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

Marek Rajman; Franziska Metge; Roberto Fiore; Sharof Khudayberdiev; Ayla Aksoy-Aksel; Silvia Bicker; Cristina Ruedell Reschke; Rana Raoof; Gary P. Brennan; Norman Delanty; Michael A. Farrell; Donncha F. O'Brien; Sebastian Bauer; Braxton Norwood; Morten T. Veno; Marcus Krueger; Thomas Braun; Jorgen Kjems; Felix Rosenow; David C. Henshall; Christoph Dieterich; Gerhard Schratt

doi:10.15252/embj.201695748

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

Marek Rajman, Franziska Metge, Roberto Fiore, Sharof Khudayberdiev, Ayla Aksoy-Aksel, Silvia Bicker, Cristina Ruedell Reschke, Rana Raoof, Gary P. Brennan, Norman Delanty, Michael A. Farrell, Donncha F. O'Brien, Sebastian Bauer, Braxton Norwood, Morten T. Veno, Marcus Krueger, Thomas Braun, Jorgen Kjems, Felix Rosenow, David C. HenshallChristoph Dieterich, Gerhard Schratt^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Journal	E M B O Journal
Volume	36
Issue	12
Pages (from-to)	1770-1787
Number of pages	18
ISSN	0261-4189
DOIs	https://doi.org/10.15252/embj.201695748
Publication status	Published - 14 Jun 2017

Keywords

epilepsy
homeostatic plasticity
microRNA
RNA-binding protein
synaptic scaling
DENDRITIC SPINE DEVELOPMENT
MESSENGER-RNA LOCALIZATION
SYNAPTIC PLASTICITY
STATUS EPILEPTICUS
MAMMALIAN BRAIN
AMPA RECEPTORS
VISUAL-CORTEX
EXPRESSION
MICRORNAS
PROTEINS

Access to Document

10.15252/embj.201695748

Cite this

Rajman, M., Metge, F., Fiore, R., Khudayberdiev, S., Aksoy-Aksel, A., Bicker, S., Reschke, C. R., Raoof, R., Brennan, G. P., Delanty, N., Farrell, M. A., O'Brien, D. F., Bauer, S., Norwood, B., Veno, M. T., Krueger, M., Braun, T., Kjems, J., Rosenow, F., ... Schratt, G. (2017). A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses. E M B O Journal, 36(12), 1770-1787. https://doi.org/10.15252/embj.201695748

@article{0689f45eec5e458b8acb759a67e7734a,

title = "A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses",

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.",

keywords = "epilepsy, homeostatic plasticity, microRNA, RNA-binding protein, synaptic scaling, DENDRITIC SPINE DEVELOPMENT, MESSENGER-RNA LOCALIZATION, SYNAPTIC PLASTICITY, STATUS EPILEPTICUS, MAMMALIAN BRAIN, AMPA RECEPTORS, VISUAL-CORTEX, EXPRESSION, MICRORNAS, PROTEINS",

author = "Marek Rajman and Franziska Metge and Roberto Fiore and Sharof Khudayberdiev and Ayla Aksoy-Aksel and Silvia Bicker and Reschke, {Cristina Ruedell} and Rana Raoof and Brennan, {Gary P.} and Norman Delanty and Farrell, {Michael A.} and O'Brien, {Donncha F.} and Sebastian Bauer and Braxton Norwood and Veno, {Morten T.} and Marcus Krueger and Thomas Braun and Jorgen Kjems and Felix Rosenow and Henshall, {David C.} and Christoph Dieterich and Gerhard Schratt",

year = "2017",

month = jun,

day = "14",

doi = "10.15252/embj.201695748",

language = "English",

volume = "36",

pages = "1770--1787",

journal = "E M B O Journal",

issn = "0261-4189",

publisher = "Wiley-Blackwell Publishing Ltd.",

number = "12",

}

Rajman, M, Metge, F, Fiore, R, Khudayberdiev, S, Aksoy-Aksel, A, Bicker, S, Reschke, CR, Raoof, R, Brennan, GP, Delanty, N, Farrell, MA, O'Brien, DF, Bauer, S, Norwood, B, Veno, MT, Krueger, M, Braun, T, Kjems, J, Rosenow, F, Henshall, DC, Dieterich, C & Schratt, G 2017, 'A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses', E M B O Journal, vol. 36, no. 12, pp. 1770-1787. https://doi.org/10.15252/embj.201695748

TY - JOUR

T1 - A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses

AU - Rajman, Marek

AU - Metge, Franziska

AU - Fiore, Roberto

AU - Khudayberdiev, Sharof

AU - Aksoy-Aksel, Ayla

AU - Bicker, Silvia

AU - Reschke, Cristina Ruedell

AU - Raoof, Rana

AU - Brennan, Gary P.

AU - Delanty, Norman

AU - Farrell, Michael A.

AU - O'Brien, Donncha F.

AU - Bauer, Sebastian

AU - Norwood, Braxton

AU - Veno, Morten T.

AU - Krueger, Marcus

AU - Braun, Thomas

AU - Kjems, Jorgen

AU - Rosenow, Felix

AU - Henshall, David C.

AU - Dieterich, Christoph

AU - Schratt, Gerhard

PY - 2017/6/14

Y1 - 2017/6/14

N2 - 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.

AB - 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.

KW - epilepsy

KW - homeostatic plasticity

KW - microRNA

KW - RNA-binding protein

KW - synaptic scaling

KW - DENDRITIC SPINE DEVELOPMENT

KW - MESSENGER-RNA LOCALIZATION

KW - SYNAPTIC PLASTICITY

KW - STATUS EPILEPTICUS

KW - MAMMALIAN BRAIN

KW - AMPA RECEPTORS

KW - VISUAL-CORTEX

KW - EXPRESSION

KW - MICRORNAS

KW - PROTEINS

U2 - 10.15252/embj.201695748

DO - 10.15252/embj.201695748

M3 - Journal article

C2 - 28487411

SN - 0261-4189

VL - 36

SP - 1770

EP - 1787

JO - E M B O Journal

JF - E M B O Journal

IS - 12

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this