title: Distinct cognitive effects and underlying transcriptome changes upon inhibition of individual miRNAs in hippocampal neurons.
abstract: MicroRNAs (miRNA) are small, non-coding RNAs mediating post-transcriptional regulation of gene expression. miRNAs have recently been implicated in hippocampus-dependent functions such as learning and memory, although the roles of individual miRNAs in these processes remain largely unknown. Here, we achieved stable inhibition using AAV-delivered miRNA sponges of individual, highly expressed and brain-enriched miRNAs; miR-124, miR-9 and miR-34, in hippocampal neurons. Molecular and cognitive studies revealed a role for miR-124 in learning and memory. Inhibition of miR-124 resulted in an enhanced spatial learning and working memory capacity, potentially through altered levels of genes linked to synaptic plasticity and neuronal transmission. In contrast, inhibition of miR-9 or miR-34 led to a decreased capacity of spatial learning and of reference memory, respectively. On a molecular level, miR-9 inhibition resulted in altered expression of genes related to cell adhesion, endocytosis and cell death, while miR-34 inhibition caused transcriptome changes linked to neuroactive ligand-receptor transduction and cell communication. In summary, this study establishes distinct roles for individual miRNAs in hippocampal function.
authors.affiliation: Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Josephine
authors.initials: J
authors.lastname: Malmevik
authors.affiliation: Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Petri
authors.affiliation: Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Pina
authors.initials: P
authors.lastname: Knauff
authors.affiliation: Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Per Ludvik
authors.initials: PL
authors.lastname: Brattås
authors.affiliation: Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Åkerblom
authors.affiliation: Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, Sölvegatan 17, 221 84 Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Jakobsson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003071:Cognition; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023061:Gene Order; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D017966:Pyramidal Cells / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D035683:MicroRNAs
references.citation: J Neurosci. 2012 Jun 27;32(26):8879-89
references.pmid: 22745489
references.citation: Nat Rev Neurosci. 2009 Dec;10(12):842-9
references.pmid: 19888283
references.citation: Semin Fetal Neonatal Med. 2012 Dec;17(6):347-52
references.pmid: 22906916
references.citation: Nat Commun. 2013;4:1770
references.pmid: 23612311
references.citation: Nat Neurosci. 2011 Sep;14(9):1125-34
references.pmid: 21857657
references.citation: Curr Biol. 2002 Apr 30;12(9):735-9
references.pmid: 12007417
references.citation: Brain Res. 1998 Nov 30;813(1):50-6
references.pmid: 9824666
references.citation: Neuron. 2012 Aug 9;75(3):363-79
references.pmid: 22884321
references.citation: J Mol Neurosci. 2014 Jan;52(1):148-55
references.pmid: 24166354
references.citation: Nat Methods. 2007 Sep;4(9):721-6
references.pmid: 17694064
references.citation: Nat Methods. 2009 Jan;6(1):63-6
references.pmid: 19043411
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D68-73
references.pmid: 24275495
references.citation: PLoS One. 2012;7(6):e38562
references.pmid: 22701667
references.citation: J Mol Neurosci. 2012 Feb;46(2):324-35
references.pmid: 21720722
references.citation: PLoS One. 2011;6(10):e25068
references.pmid: 21984899
references.citation: PLoS One. 2012;7(8):e42300
references.pmid: 22876314
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D153-9
references.pmid: 25416803
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6415-20
references.pmid: 18434550
references.citation: Hum Mol Genet. 2010 Oct 15;19(20):3959-69
references.pmid: 20660113
references.citation: Cell. 2014 Nov 20;159(5):1153-67
references.pmid: 25416952
references.citation: Intractable Rare Dis Res. 2014 Nov;3(4):118-33
references.pmid: 25606362
references.citation: Nat Neurosci. 2012 Apr 08;:null
references.pmid: 22484572
references.citation: Exp Neurol. 2012 Jun;235(2):397-401
references.pmid: 22178329
references.citation: Neurobiol Learn Mem. 2015 Mar;119:18-33
references.pmid: 25595880
references.citation: Front Neurosci. 2012 Feb 07;6:14
references.pmid: 22347160
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21099-104
references.pmid: 22160706
references.citation: Mol Ther. 2009 Sep;17(9):1574-84
references.pmid: 19584816
references.citation: Nature. 2011 Aug 11;476(7359):228-31
references.pmid: 21753754
references.citation: Cell Stem Cell. 2010 Apr 2;6(4):323-35
references.pmid: 20362537
references.citation: EMBO J. 2011 Oct 19;30(20):4299-308
references.pmid: 21946562
references.citation: Development. 2014 Apr;141(7):1580-8
references.pmid: 24598163
references.citation: PLoS One. 2011;6(5):e19077
references.pmid: 21611182
references.citation: Neurol Sci. 2015 Mar;36(3):403-9
references.pmid: 25348135
references.citation: Nature. 2012 Feb 23;482(7386):519-23
references.pmid: 22343898
references.citation: Nat Biotechnol. 2007 Dec;25(12):1457-67
references.pmid: 18026085
references.citation: Mol Cell. 2014 Oct 2;56(1):104-15
references.pmid: 25263593
references.citation: J Neurosci. 2010 Nov 3;30(44):14835-42
references.pmid: 21048142
references.citation: Cell. 2009 Jan 23;136(2):215-33
references.pmid: 19167326
references.citation: J Alzheimers Dis. 2008 May;14(1):27-41
references.pmid: 18525125
references.citation: Nat Methods. 2015 Aug;12(8):697
references.pmid: 26226356
references.citation: Sci Rep. 2015;5:12609
references.pmid: 26219083
references.citation: Science. 2013 Dec 6;342(6163):1254-8
references.pmid: 24311694
references.citation: Nat Struct Mol Biol. 2009 Apr;16(4):365-71
references.pmid: 19330006
references.citation: Nat Med. 2014 Dec;20(12):1444-51
references.pmid: 25401692