title: Dysregulated nitric oxide signaling as a candidate mechanism of fragile X syndrome and other neuropsychiatric disorders.
abstract: A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.
authors.affiliation: Department of Human Genetics - The Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School Ann Arbor, MI, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Colvin
authors.affiliation: Department of Human Genetics - The Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School Ann Arbor, MI, USA.
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Kwan
keywords: Broca’s speech and language area; anterior cingulate cortex; cerebral neocortex; human fetal brain; neural circuit assembly; neurodevelopmental disorders; nitric oxide signaling; pyramidal neurons
references.citation: Am J Hum Genet. 2014 May 1;94(5):677-94
references.pmid: 24768552
references.citation: Annu Rev Biochem. 1994;63:175-95
references.pmid: 7526779
references.citation: Psychopharmacology (Berl). 2014 Mar;231(6):1217-26
references.pmid: 24232444
references.citation: Acta Paediatr Suppl. 1997 Jul;422:27-33
references.pmid: 9298788
references.citation: Proc Natl Acad Sci U S A. 1997 May 13;94(10):5395-400
references.pmid: 9144248
references.citation: Neuroimage. 2009 Jun;46(2):516-21
references.pmid: 19264140
references.citation: J Cogn Neurosci. 2002 Feb 15;14(2):160-71
references.pmid: 11970783
references.citation: J Neurosci. 2013 Apr 24;33(17):7368-83
references.pmid: 23616543
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50
references.pmid: 12032354
references.citation: Exp Cell Res. 2000 Jul 10;258(1):162-70
references.pmid: 10912798
references.citation: Sci Transl Med. 2012 Sep 19;4(152):152ra127
references.pmid: 22993294
references.citation: Mol Psychiatry. 2014 Jun;19(6):652-8
references.pmid: 24776741
references.citation: Int J Impot Res. 1996 Jun;8(2):47-52
references.pmid: 8858389
references.citation: J Dev Behav Pediatr. 2013 Apr;34(3):147-55
references.pmid: 23572165
references.citation: Biol Psychiatry. 1999 Jun 15;45(12):1542-52
references.pmid: 10376114
references.citation: BMC Neurol. 2010 Oct 11;10:91
references.pmid: 20937127
references.citation: Neuron. 2003 Feb 6;37(3):417-31
references.pmid: 12575950
references.citation: Biol Psychiatry. 2008 Sep 1;64(5):407-18
references.pmid: 18504037
references.citation: Nature. 2011 Oct 26;478(7370):483-9
references.pmid: 22031440
references.citation: Curr Opin Neurobiol. 1997 Jun;7(3):374-8
references.pmid: 9232800
references.citation: Nature. 2014 Feb 13;506(7487):179-84
references.pmid: 24463507
references.citation: Cell. 2013 Nov 21;155(5):1008-21
references.pmid: 24267887
references.citation: Neuroscientist. 2010 Aug;16(4):435-52
references.pmid: 20817920
references.citation: Cell. 2012 May 11;149(4):899-911
references.pmid: 22579290
references.citation: Proc Natl Acad Sci U S A. 1997 May 13;94(10):5401-4
references.pmid: 9144249
references.citation: Neuropharmacology. 2013 Jan;64:114-23
references.pmid: 22776546
references.citation: Cell. 2001 Nov 16;107(4):489-99
references.pmid: 11719189
references.citation: Neurology. 2002 Feb 12;58(3):428-32
references.pmid: 11839843
references.citation: Nat Neurosci. 2007 May;10(5):578-87
references.pmid: 17417632
references.citation: Development. 2012 May;139(9):1535-46
references.pmid: 22492350
references.citation: Neuron. 2007 Dec 20;56(6):955-62
references.pmid: 18093519
references.citation: Biol Psychiatry. 2008 Oct 1;64(7):552-60
references.pmid: 18621359
references.citation: Cell. 2011 Oct 28;147(3):706, 706.e1
references.pmid: 22036574
references.citation: Int Rev Neurobiol. 2013;113:167-205
references.pmid: 24290386
references.citation: J Neurosci. 2011 Apr 13;31(15):5693-8
references.pmid: 21490210
references.citation: J Neurosci. 2002 Oct 15;22(20):8961-70
references.pmid: 12388603
references.citation: Nat Genet. 1993 Jan;3(1):36-43
references.pmid: 8490651
references.citation: Science. 1993 Oct 22;262(5133):563-6
references.pmid: 7692601
references.citation: J Comp Neurol. 2001 Dec 24;441(4):288-301
references.pmid: 11745651
references.citation: Neuroimage. 2012 Jan 2;59(1):238-47
references.pmid: 21840407
references.citation: Neurosci Biobehav Rev. 2012 Jan;36(1):626-44
references.pmid: 21963442
references.citation: Hum Genet. 2012 Nov;131(11):1687-98
references.pmid: 22736078
references.citation: Cell. 1996 Mar 8;84(5):757-67
references.pmid: 8625413
references.citation: Nature. 2009 Oct 15;461(7266):908-15
references.pmid: 19829370
references.citation: J Neurophysiol. 1993 Aug;70(2):453-69
references.pmid: 8410148
references.citation: Learn Mem. 2006 Nov-Dec;13(6):777-82
references.pmid: 17142306
references.citation: Cereb Cortex. 2000 Oct;10(10):1038-44
references.pmid: 11007554
references.citation: Nat Genet. 2011 Sep 18;43(10):969-76
references.pmid: 21926974
references.citation: Cell. 2013 Nov 21;155(5):997-1007
references.pmid: 24267886
references.citation: Cereb Cortex. 2000 Oct;10(10):981-91
references.pmid: 11007549
references.citation: Nitric Oxide. 2004 May;10(3):141-9
references.pmid: 15158693
references.citation: J Neurosci. 2004 Nov 24;24(47):10579-83
references.pmid: 15564573
references.citation: Nature. 2014 Feb 13;506(7487):185-90
references.pmid: 24463508
references.citation: Neuron. 2013 Oct 30;80(3):633-47
references.pmid: 24183016
references.citation: Science. 2012 Sep 14;337(6100):1301-3
references.pmid: 22984058
references.citation: J Neurophysiol. 2001 Jul;86(1):321-5
references.pmid: 11431513
references.citation: Nat Rev Neurosci. 2004 Oct;5(10):793-807
references.pmid: 15378039
references.citation: Science. 2008 Apr 25;320(5875):539-43
references.pmid: 18369103
references.citation: Nat Neurosci. 2011 Mar;14(3):285-93
references.pmid: 21346746
references.citation: Synapse. 2007 Sep;61(9):785-9
references.pmid: 17568429
references.citation: PLoS Biol. 2009 Jan 20;7(1):e16
references.pmid: 19166269
references.citation: Neurosci Lett. 2004 Oct 7;369(1):39-43
references.pmid: 15380304
references.citation: Neuron. 2008 Oct 23;60(2):201-14
references.pmid: 18957214
references.citation: Transl Psychiatry. 2013 Mar 05;3:e237
references.pmid: 23462988
references.citation: Arch Gen Psychiatry. 2009 Jan;66(1):41-50
references.pmid: 19124687
references.citation: Neuron. 2005 Jan 20;45(2):207-21
references.pmid: 15664173
references.citation: J Biol Chem. 2009 Feb 13;284(7):4255-66
references.pmid: 19097999
references.citation: Trends Neurosci. 2014 Feb;37(2):95-105
references.pmid: 24387789
references.citation: Synapse. 2013 Nov;67(11):741-7
references.pmid: 23620198
references.citation: CNS Spectr. 2008 Aug;13(8):663-81
references.pmid: 18704022
references.citation: J Psychiatr Res. 2010 Apr;44(6):364-72
references.pmid: 19837416
references.citation: Trends Neurosci. 1997 Jul;20(7):298-303
references.pmid: 9223222
references.citation: Behav Brain Res. 2005 Oct 14;164(1):11-6
references.pmid: 16076505
references.citation: Trends Cogn Sci. 2011 Feb;15(2):85-93
references.pmid: 21167765
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14374-8
references.pmid: 14614133
references.citation: J Med Genet. 2009 Feb;46(2):94-102
references.pmid: 18835858
references.citation: J Autism Dev Disord. 2014 Apr;44(4):958-64
references.pmid: 24272415
references.citation: Science. 1991 May 24;252(5009):1097-102
references.pmid: 2031184
references.citation: Am J Ment Retard. 2008 Nov;113(6):427-38
references.pmid: 19127654
references.citation: Neuron. 2008 Feb 7;57(3):378-92
references.pmid: 18255031
references.citation: Nat Genet. 2014 Jul;46(7):742-7
references.pmid: 24859339
references.citation: Nat Neurosci. 2004 Dec;7(12):1370-5
references.pmid: 15558064
references.citation: Cereb Cortex. 1996 May-Jun;6(3):342-53
references.pmid: 8670662
references.citation: Philos Trans R Soc Lond B Biol Sci. 2002 Aug 29;357(1424):1123-36
references.pmid: 12217179
references.citation: J Neurosci. 2013 Nov 27;33(48):18979-86
references.pmid: 24285902
references.citation: Trends Neurosci. 2004 Jul;27(7):370-7
references.pmid: 15219735
references.citation: Brain. 2002 May;125(Pt 5):935-51
references.pmid: 11960884
references.citation: Brain Lang. 2009 Apr;109(1):29-48
references.pmid: 19155059
references.citation: Ann Neurol. 2004 Dec;56(6):757-66
references.pmid: 15478219
references.citation: Philos Trans R Soc Lond B Biol Sci. 1996 Oct 29;351(1346):1445-53
references.pmid: 8941956
references.citation: Behav Pharmacol. 2010 Sep;21(5-6):540-7
references.pmid: 20555254
references.citation: Dev Med Child Neurol. 2009 Aug;51(8):593-9
references.pmid: 19416325
references.citation: Cell. 2013 Aug 1;154(3):518-29
references.pmid: 23911319
references.citation: Science. 1987 Jul 24;237(4813):420-3
references.pmid: 3603029
references.citation: J Cogn Neurosci. 2014 Mar;26(3):551-68
references.pmid: 24144246
references.citation: Science. 2000 May 19;288(5469):1254-7
references.pmid: 10818003
references.citation: Early Hum Dev. 2006 Apr;82(4):257-66
references.pmid: 16360292
references.citation: Neuropsychobiology. 2014;69(1):52-8
references.pmid: 24457222
references.citation: Neuron. 2009 May 28;62(4):494-509
references.pmid: 19477152
references.citation: Nat Genet. 1993 Aug;4(4):335-40
references.pmid: 8401578
references.citation: Sci Transl Med. 2011 Jan 5;3(64):64ra1
references.pmid: 21209411
references.citation: Science. 2003 Oct 31;302(5646):826-30
references.pmid: 14593168
references.citation: J Med Genet. 2009 Apr;46(4):266-71
references.pmid: 19126569
references.citation: Hum Psychopharmacol. 2008 Jan;23 Suppl 1:15-26
references.pmid: 18098217
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
references.pmid: 9843981
references.citation: Metab Brain Dis. 2012 Sep;27(3):337-40
references.pmid: 22359075
references.citation: Eur J Neurosci. 2008 Jun;27(11):2783-802
references.pmid: 18588525
references.citation: Neuroreport. 1997 Mar 3;8(4):1057-61
references.pmid: 9141092
references.citation: Science. 1999 Jun 11;284(5421):1845-8
references.pmid: 10364559
references.citation: Lancet. 2013 Apr 20;381(9875):1371-1379
references.pmid: 23453885
references.citation: Neuron. 2011 Nov 17;72(4):665-78
references.pmid: 22099467
references.citation: Br J Pharmacol. 2009 Jul;157(6):881-91
references.pmid: 19438508
references.citation: Science. 2005 Feb 18;307(5712):1118-21
references.pmid: 15718473
references.citation: Psychiatry Res. 2013 Dec 30;210(3):690-3
references.pmid: 23333116
references.citation: Semin Cell Dev Biol. 2012 Feb;23(1):58-64
references.pmid: 22044884
references.citation: Ment Retard Dev Disabil Res Rev. 2007;13(1):36-46
references.pmid: 17326110
references.citation: Behav Brain Res. 2013 Aug 1;250:230-7
references.pmid: 23685322
references.citation: Transl Psychiatry. 2014 May 06;4:e388
references.pmid: 24802306
references.citation: Annu Rev Physiol. 1995;57:683-706
references.pmid: 7539993
references.citation: Neuron. 2011 Jun 23;70(6):1218-25
references.pmid: 21689606
references.citation: Cell. 2001 Nov 16;107(4):477-87
references.pmid: 11719188
references.citation: Nat Rev Neurosci. 2007 Oct;8(10):766-75
references.pmid: 17882254
references.citation: Brain. 1997 Apr;120 ( Pt 4):701-22
references.pmid: 9153131
references.citation: Mol Autism. 2012 Dec 15;3(1):18
references.pmid: 23241247
references.citation: J Neurosci. 1997 Mar 1;17(5):1539-47
references.pmid: 9030614
references.citation: Results Probl Cell Differ. 2012;54:61-80
references.pmid: 22009348
references.citation: Biol Psychiatry. 2001 May 1;49(9):741-52
references.pmid: 11331082
references.citation: J Dev Behav Pediatr. 2001 Dec;22(6):409-17
references.pmid: 11773805
references.citation: Mol Autism. 2010 Sep 21;1(1):12
references.pmid: 20858229
references.citation: Cell. 2011 Jul 22;146(2):247-61
references.pmid: 21784246
references.citation: Brain. 1995 Feb;118 ( Pt 1):279-306
references.pmid: 7895011
references.citation: Psychopharmacology (Berl). 2014 Mar;231(6):1237-50
references.pmid: 24173622
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3615-20
references.pmid: 14993603
references.citation: J Cell Biol. 2008 Dec 15;183(6):1115-27
references.pmid: 19075115
references.citation: Neuron. 2012 Apr 26;74(2):285-99
references.pmid: 22542183
references.citation: Genome Med. 2009 Oct 30;1(10):102
references.pmid: 19886976
references.citation: Biol Psychiatry. 1999 May 1;45(9):1085-98
references.pmid: 10331101
references.citation: Pediatr Neurol. 2014 Apr;50(4):297-302
references.pmid: 24518745
references.citation: Behav Brain Res. 2013 Feb 15;239:72-9
references.pmid: 23142366
references.citation: Sci Signal. 2008 Feb 05;1(5):pe6
references.pmid: 18272470
references.citation: J Cogn Neurosci. 2006 May;18(5):766-80
references.pmid: 16768376
references.citation: JAMA Psychiatry. 2013 Jul;70(7):668-76
references.pmid: 23699763
references.citation: Science. 2003 Oct 10;302(5643):249-55
references.pmid: 12934013
references.citation: Front Hum Neurosci. 2013 Sep 27;7:609
references.pmid: 24098278
references.citation: Nat Genet. 1993 Jun;4(2):147-53
references.pmid: 8348153
references.citation: Arch Gen Psychiatry. 1986 Feb;43(2):114-24
references.pmid: 3947207
references.citation: Neurosci Biobehav Rev. 2009 Sep;33(8):1198-203
references.pmid: 19538989
references.citation: Brain Res. 2010 Jan 14;1309:83-94
references.pmid: 19896929
references.citation: Biol Psychiatry. 2011 Nov 1;70(9):852-8
references.pmid: 21802660
references.citation: J Neurosci. 2004 Mar 17;24(11):2648-55
references.pmid: 15028757
references.citation: Mol Psychiatry. 2012 Jan;17(1):36-48
references.pmid: 21042317
references.citation: Clin Linguist Phon. 2007 Nov-Dec;21(11-12):975-89
references.pmid: 17972193
references.citation: Science. 2007 Jul 13;317(5835):190-1
references.pmid: 17626859
references.citation: Neuron. 2008 Feb 7;57(3):364-77
references.pmid: 18255030
references.citation: Brain Res Brain Res Rev. 2000 Apr;32(2-3):476-509
references.pmid: 10760552
references.citation: J Neurosci. 2001 Jul 15;21(14):5139-46
references.pmid: 11438589
references.citation: Trends Genet. 2009 Apr;25(4):166-77
references.pmid: 19304338
references.citation: Nat Rev Neurosci. 2005 May;6(5):376-87
references.pmid: 15861180
references.citation: Neuroscientist. 2003 Dec;9(6):496-507
references.pmid: 14678582
references.citation: Annu Rev Neurosci. 2002;25:315-38
references.pmid: 12052912
references.citation: Science. 1983 Jul 29;221(4609):466-8
references.pmid: 6867723
references.citation: JAMA Psychiatry. 2013 Nov;70(11):1215-23
references.pmid: 24068330
references.citation: Cell. 1991 May 31;65(5):905-14
references.pmid: 1710175
references.citation: J Biol Chem. 2006 Aug 4;281(31):22085-22091
references.pmid: 16754686
references.citation: Cereb Cortex. 2013 Dec;23(12):2956-64
references.pmid: 22989585
references.citation: Nature. 2011 Oct 26;478(7370):519-23
references.pmid: 22031444
references.citation: Neuroscience. 1999 Mar;89(3):649-59
references.pmid: 10199602
references.citation: Nature. 2001 Oct 4;413(6855):519-23
references.pmid: 11586359
references.citation: Nature. 1991 Feb 14;349(6310):624-6
references.pmid: 1672039
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):523-8
references.pmid: 11756669
references.citation: Neuroinformatics. 2007 Spring;5(1):79-94
references.pmid: 17426354
references.citation: Nat Genet. 2008 Sep;40(9):1056-8
references.pmid: 18711365
references.citation: J Neurochem. 1999 Mar;72(3):1315-22
references.pmid: 10037505
references.citation: Psychol Med. 2012 Oct;42(10):2071-81
references.pmid: 22954259