title: MiR-134-dependent regulation of Pumilio-2 is necessary for homeostatic synaptic depression.
abstract: Neurons employ a set of homeostatic plasticity mechanisms to counterbalance altered levels of network activity. The molecular mechanisms underlying homeostatic plasticity in response to increased network excitability are still poorly understood. Here, we describe a sequential homeostatic synaptic depression mechanism in primary hippocampal neurons involving miRNA-dependent translational regulation. This mechanism consists of an initial phase of synapse elimination followed by a reinforcing phase of synaptic downscaling. The activity-regulated microRNA miR-134 is necessary for both synapse elimination and the structural rearrangements leading to synaptic downscaling. Results from miR-134 inhibition further uncover a differential requirement for GluA1/2 subunits for the functional expression of homeostatic synaptic depression. Downregulation of the miR-134 target Pumilio-2 in response to chronic activity, which selectively occurs in the synapto-dendritic compartment, is required for miR-134-mediated homeostatic synaptic depression. We further identified polo-like kinase 2 (Plk2) as a novel target of Pumilio-2 involved in the control of GluA2 surface expression. In summary, we have described a novel pathway of homeostatic plasticity that stabilizes neuronal circuits in response to increased network activity.
authors.affiliation: Institut für Physiologische Chemie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Marburg, Germany.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fiore
authors.affiliation: Institut für Physiologische Chemie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Marburg, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Rajman
authors.affiliation: Institut für Physiologie und Pathophysiologie, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Chrysovalandis
authors.initials: C
authors.lastname: Schwale
authors.affiliation: Institut für Physiologische Chemie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Marburg, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bicker
authors.affiliation: Institut für Physiologische Chemie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Marburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Antoniou
authors.affiliation: Institut für Physiologie und Pathophysiologie, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Bruehl
authors.affiliation: Institut für Physiologie und Pathophysiologie, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Draguhn
authors.affiliation: Institut für Physiologische Chemie, Biochemisch-Pharmakologisches Centrum Marburg, Philipps-Universität Marburg, Marburg, Germany schratt@staff.uni-marburg.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schratt
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D047468:Immunoprecipitation; D035683:MicroRNAs / Q000235:genetics*; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000502:physiology*
chemical_list: C581995:MIRN134 microRNA, rat; D035683:MicroRNAs; C539713:PUM2 protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA
keywords: Pum2; homeostatic plasticity; miR‐134; microRNA; neuronal activity
references.citation: EMBO J. 2009 Mar 18;28(6):697-710
references.pmid: 19197241
references.citation: J Neurophysiol. 2006 Oct;96(4):2127-33
references.pmid: 16760351
references.citation: Cell. 2006 May 19;125(4):785-99
references.pmid: 16713568
references.citation: Nature. 2006 Jan 19;439(7074):283-9
references.pmid: 16421561
references.citation: J Neurosci. 2006 Dec 20;26(51):13390-9
references.pmid: 17182790
references.citation: J Neurosci. 2008 Jun 25;28(26):6583-91
references.pmid: 18579731
references.citation: J Neurosci. 2006 Jun 14;26(24):6496-508
references.pmid: 16775137
references.citation: Genes Dev. 2010 Jul 1;24(13):1339-44
references.pmid: 20595229
references.citation: J Neurosci. 2013 Aug 7;33(32):13179-89
references.pmid: 23926271
references.citation: Nature. 2002 Nov 28;420(6914):414-8
references.pmid: 12459783
references.citation: Nat Neurosci. 2004 Dec;7(12):1353-9
references.pmid: 15543139
references.citation: Cold Spring Harb Perspect Biol. 2012 Jan 01;4(1):a005736
references.pmid: 22086977
references.citation: Nat Neurosci. 2000 Nov;3 Suppl:1178-83
references.pmid: 11127835
references.citation: Cell. 2008 Oct 31;135(3):422-35
references.pmid: 18984155
references.citation: Neuron. 2008 Mar 27;57(6):819-26
references.pmid: 18367083
references.citation: Nat Cell Biol. 2009 Jun;11(6):705-16
references.pmid: 19465924
references.citation: Nat Med. 2012 Jul;18(7):1087-94
references.pmid: 22683779
references.citation: Genes Dev. 2013 May 1;27(9):991-6
references.pmid: 23651854
references.citation: Neuron. 2006 Feb 16;49(4):563-75
references.pmid: 16476665
references.citation: Nat Rev Neurosci. 2006 Jul;7(7):563-74
references.pmid: 16791145
references.citation: Neuron. 2007 Jan 18;53(2):217-32
references.pmid: 17224404
references.citation: Nature. 2008 Oct 16;455(7215):912-8
references.pmid: 18923513
references.citation: Nat Neurosci. 2010 Oct;13(10):1199-207
references.pmid: 20802490
references.citation: J Neurosci. 2013 Jun 5;33(23):9644-54
references.pmid: 23739961
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D180-6
references.pmid: 22086949
references.citation: J Neurosci. 2004 Oct 6;24(40):8695-703
references.pmid: 15470135
references.citation: Nature. 2003 Aug 7;424(6949):677-81
references.pmid: 12904794
references.citation: Science. 2003 Nov 21;302(5649):1368-73
references.pmid: 14576440
references.citation: Neuron. 2013 Oct 16;80(2):327-34
references.pmid: 24139037
references.citation: J Neurosci. 2004 Aug 18;24(33):7366-77
references.pmid: 15317862
references.citation: Nature. 2010 Aug 26;466(7310):1105-9
references.pmid: 20622856
references.citation: Neuron. 2010 Nov 4;68(3):512-28
references.pmid: 21040851
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3222-7
references.pmid: 20133610
references.citation: Neuron. 2013 Oct 16;80(2):335-42
references.pmid: 24139038
references.citation: Neuron. 2008 May 22;58(4):571-83
references.pmid: 18498738
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11650-5
references.pmid: 21697510
references.citation: Cell. 2010 Apr 2;141(1):129-41
references.pmid: 20371350
references.citation: Curr Opin Neurobiol. 2009 Jun;19(3):327-35
references.pmid: 19640698
references.citation: Cell. 2004 Jan 23;116(2):281-97
references.pmid: 14744438
references.citation: J Neurosci. 1999 Apr 15;19(8):2876-86
references.pmid: 10191305
references.citation: Nat Rev Neurosci. 2009 Dec;10(12):842-9
references.pmid: 19888283
references.citation: Neuron. 2001 Aug 2;31(2):289-303
references.pmid: 11502259
references.citation: Nat Rev Neurosci. 2004 Feb;5(2):97-107
references.pmid: 14735113