title: S-SCAM, a rare copy number variation gene, induces schizophrenia-related endophenotypes in transgenic mouse model.
abstract: Accumulating genetic evidence suggests that schizophrenia (SZ) is associated with individually rare copy number variations (CNVs) of diverse genes, often specific to single cases. However, the causality of these rare mutations remains unknown. One of the rare CNVs found in SZ cohorts is the duplication of Synaptic Scaffolding Molecule (S-SCAM, also called MAGI-2), which encodes a postsynaptic scaffolding protein controlling synaptic AMPA receptor levels, and thus the strength of excitatory synaptic transmission. Here we report that, in a transgenic mouse model simulating the duplication conditions, elevation of S-SCAM levels in excitatory neurons of the forebrain was sufficient to induce multiple SZ-related endophenotypes. S-SCAM transgenic mice showed an increased number of lateral ventricles and a reduced number of parvalbumin-stained neurons. In addition, the mice exhibited SZ-like behavioral abnormalities, including hyperlocomotor activity, deficits in prepulse inhibition, increased anxiety, impaired social interaction, and working memory deficit. Notably, the S-SCAM transgenic mice showed a unique sex difference in showing these behavioral symptoms, which is reminiscent of human conditions. These behavioral abnormalities were accompanied by hyperglutamatergic function associated with increased synaptic AMPA receptor levels and impaired long-term potentiation. Importantly, reducing glutamate release by the group 2 metabotropic glutamate receptor agonist LY379268 ameliorated the working memory deficits in the transgenic mice, suggesting that hyperglutamatergic function underlies the cognitive functional deficits. Together, these results contribute to validate a causal relationship of the rare S-SCAM CNV and provide supporting evidence for the rare CNV hypothesis in SZ pathogenesis. Furthermore, the S-SCAM transgenic mice provide a valuable new animal model for studying SZ pathogenesis.
authors: Department of Pharmacology and Toxicology, and.
authors: Nanyan
authors: N
authors: Zhang
authors: Department of Pharmacology and Toxicology, and.
authors: Peng
authors: P
authors: Zhong
authors: Department of Pharmacology and Toxicology, and.
authors: Seung Min
authors: SM
authors: Shin
authors: Department of Pharmacology and Toxicology, and.
authors: Jacob
authors: J
authors: Metallo
authors: Department of Pharmacology and Toxicology, and.
authors: Eric
authors: E
authors: Danielson
authors: Department of Pharmacology and Toxicology, and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors: Christopher M
authors: http://orcid.org/0000-0003-2700-0310
authors: CM
authors: Olsen
authors: Department of Pharmacology and Toxicology, and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors: Qing-song
authors: QS
authors: Liu
authors: Department of Pharmacology and Toxicology, and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 shlee@mcw.edu.
authors: Sang H
authors: SH
authors: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001007:Anxiety; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D056915:DNA Copy Number Variations; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism*; D008124:Locomotion; D017774:Long-Term Potentiation; D008297:Male; D018782:Maze Learning; D008570:Memory, Short-Term; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018091:Receptors, AMPA / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012737:Sex Factors; D012919:Social Behavior; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D010320:Parvalbumins; D018091:Receptors, AMPA; D018698:Glutamic Acid; D051528:Guanylate Kinases; C405684:Magi2 protein, mouse
keywords: CNV; S-SCAM/MAGI-2; animal model; glutamatergic; schizophrenia; sexual dimorphism
references: Schizophr Res. 2004 Dec 15;72(1):29-39
references: 15531405
references: Neuron. 2011 Dec 22;72(6):951-63
references: 22196331
references: J Chem Neuroanat. 2001 Jul;22(1-2):95-100
references: 11470557
references: J Neurosci. 2002 Feb 1;22(3):757-65
references: 11826105
references: Nat Rev Neurosci. 2012 Feb;13(2):107-20
references: 22251963
references: Mol Psychiatry. 2012 Feb;17(2):142-53
references: 22083728
references: J Biol Chem. 2003 Oct 24;278(43):42313-20
references: 12896967
references: Schizophr Bull. 2014 Sep;40(5):952-7
references: 25053651
references: J Cell Biol. 1983 May;96(5):1374-88
references: 6404912
references: Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6
references: 17675407
references: J Neurosci. 2012 May 16;32(20):6967-80
references: 22593065
references: Neuroscience. 2013 Oct 22;251:90-107
references: 22546337
references: J Neurophysiol. 2003 Mar;89(3):1414-22
references: 12626620
references: PLoS Genet. 2009 Feb;5(2):e1000373
references: 19197363
references: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4507-12
references: 19240213
references: Schizophr Res. 2012 Nov;141(2-3):179-84
references: 22998932
references: Ann Neurol. 2000 Oct;48(4):556-66
references: 11026439
references: Arch Gen Psychiatry. 1991 Nov;48(11):996-1001
references: 1747023
references: Schizophr Res. 2009 May;110(1-3):1-23
references: 19328655
references: Arch Gen Psychiatry. 1990 Feb;47(2):181-8
references: 2405807
references: Neuropsychopharmacology. 2011 Jan;36(1):251-73
references: 20861829
references: Science. 2008 Apr 25;320(5875):539-43
references: 18369103
references: Mol Psychiatry. 2013 Jan;18(1):38-52
references: 22547114
references: Nat Neurosci. 2012 Dec;15(12):1723-8
references: 23143521
references: Nat Protoc. 2006;1(3):1117-9
references: 17406392
references: Front Mol Neurosci. 2008 Apr 08;1:6
references: 18946539
references: J Neurosci. 2013 Dec 4;33(49):19295-303
references: 24305825
references: Biol Psychiatry. 2012 May 15;71(10):922-30
references: 22381734
references: Neuropsychopharmacology. 2011 Sep;36(10):2103-10
references: 21677653
references: Cell. 2001 Nov 30;107(5):617-29
references: 11733061
references: Br J Pharmacol. 2011 Oct;164(4):1162-94
references: 21449915
references: Mol Psychiatry. 2008 Feb;13(2):162-72
references: 17579610
references: PLoS One. 2012;7(9):e46604
references: 23029555
references: PLoS One. 2012;7(5):e36836
references: 22649501
references: J Biol Chem. 2000 Feb 25;275(8):5485-92
references: 10681527
references: Curr Opin Psychiatry. 2012 Mar;25(2):89-95
references: 22249082
references: J Pharmacol Exp Ther. 2009 Nov;331(2):591-7
references: 19666749
references: Biol Psychiatry. 2001 Jul 15;50(2):84-97
references: 11526999
references: Neuroscience. 2003;117(3):697-706
references: 12617973
references: J Med Chem. 1999 Mar 25;42(6):1027-40
references: 10090786
references: Int Rev Psychiatry. 2010;22(5):417-28
references: 21047156
references: Neuropharmacology. 2001 Nov;41(6):680-92
references: 11640922
references: J Neurosci. 2011 Feb 16;31(7):2675-87
references: 21325536
references: J Neurochem. 2004 Jul;90(2):332-9
references: 15228590
references: Curr Opin Pharmacol. 2006 Feb;6(1):18-23
references: 16376150
references: Neuroscience. 2013 Jun 3;239:67-83
references: 23085218
references: Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11116-21
references: 20534458
references: Nature. 2010 Apr 29;464(7293):1376-80
references: 20393464
references: Front Cell Neurosci. 2014 Oct 27;8:327
references: 25386117
references: Am J Hum Genet. 2002 Oct;71(4):877-92
references: 12145742
references: Nat Rev Neurosci. 2005 Apr;6(4):312-24
references: 15803162
references: Mol Psychiatry. 2008 Feb;13(2):173-86, 115
references: 17848917
references: Cell. 1996 Dec 27;87(7):1317-26
references: 8980237
references: J Biol Chem. 1998 Aug 14;273(33):21105-10
references: 9694864
references: Cereb Cortex. 2003 Mar;13(3):252-64
references: 12571115
references: Neuron. 2013 May 22;78(4):644-57
references: 23719163
references: Hum Mol Genet. 2011 Aug 1;20(15):3042-51
references: 21551456
references: Neurosci Biobehav Rev. 2004 Sep;28(5):497-505
references: 15465137
references: Neuron. 2000 Aug;27(2):219-25
references: 10985343
references: Trends Neurosci. 2012 Jan;35(1):57-67
references: 22154068
references: Biol Psychiatry. 1999 May 1;45(9):1099-119
references: 10331102
references: Neurosci Res. 2003 Jun;46(2):127-34
references: 12767475
references: J Neurosci. 2009 Sep 30;29(39):12255-64
references: 19793984
references: Cell. 2014 May 22;157(5):1216-29
references: 24855953
references: Hum Mol Genet. 2000 May 22;9(9):1415-23
references: 10814723
references: Nat Rev Neurosci. 2008 Jun;9(6):437-52
references: 18478032
references: J Neural Transm (Vienna). 2002 May;109(5-6):881-9
references: 12111475
references: J Neurochem. 2007 Jan;100(1):154-66
references: 17059560
references: Neuron. 2007 May 24;54(4):583-97
references: 17521571
references: Neuron. 2013 Apr 10;78(1):81-93
references: 23583108
references: Genes Brain Behav. 2004 Oct;3(5):287-302
references: 15344922