12). S. 1770 - 1788. HOBOKEN: WILEY. ISSN 1460-2075

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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 activitydependent miRNA/RBP crosstalk during synaptic scaling, with potential implications for neural network homeostasis and epileptogenesis.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rajman, MarekUNSPECIFIEDorcid.org/0000-0001-9060-2432UNSPECIFIED
Metge, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fiore, RobertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khudayberdiev, SharofUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aksoy-Aksel, AylaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bicker, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reschke, Cristina RuedellUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raoof, RanaUNSPECIFIEDorcid.org/0000-0001-5418-1407UNSPECIFIED
Brennan, Gary P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delanty, NormanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Farrell, Michael A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Brien, Donncha F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bauer, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Norwood, BraxtonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Veno, Morten T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, ThomasUNSPECIFIEDorcid.org/0000-0002-6165-4804UNSPECIFIED
Kjems, JorgenUNSPECIFIEDorcid.org/0000-0003-4128-9317UNSPECIFIED
Rosenow, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henshall, David C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dieterich, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schratt, GerhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-227723
DOI: 10.15252/embj.201695748
Journal or Publication Title: Embo J.
Volume: 36
Number: 12
Page Range: S. 1770 - 1788
Date: 2017
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DENDRITIC SPINE DEVELOPMENT; MESSENGER-RNA LOCALIZATION; SYNAPTIC PLASTICITY; STATUS EPILEPTICUS; MAMMALIAN BRAIN; AMPA RECEPTORS; VISUAL-CORTEX; EXPRESSION; MICRORNAS; PROTEINSMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22772

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