Home LiteratureArticle Details
PMID: 21145444 Published · ppublish English Journal Article

Lack of change in markers of presynaptic terminal abundance alongside subtle reductions in markers of presynaptic terminal plasticity in prefrontal cortex of schizophrenia patients.

Biological psychiatry ·Vol. 69 ·No. 1 ·2011-01-01 ·Pages 71-9

Fung SJ, Sivagnanasundaram S, Weickert CS

Abstract

Reduced synaptic connectivity in frontal cortex may contribute to schizophrenia symptoms. While altered messenger RNA (mRNA) and protein expression of various synaptic genes have been found, discrepancies between studies mean a generalizable synaptic pathology has not been identified. We determined if mRNAs encoding presynaptic proteins enriched in inhibitory (vesicular gamma-aminobutyric acid transporter [VGAT] and complexin 1) and/or excitatory (vesicular glutamate transporter 1 [VGluT1] and complexin 2) terminals are altered in the dorsolateral prefrontal cortex of subjects with schizophrenia (n = 37 patients, n = 37 control subjects). We also measured mRNA expression of markers associated with synaptic plasticity/neurite outgrowth (growth associated protein 43 [GAP43] and neuronal navigators [NAVs] 1 and 2) and mRNAs of other synaptic-associated proteins previously implicated in schizophrenia: dysbindin and vesicle-associated membrane protein 1 (VAMP1) mRNAs using quantitative polymerase chain reaction. No significant changes in complexin 1, VGAT, complexin 2, VGluT1, dysbindin, NAV2, or VAMP1 mRNA expression were found; however, expression of mRNAs associated with plasticity/cytoskeletal modification (GAP43 and NAV1) was reduced in schizophrenia. Although dysbindin mRNA did not differ in schizophrenia compared with control subjects, dysbindin mRNA positively correlated with GAP43 and NAV1 in schizophrenia but not in control subjects, suggesting low levels of dysbindin may be linked to reduced plasticity in the disease state. No relationships between three dysbindin genetic polymorphisms previously associated with dysbindin mRNA levels were found. A reduction in the plasticity of synaptic terminals supports the hypothesis that their reduced modifiability may contribute to neuropathology and working memory deficits in schizophrenia.

MeSH Terms
Adaptor Proteins, Vesicular Transport/metabolism Biomarkers/metabolism Carrier Proteins/genetics,metabolism DNA Helicases Dysbindin Dystrophin-Associated Proteins GAP-43 Protein/metabolism Gene Expression Humans Microtubule-Associated Proteins Nerve Growth Factors/metabolism Nerve Tissue Proteins/metabolism Neuronal Plasticity Polymorphism, Single Nucleotide Prefrontal Cortex/metabolism Presynaptic Terminals/metabolism Schizophrenia/metabolism Vesicle-Associated Membrane Protein 1/metabolism Vesicular Glutamate Transport Protein 1/metabolism Vesicular Inhibitory Amino Acid Transport Proteins/metabolism
Chemicals
Adaptor Proteins, Vesicular Transport Biomarkers Carrier Proteins DTNBP1 protein, human Dysbindin Dystrophin-Associated Proteins GAP-43 Protein Microtubule-Associated Proteins NAV1 protein, human Nerve Growth Factors Nerve Tissue Proteins SLC17A7 protein, human SLC32A1 protein, human VAMP1 protein, human Vesicle-Associated Membrane Protein 1 Vesicular Glutamate Transport Protein 1 Vesicular Inhibitory Amino Acid Transport Proteins complexin I complexin II DNA Helicases NAV2 protein, human
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Fung Samantha J
Schizophrenia Research Institute, University of New South Wales, Sydney, Australia. [email protected]
Sivagnanasundaram Sinthuja
Weickert Cynthia Shannon
References (72)
72 references, click to expand
  1. Synaptophysin gene expression in schizophrenia. Investigation of synaptic pathology in the cerebral cortex.
    Br J Psychiatry. 2000 Mar;176:236-42 PMID: 10755070
  2. Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity.
    Arch Gen Psychiatry. 1997 Oct;54(10):943-52 PMID: 9337775
  3. Synaptophysin gene expression in human brain: a quantitative in situ hybridization and immunocytochemical study.
    Neuroscience. 1994 Apr;59(4):881-92 PMID: 8058126
  4. Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins.
    Brain Res Bull. 2001 Jul 15;55(5):569-78 PMID: 11576753
  5. Immunoreactivity of 43 kDa growth-associated protein is decreased in post mortem hippocampus of bipolar disorder and schizophrenia.
    Neurosci Lett. 2007 Jan 10;411(2):123-7 PMID: 17095155
  6. Altered immunoreactivity of complexin protein in prefrontal cortex in severe mental illness.
    Mol Psychiatry. 2002;7(5):484-92 PMID: 12082566
  7. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.
    Mol Psychiatry. 2005 Jan;10(1):40-68; image 5 PMID: 15263907
  8. Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse.
    Trends Neurosci. 2001 Aug;24(8):479-86 PMID: 11476888
  9. Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness.
    Neuroscience. 1999;91(4):1247-55 PMID: 10391432
  10. The schizophrenia susceptibility gene dysbindin controls synaptic homeostasis.
    Science. 2009 Nov 20;326(5956):1127-30 PMID: 19965435
  11. Quantitative comparison of glutamatergic and GABAergic synaptic vesicles unveils selectivity for few proteins including MAL2, a novel synaptic vesicle protein.
    J Neurosci. 2010 Jan 6;30(1):2-12 PMID: 20053882
  12. Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development.
    Mol Psychiatry. 2003 Sep;8(9):797-810 PMID: 12931207
  13. Synaptophysin and GAP-43 mRNA levels in the hippocampus of subjects with schizophrenia.
    Schizophr Res. 2001 Apr 15;49(1-2):89-98 PMID: 11343868
  14. Region and diagnosis-specific changes in synaptic proteins in schizophrenia and bipolar I disorder.
    Psychiatry Res. 2010 Jul 30;178(2):374-80 PMID: 20488553
  15. Cortical abnormalities in schizophrenia identified by structural magnetic resonance imaging.
    Arch Gen Psychiatry. 1999 Jun;56(6):537-47 PMID: 10359468
  16. Complexins regulate a late step in Ca2+-dependent neurotransmitter release.
    Cell. 2001 Jan 12;104(1):71-81 PMID: 11163241
  17. Mouse neuron navigator 1, a novel microtubule-associated protein involved in neuronal migration.
    Mol Cell Neurosci. 2005 Apr;28(4):599-612 PMID: 15797708
  18. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.
    J Neurosci. 2003 Jul 16;23(15):6315-26 PMID: 12867516
  19. Increased interstitial white matter neuron density in the dorsolateral prefrontal cortex of people with schizophrenia.
    Biol Psychiatry. 2011 Jan 1;69(1):63-70 PMID: 20974464
  20. The reduced neuropil hypothesis: a circuit based model of schizophrenia.
    Biol Psychiatry. 1999 Jan 1;45(1):17-25 PMID: 9894571
  21. Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia.
    Neuroscience. 1995 May;66(2):309-19 PMID: 7477874
  22. Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17.
    Arch Gen Psychiatry. 1995 Oct;52(10):805-18; discussion 819-20 PMID: 7575100
  23. Increased levels of SNAP-25 and synaptophysin in the dorsolateral prefrontal cortex in bipolar I disorder.
    Bipolar Disord. 2006 Apr;8(2):133-43 PMID: 16542183
  24. Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia.
    Am J Psychiatry. 2010 Dec;167(12):1479-88 PMID: 21041246
  25. Neuron navigator: a human gene family with homology to unc-53, a cell guidance gene from Caenorhabditis elegans.
    Genomics. 2002 Jul;80(1):21-30 PMID: 12079279
  26. Gene expression profiling in Brodmann's area 46 from subjects with schizophrenia.
    Aust N Z J Psychiatry. 2007 Apr;41(4):308-20 PMID: 17464717
  27. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia.
    Arch Gen Psychiatry. 2000 Jan;57(1):65-73 PMID: 10632234
  28. Increased levels of GAP-43 protein in schizophrenic brain tissues demonstrated by a novel immunodetection method.
    Mol Chem Neuropathol. 1995 Jan;24(1):1-11 PMID: 7755843
  29. Synapse formation and regression in the cortex during adolescence and in schizophrenia.
    Med J Aust. 2009 Feb 16;190(S4):S14-6 PMID: 19220167
  30. Altered complexin expression in psychiatric and neurological disorders: cause or consequence?
    Mol Cells. 2008 Feb 29;25(1):7-19 PMID: 18319609
  31. Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression.
    Hum Mol Genet. 2005 Jul 15;14(14):1947-54 PMID: 15917270
  32. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence?
    J Psychiatr Res. 1982-1983;17(4):319-34 PMID: 7187776
  33. Prefrontal GABA(A) receptor alpha-subunit expression in normal postnatal human development and schizophrenia.
    J Psychiatr Res. 2010 Jul;44(10):673-81 PMID: 20100621
  34. Cytoarchitectonic definition of prefrontal areas in the normal human cortex: I. Remapping of areas 9 and 46 using quantitative criteria.
    Cereb Cortex. 1995 Jul-Aug;5(4):307-22 PMID: 7580124
  35. Disturbed synaptic connectivity in schizophrenia: convergence of genetic risk factors during neurodevelopment.
    Brain Res Bull. 2010 Sep 30;83(3-4):140-6 PMID: 20433911
  36. Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia.
    Arch Gen Psychiatry. 2000 Mar;57(3):237-45 PMID: 10711910
  37. Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain.
    Arch Gen Psychiatry. 2004 Jun;61(6):544-55 PMID: 15184234
  38. Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional, stereologic counting method.
    J Comp Neurol. 1998 Mar 16;392(3):402-12 PMID: 9511926
  39. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for 'hypofrontality'.
    Mol Psychiatry. 1999 Jan;4(1):39-45 PMID: 10089007
  40. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex.
    Neuron. 2000 Oct;28(1):53-67 PMID: 11086983
  41. Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs.
    Mol Psychiatry. 2000 Jul;5(4):425-32 PMID: 10889554
  42. The cell migration molecule UNC-53/NAV2 is linked to the ARP2/3 complex by ABI-1.
    Development. 2009 Feb;136(4):563-74 PMID: 19168673
  43. Expression of complexin I and II mRNAs and their regulation by antipsychotic drugs in the rat forebrain.
    Synapse. 2000 Jun 1;36(3):167-77 PMID: 10819897
  44. Selection of reference gene expression in a schizophrenia brain cohort.
    Aust N Z J Psychiatry. 2010 Jan;44(1):59-70 PMID: 20073568
  45. Identification of two highly homologous presynaptic proteins distinctly localized at the dendritic and somatic synapses.
    FEBS Lett. 1995 Jul 24;368(3):455-60 PMID: 7635198
  46. Lamina-specific deficits in parvalbumin-immunoreactive varicosities in the prefrontal cortex of subjects with schizophrenia: evidence for fewer projections from the thalamus.
    Am J Psychiatry. 2001 Sep;158(9):1411-22 PMID: 11532725
  47. Mammalian Navigators are microtubule plus-end tracking proteins that can reorganize the cytoskeleton to induce neurite-like extensions.
    Cell Motil Cytoskeleton. 2009 Oct;66(10):824-38 PMID: 19396870
  48. Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia.
    Lancet. 1998 Nov 21;352(9141):1669-73 PMID: 9853440
  49. Single nucleotide polymorphism detection: allelic discrimination using TaqMan.
    Psychiatr Genet. 2002 Sep;12(3):133-6 PMID: 12218656
  50. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia.
    J Neurol Neurosurg Psychiatry. 1998 Oct;65(4):446-53 PMID: 9771764
  51. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia.
    J Clin Invest. 2004 May;113(9):1353-63 PMID: 15124027
  52. The growth-associated protein GAP-43 is increased in the hippocampus and in the gyrus cinguli in schizophrenia.
    J Mol Neurosci. 1999 Aug-Oct;13(1-2):101-9 PMID: 10691297
  53. GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons.
    Am J Psychiatry. 2001 Feb;158(2):256-65 PMID: 11156808
  54. Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex? The Feinberg hypothesis revisited.
    J Psychiatr Res. 1994 May-Jun;28(3):239-65 PMID: 7932285
  55. A mammalian homolog of unc-53 is regulated by all-trans retinoic acid in neuroblastoma cells and embryos.
    Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3422-7 PMID: 11904404
  56. The atRA-responsive gene neuron navigator 2 functions in neurite outgrowth and axonal elongation.
    Dev Neurobiol. 2008 Nov;68(13):1441-53 PMID: 18726912
  57. Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia.
    Cereb Cortex. 2001 Feb;11(2):136-47 PMID: 11208668
  58. Normal cellular levels of synaptophysin mRNA expression in the prefrontal cortex of subjects with schizophrenia.
    Biol Psychiatry. 2000 Sep 1;48(5):389-97 PMID: 10978722
  59. The dystrobrevin-binding protein 1 gene: features and networks.
    Mol Psychiatry. 2009 Jan;14(1):18-29 PMID: 18663367
  60. Growth-associated protein 43 (GAP-43) and synaptophysin alterations in the dentate gyrus of patients with schizophrenia.
    Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb;29(2):283-90 PMID: 15694236
  61. Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms.
    Arch Gen Psychiatry. 2000 May;57(5):471-80 PMID: 10807487
  62. Dysbindin regulates hippocampal LTP by controlling NMDA receptor surface expression.
    Proc Natl Acad Sci U S A. 2009 Dec 15;106(50):21395-400 PMID: 19955431
  63. Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects.
    Am J Psychiatry. 1999 Nov;156(11):1709-19 PMID: 10553733
  64. Molecular mechanisms, biological actions, and neuropharmacology of the growth-associated protein GAP-43.
    Curr Neuropharmacol. 2006 Oct;4(4):293-304 PMID: 18654638
  65. Quantitative immunohistochemistry of synaptophysin in human neocortex: an alternative method to estimate density of presynaptic terminals in paraffin sections.
    J Histochem Cytochem. 1990 Jun;38(6):837-44 PMID: 2110586
  66. Hippocampal and cortical growth-associated protein-43 messenger RNA in schizophrenia.
    Neuroscience. 1998 Sep;86(2):437-48 PMID: 9881859
  67. Heterogeneity of glutamatergic and GABAergic release machinery in cerebral cortex: analysis of synaptogyrin, vesicle-associated membrane protein, and syntaxin.
    Neuroscience. 2010 Feb 3;165(3):934-43 PMID: 19909789
  68. Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients.
    Schizophr Res. 2008 Jan;98(1-3):105-10 PMID: 17961984
  69. Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14182-7 PMID: 8943081
  70. Schizophrenia as a disorder of developmentally reduced synaptic connectivity.
    Arch Gen Psychiatry. 2000 Jul;57(7):637-48 PMID: 10891034
  71. Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons.
    Schizophr Res. 2005 Mar 1;73(2-3):159-72 PMID: 15653259
  72. Hippocampal complexin proteins and cognitive dysfunction in schizophrenia.
    Arch Gen Psychiatry. 2005 Mar;62(3):263-72 PMID: 15753239
Article Info
Journal
Biological psychiatry
Abbr.
Biol Psychiatry
ISSN
1873-2402
DOI
10.1016/j.biopsych.2010.09.036
Email
[email protected]
Published
2011-01-01
Pages
71-9
Language
English
Region
United States
NLM ID
0213264
PMCID
PMC3001685
Subset
IM
Grants
NIAAA NIH HHS · R24 AA012725 · United States
NIAAA NIH HHS · R24 AA012725-11 · United States
NIAAA NIH HHS · R28 AA012725 · United States
External Links
PubMed source DOI: 10.1016/j.biopsych.2010.09.036 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2