title: Neurobiology of schizophrenia onset.
abstract: The clinical symptoms and cognitive and functional deficits of schizophrenia typically begin to gradually emerge during late adolescence and early adulthood. Recent findings suggest that disturbances of a specific subset of inhibitory neurons that contain the calcium-binding protein parvalbumin (PV), which may regulate the course of postnatal developmental experience-dependent synaptic plasticity in the cerebral cortex, including the prefrontal cortex (PFC), may be involved in the pathogenesis of the onset of this illness. Specifically, converging lines of evidence suggest that oxidative stress, extracellular matrix (ECM) deficit and impaired glutamatergic innervation may contribute to the functional impairment of PV neurons, which may then lead to aberrant developmental synaptic pruning of pyramidal cell circuits during adolescence in the PFC. In addition to promoting the functional integrity of PV neurons, maturation of ECM may also play an instrumental role in the termination of developmental PFC synaptic pruning; thus, ECM deficit can directly lead to excessive loss of synapses by prolonging the course of pruning. Together, these mechanisms may contribute to the onset of schizophrenia by compromising the integrity, stability, and fidelity of PFC connectional architecture that is necessary for reliable and predictable information processing. As such, further characterization of these mechanisms will have implications for the conceptualization of rational strategies for the diagnosis, early intervention, and prevention of this debilitating disorder.
authors: Laboratory of Cellular Neuropathology, MRC303E, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA, wwoo@hms.harvard.edu.
authors: Tsung-Ung W
authors: TU
authors: Woo
mesh_terms: D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D012559:Schizophrenia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013569:Synapses / Q000473:pathology / Q000502:physiology*
references: Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9866-71
references: 19478071
references: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7717-21
references: 12032349
references: J Neurosci. 2007 Oct 24;27(43):11496-500
references: 17959792
references: Am J Hum Genet. 2005 Dec;77(6):937-44
references: 16380906
references: Brain Res Dev Brain Res. 2002 Dec 15;139(2):139-50
references: 12480128
references: Psychol Med. 1995 Sep;25(5):887-94
references: 8588007
references: J Neurosci. 1998 Jan 1;18(1):174-83
references: 9412498
references: Crit Rev Neurobiol. 2004;16(1-2):1-23
references: 15581395
references: Br J Psychiatry. 2002 Apr;180:345-50
references: 11925358
references: Nat Rev Neurosci. 2003 Jun;4(6):456-68
references: 12778118
references: Synapse. 2002 Dec 1;46(3):206-14
references: 12325047
references: Mol Psychiatry. 2003 Sep;8(9):797-810
references: 12931207
references: Prostaglandins Leukot Essent Fatty Acids. 1996 Aug;55(1-2):33-43
references: 8888121
references: Cell. 1999 Sep 17;98(6):739-55
references: 10499792
references: Eur J Neurosci. 2000 Oct;12(10):3721-8
references: 11029642
references: Brain Res Brain Res Rev. 2000 Mar;31(2-3):270-6
references: 10719153
references: Cereb Cortex. 1992 Sep-Oct;2(5):401-16
references: 1330122
references: J Psychopharmacol. 2005 Mar;19(2):187-94
references: 15871146
references: Dev Neurobiol. 2011 Nov;71(11):1040-53
references: 21793226
references: Arch Gen Psychiatry. 1987 Jul;44(7):660-9
references: 3606332
references: Schizophr Res. 1997 Apr 11;24(3):357-64
references: 9134597
references: Cell Death Differ. 1996 Jan;3(1):71-8
references: 17180057
references: Biol Psychiatry. 2008 Jun 1;63(11):1075-83
references: 18261715
references: J Neurosci. 2004 Oct 13;24(41):9067-75
references: 15483125
references: Curr Opin Neurobiol. 2009 Apr;19(2):220-30
references: 19481443
references: Prog Neurobiol. 2010 Nov;92(3):370-85
references: 20624444
references: Adv Exp Med Biol. 2012;970:153-71
references: 22351055
references: Neurobiol Dis. 2006 Jun;22(3):624-37
references: 16481179
references: J Physiol. 2012 Feb 15;590(4):715-24
references: 22219337
references: J Neurosci. 2003 Jul 16;23(15):6315-26
references: 12867516
references: Neuropsychopharmacology. 2003 Aug;28(8):1515-20
references: 12799618
references: Trends Cogn Sci. 1999 Apr;3(4):151-162
references: 10322469
references: Neuropsychiatr Dis Treat. 2005 Jun;1(2):171-7
references: 18568063
references: Biol Psychiatry. 2009 Jun 15;65(12):1015-23
references: 19249749
references: Cereb Cortex. 2007 Apr;17(4):894-908
references: 16740581
references: Curr Top Dev Biol. 2005;69:215-37
references: 16243601
references: Neuroreport. 2004 Mar 22;15(4):677-80
references: 15094474
references: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5341-6
references: 9560277
references: Nature. 2003 Jul 31;424(6948):552-6
references: 12891358
references: Am J Physiol. 1996 Nov;271(5 Pt 1):C1424-37
references: 8944624
references: Schizophr Res. 1999 Nov 9;40(1):23-9
references: 10541003
references: Trends Neurosci. 1996 Apr;19(4):130-7
references: 8658595
references: Brain Res Brain Res Rev. 2000 Mar;31(2-3):251-69
references: 10719152
references: Nat Rev Neurosci. 2010 Feb;11(2):100-13
references: 20087360
references: Cereb Cortex. 1993 Sep-Oct;3(5):361-72
references: 8260806
references: Trends Neurosci. 2008 May;31(5):234-42
references: 18395805
references: Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16621-6
references: 17921251
references: Neuron. 2010 Nov 4;68(3):557-69
references: 21040854
references: Mol Psychiatry. 2004 Jul;9(7):684-97, 643
references: 15098003
references: Psychopharmacology (Berl). 1997 May;131(2):167-73
references: 9201805
references: Biol Psychiatry. 1999 Jan 1;45(1):17-25
references: 9894571
references: Trends Neurosci. 2001 Aug;24(8):455-63
references: 11476885
references: J Neurosci. 2007 Feb 28;27(9):2241-52
references: 17329421
references: Neuroscience. 1995 May;66(2):309-19
references: 7477874
references: Pharmacol Biochem Behav. 2007 Jan;86(1):1-7
references: 16806445
references: Glia. 1993 Jul;8(3):183-200
references: 7693589
references: Psychopharmacology (Berl). 2007 Jun;192(2):283-90
references: 17265073
references: Arch Gen Psychiatry. 1995 Dec;52(12):998-1007
references: 7492260
references: Nat Rev Neurosci. 2005 Nov;6(11):877-88
references: 16261181
references: Schizophr Res. 2006 Jan 1;81(1):47-63
references: 16226876
references: J Psychopharmacol. 2007 Mar;21(2):198-205
references: 17329300
references: Magn Reson Med. 1999 Aug;42(2):283-9
references: 10440953
references: J Neurosci. 1999 Nov 15;19(22):RC40
references: 10559430
references: J Neurosci. 2008 Dec 17;28(51):13957-66
references: 19091984
references: Science. 2004 Jun 25;304(5679):1926-9
references: 15218136
references: Neuroreport. 2000 Nov 9;11(16):3621-5
references: 11095531
references: J Neurosci. 2012 Nov 28;32(48):17365-72
references: 23197727
references: J Neurosci. 1998 Dec 15;18(24):10464-72
references: 9852584
references: Proc Natl Acad Sci U S A. 2004 May 25;101(21):8174-9
references: 15148381
references: Neurosci Biobehav Rev. 2003 Jan-Mar;27(1-2):3-18
references: 12732219
references: Neuroscience. 2004;126(3):591-8
references: 15183509
references: Schizophr Bull. 2004;30(4):923-34
references: 15954198
references: J Neurosci. 1996 Mar 15;16(6):2034-43
references: 8604048
references: Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1368-73
references: 14742867
references: Arch Gen Psychiatry. 2000 Jan;57(1):65-73
references: 10632234
references: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12486-91
references: 14514885
references: J Neurosci. 1999 Nov 1;19(21):9587-603
references: 10531461
references: Brain Res Dev Brain Res. 1992 Nov 20;70(1):53-63
references: 1473278
references: Arch Gen Psychiatry. 2010 Feb;67(2):155-66
references: 20124115
references: J Neurosci. 2002 Apr 1;22(7):2513-21
references: 11923416
references: Nat Rev Neurosci. 2010 Nov;11(11):735-46
references: 20944663
references: Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19878-83
references: 17170134
references: Brain Res Brain Res Rev. 1994 Jan;19(1):128-45
references: 8167657
references: Methods Mol Biol. 2011;755:327-43
references: 21761317
references: Neuron. 2007 Mar 15;53(6):805-12
references: 17359916
references: Psychopharmacology (Berl). 2001 Jul;156(2-3):182-6
references: 11549221
references: Exp Neurol. 2002 Jul;176(1):41-54
references: 12093081
references: Harv Rev Psychiatry. 2010 May-Jun;18(3):173-89
references: 20415633
references: Prog Neuropsychopharmacol Biol Psychiatry. 2007 May 9;31(4):832-8
references: 17374554
references: Schizophr Res. 2002 Oct 1;57(2-3):247-58
references: 12223256
references: J Psychiatr Res. 1982-1983;17(4):319-34
references: 7187776
references: Cereb Cortex. 1998 Oct-Nov;8(7):614-22
references: 9823482
references: Am J Psychiatry. 1991 Oct;148(10):1301-8
references: 1654746
references: J Comp Neurol. 2003 Oct 20;465(3):385-400
references: 12966563
references: BMC Psychiatry. 2009 Nov 16;9:71
references: 19917116
references: Trends Neurosci. 2003 Sep;26(9):489-95
references: 12948660
references: Neuroscience. 2013 Sep 26;249:172-91
references: 23298853
references: Nat Neurosci. 2006 May;9(5):660-8
references: 16633343
references: J Neurophysiol. 2008 May;99(5):2656-71
references: 18287555
references: Curr Opin Neurobiol. 2000 Feb;10(1):138-45
references: 10679428
references: J Comp Neurol. 2006 Feb 1;494(4):559-77
references: 16374793
references: J Neurosci. 2006 Feb 1;26(5):1604-15
references: 16452684
references: Science. 1997 Jan 10;275(5297):209-13
references: 8985013
references: Nature. 1995 May 25;375(6529):328-31
references: 7753198
references: Cell Mol Life Sci. 2000 Feb;57(2):276-89
references: 10766023
references: J Comp Neurol. 1995 Jul 31;358(3):383-400
references: 7560293
references: Neurosci Biobehav Rev. 2011 Jan;35(3):878-93
references: 20974172
references: Neuron. 2000 Oct;28(1):53-67
references: 11086983
references: Curr Top Behav Neurosci. 2010;4:485-508
references: 21312410
references: Trends Neurosci. 1992 Jun;15(6):218-26
references: 1378666
references: Neuron. 1994 May;12(5):1031-40
references: 7514425
references: Neuroscience. 1995 Jul;67(1):7-22
references: 7477911
references: Ann N Y Acad Sci. 2004 Jun;1021:143-7
references: 15251883
references: Front Biosci (Landmark Ed). 2010 Jan 01;15:626-44
references: 20036837
references: Arch Gen Psychiatry. 1991 Dec;48(12):1097-106
references: 1845228
references: Neurotox Res. 2004;6(1):57-61
references: 15184106
references: Eur J Neurosci. 1994 May 1;6(5):837-53
references: 8075825
references: Neurosci Lett. 2001 Mar 23;301(1):69-71
references: 11239718
references: Science. 2002 Nov 8;298(5596):1248-51
references: 12424383
references: Biol Psychiatry. 2003 Apr 1;53(7):624-6
references: 12679242
references: Dev Growth Differ. 2009 Apr;51(3):369-77
references: 19298552
references: Neuroscience. 1993 Jun;54(4):881-92
references: 8393540
references: Schizophr Res. 2007 Dec;97(1-3):254-63
references: 17601703
references: Neuropsychopharmacology. 2001 Jul;25(1):1-27
references: 11377916
references: Neurosci Res. 2003 Sep;47(1):17-22
references: 12941442
references: Cereb Cortex. 1997 Sep;7(6):476-86
references: 9276173
references: Neuropsychopharmacology. 2009 Jul;34(8):2028-40
references: 19242405
references: Neuropsychopharmacology. 1997 Jun;16(6):385-98
references: 9165494
references: Neuropsychopharmacology. 2003 Feb;28(2):265-75
references: 12589379
references: Science. 2007 Dec 7;318(5856):1645-7
references: 18063801
references: J Neurol Neurosurg Psychiatry. 1998 Oct;65(4):446-53
references: 9771764
references: Neuropsychopharmacology. 2011 Sep;36(10):2103-10
references: 21677653
references: Biol Psychiatry. 2013 Sep 15;74(6):427-35
references: 23790226
references: Arch Gen Psychiatry. 1997 Jul;54(7):660-9
references: 9236550
references: Arch Gen Psychiatry. 1995 Apr;52(4):269-73; discussion 277-8
references: 10681304
references: Eur J Neurosci. 2010 Jun;31(12):2156-65
references: 20497467
references: Schizophr Res. 2003 Dec 1;65(1):33-8
references: 14623372
references: J Vis Exp. 2009 Aug 06;(30):
references: 19684564
references: Br J Psychiatry. 2009 May;194(5):434-8
references: 19407273
references: J Neurocytol. 2002 Mar-Jun;31(3-5):277-87
references: 12815247
references: Biol Psychiatry. 2013 Mar 15;73(6):574-82
references: 23140664
references: J Biol Chem. 2006 Jun 30;281(26):17789-800
references: 16644727
references: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4746-51
references: 11296301
references: Prostaglandins Leukot Essent Fatty Acids. 1996 Aug;55(1-2):45-54
references: 8888122
references: Glia. 1999 Oct;28(1):13-24
references: 10498818
references: Curr Psychiatry Rep. 2010 Aug;12(4):335-44
references: 20556669
references: Neurobiol Dis. 2001 Oct;8(5):723-42
references: 11592844
references: Science. 1996 Nov 15;274(5290):1133-8
references: 8895456
references: Neuroscience. 2012 Aug 30;218:367-84
references: 22659016
references: J Physiol. 2009 May 1;587(Pt 9):1881-8
references: 19188247
references: Neuron. 2004 Dec 16;44(6):1031-41
references: 15603745
references: J Psychiatr Res. 1994 May-Jun;28(3):239-65
references: 7932285
references: Nat Neurosci. 2012 Jan 15;15(3):414-22, S1-2
references: 22246436
references: Arch Gen Psychiatry. 2004 Jul;61(7):649-57
references: 15237077
references: J Psychiatr Res. 1999 Nov-Dec;33(6):523-33
references: 10628529
references: Brain Res Bull. 1999 Mar 15;48(5):467-73
references: 10372507
references: Brain Res. 1999 Sep 18;842(1):15-29
references: 10526091
references: Brain Res Brain Res Rev. 2005 Dec 1;50(1):126-33
references: 16024085
references: Neuropsychobiology. 2003;47(2):61-5
references: 12707486
references: J Neurosci. 2001 Nov 15;21(22):8819-29
references: 11698594
references: J Neurosci. 2003 Aug 13;23(19):7407-11
references: 12917376
references: Neuropharmacology. 2009 Sep;57(3):193-200
references: 19523965
references: Biol Psychiatry. 2008 Sep 1;64(5):361-8
references: 18436195
references: Biochem Pharmacol. 2004 Oct 15;68(8):1507-14
references: 15451393
references: Arch Gen Psychiatry. 2001 May;58(5):466-73
references: 11343526
references: J Neurosci. 2006 Mar 8;26(10):2767-76
references: 16525056
references: J Psychiatr Res. 2002 Sep-Oct;36(5):309-15
references: 12127598
references: Neuroscience. 1997 Oct;80(4):1149-58
references: 9284067
references: Mol Psychiatry. 2002;7(5):484-92
references: 12082566
references: J Neurosci. 1998 Jan 15;18(2):687-97
references: 9425011
references: Cell Mol Life Sci. 2004 Aug;61(16):2031-45
references: 15316653
references: Annu Rev Neurosci. 2002;25:409-32
references: 12052915
references: Brain Res Bull. 2001 Jul 15;55(5):641-50
references: 11576761
references: Brain Res Rev. 2007 Apr;54(1):1-18
references: 17222456
references: Brain Res Bull. 2000 Jul 15;52(5):309-17
references: 10922508
references: Neuroscience. 2006 Apr 28;139(1):263-76
references: 16310964
references: Am J Hum Genet. 2006 Sep;79(3):586-92
references: 16909399
references: Arch Gen Psychiatry. 2000 Dec;57(12):1180-1; author reply 1182-3
references: 11115333
references: Cereb Cortex. 2002 Oct;12(10):1063-70
references: 12217970
references: Arch Gen Psychiatry. 1992 Dec;49(12):975-82
references: 1449384
references: Aust N Z J Psychiatry. 2008 May;42(5):357-68
references: 18473254
references: Med Biol. 1984;62(2):71-7
references: 6088908
references: Nat Rev Neurosci. 2005 May;6(5):399-407
references: 15861182
references: Neurochem Res. 2002 Oct;27(10):1049-63
references: 12462404
references: Curr Mol Med. 2003 Aug;3(5):437-46
references: 12942997
references: Child Dev. 1987 Jun;58(3):601-22
references: 3608641
references: J Neurosci. 1998 Dec 15;18(24):10553-65
references: 9852592
references: Dev Neurobiol. 2011 Jan 1;71(1):118-27
references: 21154915
references: PLoS One. 2008 Apr 09;3(4):e1944
references: 18398470
references: Neuroscience. 2006 Feb;137(3):807-19
references: 16330153
references: Neuropsychopharmacology. 2008 Aug;33(9):2187-99
references: 18004285
references: Prog Neuropsychopharmacol Biol Psychiatry. 2002 Jun;26(5):995-1005
references: 12369276
references: Arch Gen Psychiatry. 1994 Mar;51(3):199-214
references: 8122957
references: J Comp Neurol. 1996 Jan 22;364(4):567-608
references: 8821449
references: Biol Psychiatry. 1998 May 1;43(9):674-9
references: 9583001
references: Neurosci Lett. 1993 Nov 12;162(1-2):137-40
references: 7510052
references: Nat Rev Neurosci. 2005 Apr;6(4):312-24
references: 15803162
references: J Neurosci. 2008 Apr 2;28(14):3586-94
references: 18385317
references: Am J Psychiatry. 1999 Nov;156(11):1709-19
references: 10553733
references: Trends Cogn Sci. 2010 Feb;14(2):72-80
references: 20080054
references: Brain Res. 2008 Jul 7;1218:267-77
references: 18534564
references: Cereb Cortex. 1994 Jan-Feb;4(1):78-96
references: 8180493
references: Neuron Glia Biol. 2008 Aug;4(3):249-57
references: 19811705
references: Science. 2004 Mar 12;303(5664):1681-3
references: 15017002
references: Nat Rev Neurosci. 2001 Aug;2(8):539-50
references: 11483997
references: Ann Med. 1996 Dec;28(6):533-9
references: 9017112
references: Cereb Cortex. 2003 Dec;13(12):1369-74
references: 14615302
references: Biol Psychiatry. 2006 Apr 15;59(8):721-9
references: 16427029
references: Schizophr Res. 2005 Mar 1;73(2-3):193-207
references: 15653262
references: Neuron. 2002 Dec 5;36(5):955-68
references: 12467598
references: J Neurosci. 2002 Sep 1;22(17):7536-47
references: 12196577
references: Neuropharmacology. 2012 Mar;62(3):1584-97
references: 21856318
references: Br J Psychiatry Suppl. 2005 Aug;48:s108-10
references: 16055797
references: Arch Gen Psychiatry. 2000 Jul;57(7):637-48
references: 10891034
references: CNS Drugs. 2001;15(4):287-310
references: 11463134
references: Clin Genet. 2007 Jul;72(1):1-8
references: 17594392
references: Cereb Cortex. 2002 Apr;12(4):349-56
references: 11884350
references: Cold Spring Harb Symp Quant Biol. 1990;55:505-14
references: 2132834
references: Hippocampus. 2001;11(5):529-42
references: 11732706
references: J Neurosci. 2012 Sep 5;32(36):12411-20
references: 22956832
references: Biol Psychiatry. 2000 Feb 1;47(3):221-30
references: 10682219