Schizophrenia Research
Volume 73, Issue 2 , Pages 159-172 , 1 March 2005

Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons

Received 23 April 2004 ,Revised 24 May 2004 ,Accepted 24 May 2004.

References 

  1. Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE, et al. Gene expression for glutamic acid carboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch. Gen. Psychiatry. 1995;52:258–266
  2. Bai L, Xu H, Collins JF, Ghishan FK. Molecular and functional analysis of a novel neuronal vesicular glutamate transporter. J. Biol. Chem. 2001;276:36764–36769
  3. Barton AJL, Najlerahim A, Pearson RCA, Harrison PJ. Pre- and postmortem influences on brain RNA. J. Neurochem. 1993;61:1–11
  4. Bartzokis G. Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology. 2002;27:672–683
  5. Beasley CL, Zhang ZJ, Patten I, Reynolds GP. Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Biol. Psychiatry. 2002;52:708–715
  6. Bellochio EE, Hu H, Pohorille A, Chan J, Pickel VM, Edwards RH. The localization of the brain-specific inorganic phosphate transporter suggests a presynaptic role in glutamatergic neurotransmission. J. Neurosci. 1998;18:638–8659
  7. Bellochio EE, Reimer RJ, Fremeau RT, Edwards RH. Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science. 2000;289:957–960
  8. Benes FM, Berretta S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology. 2001;25:1–27
  9. Benes FM, McSparren J, Bird E, SanGiovanni J, Vincent SL. Deficits in small interneurons in pre-frontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch. Gen. Psychiatry. 1991;48:996–1001
  10. Browning MD, Dudek EM, Rapier JL, Leonard S, Freedman R. Significant reductions in synapsin but not synaptophysin specific activity in the brains of some schizophrenics. Biol. Psychiatry. 1993;34:529–535
  11. Burnet PWJ, Eastwood SL, Harrison PJ. 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially affected in schizophrenia. Neuropsychopharmacology. 1996;15:442–455
  12. Davidsson P, Gottfries J, Bogdanovic N, Ekman R, Karlsson I, Gottfries C-G, et al. The synaptic-vesicle-specific proteins rab3a and synaptophysin are reduced in thalamus and related cortical brain regions in schizophrenic brains. Schizophr. Res. 1999;40:23–29
  13. DeLisi L. Is schizophrenia a lifetime disorder of brain plasticity, growth and aging?. Schizophr. Res. 1997;23:119–129
  14. Eastwood SL. The synaptic pathology of schizophrenia: is aberrant neurodevelopment and plasticity to blame?. In:  Smythies J editors. Disorders of Synaptic Plasticity and Schizophrenia. International Reviews of Neurobiology. vol. 59:Amsterdam: Elsevier; 2004;p. 47–72
  15. Eastwood SL, Harrison PJ. Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography. Neuroscience. 1995;69:339–343
  16. Eastwood SL, Harrison PJ. Hippocampal and cortical growth-associated protein-43 messenger RNA in schizophrenia. Neuroscience. 1998;86:437–448
  17. Eastwood SL, Harrison PJ. Detection and quantification of hippocampal synaptophysin messenger RNA in schizophrenia using autoclaved, formalin-fixed, paraffin wax-embedded sections. Neuroscience. 1999;93:99–106
  18. Eastwood SL, Harrison PJ. Hippocampal synaptic pathology in schizophrenia bipolar disorder and major depression: a study of complexin mRNAs. Mol. Psychiatry. 2000;5:425–432
  19. Eastwood SL, Harrison PJ. 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;55:569–578
  20. Eastwood SL, Harrison PJ. Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis. Mol. Psychiatry. 2003;8:821–831
  21. Eastwood SL, Burnet PWJ, Harrison PJ. Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia. Neuroscience. 1995;66:309–319
  22. Eastwood SL, McDonald B, Burnet PWJ, Beckwith JP, Kerwin RW, Harrison PJ. Decreased expression of mRNAs encoding non-NMDA glutamate receptors GluR1 and GluR2 in medial temporal lobe neurons in schizophrenia. Mol. Brain Res. 1995;29:211–223
  23. Eastwood SL, Heffernan J, Harrison PJ. Chronic haloperidol differentially affects the expression of synaptic and neuronal plasticity-associated genes. Mol. Psychiatry. 1997;2:322–329
  24. Eastwood SL, Cairns NJ, Harrison PJ. Synaptophysin gene expression in schizophrenia: investigation of synaptic pathology in the cerebral cortex. Br. J. Psychiatry. 2000;176:236–242
  25. Eastwood SL, Burnet PWJ, Harrison PJ. Expression of complexin I and II mRNAs and their regulation by antipsychotic drugs in the rat forebrain. Synapse. 2000;36:167–177
  26. Eastwood SL, Cotter D, Harrison PJ. Cerebellar synaptic protein expression in schizophrenia. Neuroscience. 2001;105:219–229
  27. Eastwood SL, Law AJ, Everall IP, Harrison PJ. The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology. Mol. Psychiatry. 2003;8:148–155
  28. Fatemi SH, Earle JA, Stary J, Lee S, Sedgwick J. Altered levels of the synaptosome associated protein SNAP-25 in hippocampus of subjects with mood disorders and schizophrenia. NeuroReport. 2001;12:3257–3262
  29. Frankle WG, Lerma J, Laruelle M. The synaptic hypothesis of schizophrenia. Neuron. 2003;39:205–216
  30. Fremeau RT, Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ, et al. The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron. 2001;31:247–260
  31. Guidotti A, Auta J, Davis JM, Gerevini VD, Dwivedi Y, Grayson DR, et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder—a postmortem brain study. Arch. Gen. Psychiatry. 2000;57:1061–1069
  32. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain. 1999;122:593–624
  33. Harrison PJ. The neuropathological effects of antipsychotic drugs. Schizophr. Res. 1999;40:87–99
  34. Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology. 2004;174:151–162
  35. Harrison PJ, Eastwood SL. Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia. Lancet. 1998;352:1669–1673
  36. Harrison PJ, Eastwood SL. Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus. 2001;11:508–519
  37. Harrison PJ, Owen MJ. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet. 2003;361:417–419
  38. Harrison PJ, Heath PR, Eastwood SL, Burnet PWJ, McDonald B, Pearson RCA. The relative importance of premortem acidosis and postmortem interval for human brain gene expression studies: selective mRNA vulnerability and comparison with their encoded proteins. Neurosci. Lett. 1995;200:151–154
  39. Harrison PJ, Burnet PWJ, Falkai P, Bogerts B, Eastwood SL. Gene expression and neuronal activity in schizophrenia: a study of polyadenylated mRNA in the hippocampal formation and cerebral cortex. Schizophr. Res. 1997;26:93–102
  40. Harrison PJ, Law AJ, Eastwood SL. Glutamate receptors and transporters in the hippocampus in schizophrenia. Ann. N.Y. Acad. Sci. 2003;1003:94–101
  41. Harvey PD, Silverman JM, Mohs RC, Parrella M, White L, Powchik P, et al. Cognitive decline in late-life schizophrenia: a longitudinal study of geriatric chronically hospitalized patients. Biol. Psychiatry. 1999;45:32–40
  42. Heffernan JM, Eastwood SL, Nagy Z, Sanders MW, McDonald B, Harrison PJ. Temporal cortex synaptophysin mRNA is reduced in Alzheimer's disease and is negatively correlated with the severity of dementia. Exp. Neurol. 1998;150:235–239
  43. Hemby SE, Ginsberg SD, Brunk B, Arnold SE, Trojanowski JQ, Eberwine JH. Gene expression profile for schizophrenia—discrete neuron transcription patterns in the entorhinal cortex. Arch. Gen. Psychiatry. 2002;59:631–640
  44. Herzog E, Bellenchi GC, Gras C, Bernard V, Ravassard P, Bedet C, et al. The existence of a second vesicular glutamate transporter specified subpopulations of glutamatergic neurons. J. Neurosci. 2001;21:1–6
  45. Holinger DP, Galaburda AM, Harrison PJ. Cerebral asymmetry. In:  Harrison PJ,  Roberts GW editor. The Neuropathology of Schizophrenia. Progress and Interpretation. Oxford: Oxford Univ. Press; 2000;p. 151–172
  46. Honer WG. Pathology of presynaptic proteins in Alzheimer's disease: more than simple loss of terminals. Neurobiol. Aging. 2003;8:1047–1062
  47. Honer WG, Young CE. Presynaptic proteins and schizophrenia. In:  Smythies J editors. Disorders of Synaptic Plasticity and Schizophrenia. International Reviews of Neurobiology. vol. 59:Amsterdam: Elsevier; 2003;p. 175–199
  48. Honer WG, Young C, Falkai P. Synaptic pathology. In:  Harrison PJ,  Roberts GW editor. The Neuropathology of Schizophrenia. Progress and Interpretation. Oxford: Oxford Univ. Press; 2000;p. 105–136
  49. Kaneko T, Fujiuyama F, Hioke H. Immunohistochemical localization of candidates for vesicular glutamate transporters in the rat brain. J. Comp. Neurol. 2002;444:39–62
  50. Karson CN, Mrak RE, Schluterman KO, Sturner WQ, Sheng JG, Griffin WST. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible basis for ‘hypofrontality’. Mol. Psychiatry. 1999;4:39–45
  51. Keshavan MS, Anderson S, Pettegrew JW. Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex—the Feinberg hypothesis revisited. J. Psychiat. Res. 1993;23:239–265
  52. Konradi C, Heckers S. Antipsychotic drugs and neuroplasticity: insights into the treatment and neurobiology of schizophrenia. Biol. Psychiatry. 2001;50:729–742
  53. Konradi C, Heckers S. Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol. Ther. 2003;97:153–179
  54. Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ. Reduced spinophilin but not MAP2 expression in the hippocampal formation in schizophrenia and mood disorder: molecular evidence for a pathology of dendritic spines. Am. J. Psychiatry. 2004;(in press)
  55. Lewis DA, Pierri JN, Volk DW, Melchitzky DS, Woo TU. Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia. Biol. Psychiatry. 1999;46:616–626
  56. Lewis DA, Cruz DA, Melchitzky DS, Pierri JN. 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;158:1411–1422
  57. Lipton AM, Cullum C, Satumtira S, Sontag E, Hynan L, White CL, et al. Contribution of asymmetric synapse loss to lateralizing clinical deficits in frontotemporal dementias. Ann. Neurol. 2001;58:1233–1239
  58. McClure RK, Lieberman JA. Neurodevelopmental and neurodegenerative hypotheses of schizophrenia: a review and critique. Curr. Opin. Psychiatry. 2003;16(Suppl. 2):S15–S28
  59. McCullumsmith RE, Meador-Woodruff JH. Expression of vesicular glutamate transporters one and two in medial temporal lobe structures in schizophrenia bipolar disorder, and major depressive disorder. [Abstract] Schizophr. Res. 2003;60:65;(suppl.)
  60. McGlashan TH, Hoffman RE. Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch. Gen. Psychiatry. 2000;57:637–648
  61. Meador-Woodruff JH, Healy DJ. Glutamate receptor expression in schizophrenic brain. Brain Res. Rev. 2000;31:288–294
  62. Mirnics K, Middleton FA, Lewis DA, Levitt P. Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Trends Neurosci. 2001;24:479–486
  63. Moises HW, Zoega T, Gottesman I. The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. BMC Psychiatry. 2002;2:(www.biomedcentral.com/1471-244X/2/8)
  64. Morimoto R, Hayashi M, Yatsushiro S, Otsuka M, Yamamoto A, Moriyama Y. Co-expression of vesicular glutamate transporters (VGLUT1 and VGLUT2) and their association with synaptic-like microvesicles in rat pinealocytes. J. Neurochem. 2003;84:382–391
  65. Mukaetvoa-Ladinska EB, Hurt J, Honer WG, Harrington CR, Wischik CM. Loss of synaptic but not cytoskeletal proteins in the cerebellum of chronic schizophrenics. Neurosci. Lett. 2002;317:161–165
  66. Nakahara T, Motomura K, Hashimoto K, Ueki H, Goto L, Hondo H, et al. Long-term treatment with haloperidol decreases the mRNA levels of complexin I, but not complexin II, in rat prefrontal cortex, nucleus accumbens and ventral tegmental area. Neurosci. Lett. 2000;290:29–32
  67. Novak G, Kim D, Seeman P, Tallerico T. Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. Mol. Brain Res. 2002;107:183–189
  68. Nowakowski C, Kaufmann WA, Adlassnig C, Maier H, Salimi K, Jellinger KA, et al. Reduction of chromogranin B-like immunoreactivity in distinct subregions of the hippocampus from individuals with schizophrenia. Schizophr. Res. 2002;58:43–53
  69. Ohnuma T, Augood SJ, Arai H, McKenna PJ, Emson PC. Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: focus on GABA content GABA(A) receptor alpha-1 subunit messenger RNA and human GABA transporter-1 (HGAT-1) messenger RNA expression. Neuroscience. 1999;93:441–448
  70. Preece P, Cairns NJ. Quantifying mRNA in postmortem human brain: influence of gender, age at death, postmortem interval, brain pH, agonal state and inter-lobe mRNA variance. Mol. Brain Res. 2003;118:60–71
  71. Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N, et al. Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders—preliminary findings. Arch. Gen. Psychiatry. 2000;57:349–356
  72. Sawada K, Young CE, Barr AM, Longworth K, Takahashi S, Arango V, et al. Altered immunoreactivity of complexin protein in prefrontal cortex in severe mental illness. Mol. Psychiatry. 2002;7:484–492
  73. Sawada K, Barr AM, Takahashi S, Arima K, Falkai P, Phillips A, et al. Complexins I and II in hippocampus in schizophrenia. [Abstract] Schizophr. Res. 2003;60:74–75(suppl.)
  74. Smith RE, Haroutunian V, Davis KL, Meador-Woodruff JH. Vesicular glutamate transporter transcript expression in the thalamus in schizophrenia. NeuroReport. 2001;12:2885–2887
  75. Sokolov BP, Tcherepanov AA, Haroutunian V, Davis KL. Levels of mRNAs encoding synaptic vesicle and synaptic plasma membrain proteins in the temporal cortex of elderly schizophrenic patients. Biol. Psychiatry. 2000;48:184–196
  76. Südhof TC. The synaptic vesicle cascade: a cascade of protein–protein interactions. Nature. 1995;375:645–653
  77. Südhof TC. The synaptic vesicle cycle. Annu. Rev. Neurosci. 2004;27:509–547
  78. Takahashi S, Yamamoto H, Matsuda Z, Ogawa M, Yagyu K, Taniguchi T, et al. Identification of two highly homologous presynaptic proteins distinctly localised at the dendritic and somatic synapses. FEBS Lett. 1995;368:455–460
  79. Takahashi S, Ujihara H, Huang GZ, Yagyu K, Sanbo M, Kaba H, et al. Reduced hippocampal LTP in mice lacking a presynaptic protein, complexin II. Eur. J. Neurosci. 1999;11:2359–2366
  80. Talbot K, Eidem WL, Tinsley CL, Benson MA, Thompson EW, Smith RJ, et al. Dysbindin-1 is reduced in intrinsic glutamatergic terminals of the hippocampal formation in schizophrenia. J. Clin. Invest. 2004;113:1353–1363
  81. Tcherepanov AA, Sokolov BP. Age-related abnormalities in expression of mRNAs encoding synapsin 1A, synapsin 1B, and synaptophysin in the temporal cortex of schizophrenics. J. Neurosci. 1997;49:639–644
  82. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 1991;30:572–580
  83. Thompson PM, Egbufoama S, Vawter MP. SNAP-25 reduction in the hippocampus of patients with schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2003;27:411–417
  84. Varoqui H, Schäfer MK-H, Zhu H, Weihe E, Erickson JD. Identification of the differentiation-associated Na+/P1 transporter as a novel vesicular glutamate transporter expressed in a distinct set of glutamatergic synapses. J. Neurosci. 2002;22:142–155
  85. Vawter MP, Thatcher L, Usen N, Hyde TM, Kleinman JE, Freed WJ. Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia. Mol. Psychiatry. 2002;7:571–579
  86. Verderio C, Pozzi D, Pravettoni E, Inverardi F, Schenk U, Coco S, et al. SNAP-25 modulation of calcium dynamics underlies differences in GABAergic and glutamatergic responsiveness to depolarization. Neuron. 2004;41:599–610
  87. Volk D, Austin M, Pierri J, Sampson A, Lewis D. GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. Am. J. Psychiatry. 2001;158:256–265
  88. Webster MJ, Weickert CS, Herman MM, Hyde TM, Kleinman JE. Synaptophysin and GAP-43 mRNA levels in the hippocampus of subjects with schizophrenia. Schizophr. Res. 2001;49:89–98
  89. Weinberger DR. From neuropathology to neurodevelopment. Lancet. 1995;346:552–557
  90. Weinberger DR. Cell biology of the hippocampal formation in schizophrenia. Biol. Psychiatry. 1999;45:395–402
  91. Wojcik SM, Rhee JS, Herzog E, Sigler A, Jahn R, Takamori S, et al. An essential role for vesicular glutamate transporter 1 (VGLUT1) in postnatal development and quantal size. Proc. Natl. Acad. Sci. U. S. A. 2004;101:7158–7163
  92. Woo TU, Whitehead RE, Melchitsky DS, Lewis DA. A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 1998;95:5341–5346
  93. Young CE, Arima K, Xie J, Hu L, Beach TG, Falkai P, et al. SNAP-25 deficit and hippocampal connectivity in schizophrenia. Cereb. Cortex. 1998;8:261–268
  94. Zhang ZJ, Reynolds GP. A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr. Res. 2002;55:1–10

PII: S0920-9964(04)00175-6

doi: 10.1016/j.schres.2004.05.010

Schizophrenia Research
Volume 73, Issue 2 , Pages 159-172 , 1 March 2005

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