title: The pattern of cortical dysfunction in a mouse model of a schizophrenia-related microdeletion.
abstract: We used a mouse model of the schizophrenia-predisposing 22q11.2 microdeletion to evaluate how this genetic lesion affects cortical neural circuits at the synaptic, cellular, and molecular levels. Guided by cognitive deficits, we demonstrated that mutant mice display robust deficits in high-frequency synaptic transmission and short-term plasticity (synaptic depression and potentiation), as well as alterations in long-term plasticity and dendritic spine stability. Apart from previously reported reduction in dendritic complexity of layer 5 pyramidal neurons, altered synaptic plasticity occurs in the context of relatively circumscribed and often subtle cytoarchitectural changes in neuronal density and inhibitory neuron numbers. We confirmed the pronounced DiGeorge critical region 8 (Dgcr8)-dependent deficits in primary micro-RNA processing and identified additional changes in gene expression and RNA splicing that may underlie the effects of this mutation. Reduction in Dgcr8 levels appears to be a major driver of altered short-term synaptic plasticity in prefrontal cortex and working memory but not of long-term plasticity and cytoarchitecture. Our findings inform the cortical synaptic and neuronal mechanisms of working memory impairment in the context of psychiatric disorders. They also provide insight into the link between micro-RNA dysregulation and genetic liability to schizophrenia and cognitive dysfunction.
authors.affiliation: Departments of Physiology and Cellular Biophysics, Psychiatry, and Neuroscience, Columbia University Medical Center, New York, New York 10032, Integrated Program in Cellular, Molecular, and Biophysical Studies, Columbia University, New York, New York 10032, New York State Psychiatric Institute, New York, New York 10032, The Simons Foundation Autism Research Initiative, New York, New York 10010, and Molecular Neurobiology Program, Skirball Institute, Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016.
authors.forename: Karine
authors.initials: K
authors.lastname: Fénelon
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Cora S
authors.initials: CS
authors.lastname: Lai
authors.forename: Jun
authors.initials: J
authors.lastname: Mukai
authors.forename: Sander
authors.initials: S
authors.lastname: Markx
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Stark
authors.forename: Pei-Ken
authors.initials: PK
authors.lastname: Hsu
authors.forename: Wen-Biao
authors.initials: WB
authors.lastname: Gan
authors.forename: Gerald D
authors.initials: GD
authors.lastname: Fischbach
authors.forename: Amy B
authors.initials: AB
authors.lastname: MacDermott
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D049229:Dendritic Spines / Q000473:pathology / Q000648:ultrastructure; D004062:DiGeorge Syndrome / Q000150:complications / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics*; D036881:Long-Term Synaptic Depression / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017397:Prefrontal Cortex / Q000473:pathology*; D011506:Proteins / Q000235:genetics; D016601:RNA-Binding Proteins; D021641:Recognition, Psychology / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: C474044:Dgcr8 protein, mouse; D011506:Proteins; D016601:RNA-Binding Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D010751:Phosphopyruvate Hydratase; C506947:Atp2a2 protein, mouse
references.citation: Hum Mol Genet. 2008 Apr 15;17(8):1156-68
references.pmid: 18184693
references.citation: Neuropsychologia. 2007 Sep 20;45(12):2863-73
references.pmid: 17618656
references.citation: Nat Genet. 2008 Jul;40(7):880-5
references.pmid: 18511947
references.citation: Nat Rev Neurosci. 2010 Jun;11(6):402-16
references.pmid: 20485365
references.citation: J Neurosci. 2006 Mar 22;26(12):3169-81
references.pmid: 16554468
references.citation: Prog Brain Res. 2008;169:199-207
references.pmid: 18394475
references.citation: J Neurosci. 2011 Oct 5;31(40):14324-34
references.pmid: 21976518
references.citation: PLoS One. 2011;6(6):e21635
references.pmid: 21738743
references.citation: Neurosci Res. 1994 Jul;20(1):15-25
references.pmid: 7984337
references.citation: Prog Brain Res. 1990;83:223-32
references.pmid: 2203099
references.citation: Nat Struct Mol Biol. 2012 Aug;19(8):760-6
references.pmid: 22796965
references.citation: Trends Neurosci. 2012 Jan;35(1):3-13
references.pmid: 22177981
references.citation: Neuroscience. 2003;117(3):681-95
references.pmid: 12617972
references.citation: Curr Top Behav Neurosci. 2010;4:629-56
references.pmid: 21312416
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1349-58
references.pmid: 22049344
references.citation: J Neurophysiol. 2000 May;83(5):3031-41
references.pmid: 10805698
references.citation: Nat Neurosci. 2012 Dec;15(12):1723-8
references.pmid: 23143521
references.citation: Nat Genet. 2008 Jun;40(6):751-60
references.pmid: 18469815
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W755-62
references.pmid: 20513647
references.citation: Brief Bioinform. 2011 Nov;12(6):634-44
references.pmid: 21498550
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7612-6
references.pmid: 7644464
references.citation: Nat Neurosci. 2012 Jun 17;15(7):962-9
references.pmid: 22706270
references.citation: J Neurosci. 1996 Aug 15;16(16):5154-67
references.pmid: 8756444
references.citation: PLoS Biol. 2011 May;9(5):e1001060
references.pmid: 21572988
references.citation: Genome Biol. 2007;8(2):R27
references.pmid: 17326821
references.citation: Biol Psychiatry. 2011 Jan 15;69(2):188-93
references.pmid: 21183010
references.citation: PLoS One. 2012;7(7):e40663
references.pmid: 22844407
references.citation: Nat Neurosci. 2008 Nov;11(11):1302-10
references.pmid: 18836441
references.citation: J Biol Chem. 2011 Aug 26;286(34):29556-67
references.pmid: 21730062
references.citation: Annu Rev Physiol. 2009;71:261-82
references.pmid: 19575680
references.citation: RNA. 2002 Apr;8(4):426-39
references.pmid: 11991638
references.citation: Neuroscience. 2005;136(3):661-80
references.pmid: 16344143
references.citation: Schizophr Bull. 2010 Mar;36(2):289-300
references.pmid: 20026558
references.citation: Proc R Soc Lond B Biol Sci. 1978 May 16;201(1144):219-48
references.pmid: 27801
references.citation: Dev Neurobiol. 2008 May;68(6):771-8
references.pmid: 18383548
references.citation: Genes Dev. 2010 Sep 1;24(17):1951-60
references.pmid: 20713509
references.citation: Neuron. 2006 Oct 5;52(1):179-96
references.pmid: 17015235
references.citation: PLoS Genet. 2011 Oct;7(10):e1002330
references.pmid: 22028668
references.citation: Nat Genet. 2012 Dec;44(12):1365-9
references.pmid: 23042115
references.citation: Mol Psychiatry. 2012 Jul;17(8):827-40
references.pmid: 21727898
references.citation: J Physiol. 2003 Jul 15;550(Pt 2):459-92
references.pmid: 12794181
references.citation: Trends Cogn Sci. 2012 Jan;16(1):27-34
references.pmid: 22169777
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4447-52
references.pmid: 21368174
references.citation: J Neurophysiol. 1997 Jul;78(1):321-34
references.pmid: 9242283
references.citation: Nature. 2012 Feb 19;483(7387):87-91
references.pmid: 22343895
references.citation: Am J Med Genet. 1998 Jul 10;81(4):328-37
references.pmid: 9674980
references.citation: BMC Syst Biol. 2007 Nov 21;1:54
references.pmid: 18031580
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3125-30
references.pmid: 22315408
references.citation: J Physiol. 1990 Aug;427:31-49
references.pmid: 2213602
references.citation: Nat Protoc. 2010 Feb;5(2):201-8
references.pmid: 20134419
references.citation: Prog Brain Res. 1991;87:201-11
references.pmid: 1907745
references.citation: J Neurochem. 2009 Feb;108(3):662-75
references.pmid: 19187093
references.citation: Mol Cell Neurosci. 2011 Aug;47(4):293-305
references.pmid: 21635953
references.citation: Neurobiol Dis. 2012 May;46(2):291-301
references.pmid: 22406400
references.citation: J Neurosci. 2012 Oct 10;32(41):14132-44
references.pmid: 23055483
references.citation: Proc Natl Acad Sci U S A. 2008 May 13;105(19):7076-81
references.pmid: 18458327
references.citation: Nature. 2010 Apr 1;464(7289):763-7
references.pmid: 20360742
references.citation: Trends Neurosci. 2001 Feb;24(2):99-106
references.pmid: 11164940
references.citation: Ann N Y Acad Sci. 1995 Dec 15;769:71-83
references.pmid: 8595045
references.citation: Nat Neurosci. 2012 May 25;15(6):811-2
references.pmid: 22627793
references.citation: Stat Appl Genet Mol Biol. 2005;4:Article17
references.pmid: 16646834
references.citation: J Biol Chem. 2011 May 13;286(19):16693-706
references.pmid: 21454531
references.citation: Cereb Cortex. 2009 Jan;19(1):115-26
references.pmid: 18483006
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16906-11
references.pmid: 17077150
references.citation: PLoS One. 2012;7(11):e48084
references.pmid: 23152763
references.citation: Trends Neurosci. 2010 Mar;33(3):121-9
references.pmid: 20138375
references.citation: Nat Neurosci. 2008 Jul;11(7):823-33
references.pmid: 18516033
references.citation: Cell. 2013 Jan 17;152(1-2):262-75
references.pmid: 23332760
references.citation: Nature. 2009 Dec 17;462(7275):920-4
references.pmid: 19946265
references.citation: BMC Genomics. 2006 Dec 27;7:325
references.pmid: 17192196
references.citation: Am J Psychiatry. 2003 Sep;160(9):1580-6
references.pmid: 12944331
references.citation: Brain Res. 2010 Jun 18;1338:78-88
references.pmid: 20388499
references.citation: Annu Rev Med. 2012;63:63-80
references.pmid: 22034867
references.citation: Behav Brain Res. 1997 May;85(2):187-201
references.pmid: 9105575
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D202-9
references.pmid: 21037263
references.citation: Neuron. 2000 Oct;28(1):41-51
references.pmid: 11086982
references.citation: Nat Neurosci. 2005 Jan;8(1):34-42
references.pmid: 15608632
references.citation: Neurosci Res. 2005 Oct;53(2):95-103
references.pmid: 16054257