Indications of Abnormal Connectivity in Neuropsychiatric Disorders in Postmortem Studies

  • William G. Honer
Part of the Neurobiological Foundation of Aberrant Behaviors book series (NFAB, volume 4)


Proteins enriched in presynaptic terminals are frequently used as postmortem markers for neural connectivity in neuropsychiatric disorders. This chapter describes the animal studies which form the foundation for interpreting results in humans, followed by comments on studies in dementia and other disorders. Studies of presynaptic proteins and their mRNAs in schizophrenia and affective disorders indicate that multiple proteins are abnormally expressed or regulated. In the future, an approach which considers interactions between presynaptic proteins involved in neurotransmission may be fruitful.


Synaptic Protein Synaptic Vesicle Protein Presynaptic Protein Bioi Psychiatry Mossy Fibre Terminal 
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  1. Barbeau D, Liang JJ, Robitaille Y, Quirion R, Srivastava LK. Decreased expression of the embyronic form of the nerve cell adhesion molecule in schizophrenic brains. Proc Nat Acad Sciences USA 1995; 92: 2785–2789.CrossRefGoogle Scholar
  2. Blennow K, Bogdanovic N, Gottfries CG, Davidsson P. The growth-associated protein GAP-43 is increased in the hippocampus and in the gyrus cinguli in schizophrenia. Journal of Molec Neurosci 1999; 13: 101–109.CrossRefGoogle Scholar
  3. Breese CR, Freedman R, Leonard SS. Glutamate receptor subtype expression in human postmortem brain tissue from schizophrenics and alcohol abusers. Brain Res 1995; 674: 82–90.PubMedCrossRefGoogle Scholar
  4. Brock T, O’Callaghan J. Quantitative changes in the synaptic vesicle proteins synapsin I and p38 and the astrocyte-specific protein glial fibrillary acidic protein are associated with chemical-induced injury to the rat central nervous system. J Neurosci 1987; 7: 931–942.PubMedGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. Cabalka L, Hyman B, Goodlett C, Ritchie T, Van Hoesen G. Alteration in the pattern of nerve terminal protein immunoreactivity in the perforant pathway in Alzheimer’s disease and in rats after entorhinal lesions. Neurobiol Aging 1992; 13: 283–291.PubMedCrossRefGoogle Scholar
  7. Daly C, Ziff EB. Post-transcriptional regulation of synaptic vesicle protein expression and the developmental control of synaptic vesicle formation. J Neurosci 1997; 17: 2365–2375.PubMedGoogle Scholar
  8. Davidsson P, Gottfries J, Bogdanovic N, 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.PubMedCrossRefGoogle Scholar
  9. Davis S, Rodger J, Hicks A, Mallet J, Laroche S. Brain structure and task-specific increase in expression of the gene encoding syntaxin 1B during learning in the rat: a potential molecular marker for learning-induced synaptic plasticity in neural networks. Eur J Neurosci 1996; 8: 2068–2074.PubMedCrossRefGoogle Scholar
  10. Eastwood SL, Burnet PWJ, Harrison PJ. Striatal synaptophysin and haloperidol-induced synaptic plasticity. NeuroReport 1994; 5: 677–680.Google Scholar
  11. Eastwood SL, Burnet PWJ, Harrison PJ. Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia. Neuroscience 1995; 66: 309–319.PubMedCrossRefGoogle Scholar
  12. Eastwood SL, Burnet PWJ, Harrison PJ. Expression of complexin I and II mRNAs and their regulation by antipsychotic drugs in the rat forebrain. Synapse 2000a; 36: 167–177.PubMedCrossRefGoogle Scholar
  13. Eastwood SL, Cairns NJ, Harrison Pi. Synaptophysin gene expression in schizophrenia. Brit J Psychiatry 2000b; 176: 236–242.CrossRefGoogle Scholar
  14. Eastwood SL, Cotter D, Harrison PJ. Cerebellar synaptic protein expression in schizophrenia. Neuroscience 2001; (in press).Google Scholar
  15. Eastwood SL, Harrison PJ. Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography. Neuroscience 1995; 69: 339343.Google Scholar
  16. Eastwood SL, Harrison PJ. Hippocampal and cortical growth-associated protein-43 messenger RNA in schizophrenia. Neuroscience 1998; 86: 437–448.PubMedCrossRefGoogle Scholar
  17. Eastwood SL, Harrison PJ. Detection and quantification of hippocampal synaptophysin messenger RNA in schizophrenia using autoclaved, fonnalin-fixed, paraffin wax-embedded sections. Neuroscience 1999; 93: 99–106.PubMedCrossRefGoogle Scholar
  18. Eastwood SL, Harrison PJ. Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. Brain Res Bull 2001; (ín press).Google Scholar
  19. Eastwood SL, Heffernan J, Harrison PJ. Chronic haloperidol treatment differentially affects the expression of synaptic and neuronal plasticity-associated genes. Molec Psychiatry 1997; 2: 322–329.CrossRefGoogle Scholar
  20. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatric Res 1982–83; 17: 319–334.Google Scholar
  21. Fog R, Pakkenberg H, Juul P, Bock E, Jorgensen OS, Andersen J. High-dose treatment of rats with perphenazine. Psychopharmacol 1976; 50: 305–307.CrossRefGoogle Scholar
  22. Gabriel SM, Haroutunian V, Powchik P, et al. Increased concentrations of presynaptic proteins in the cingulate cortex of schizophrenics. Arch Gen Psychiatry 1997; 54: 559–566.PubMedCrossRefGoogle Scholar
  23. Geddes JW, Hess EJ, Hart RA, Kesslak JP, Cotman CW, Wilson MC. Lesions of hippocampal circuitry define synaptosomal-associated protein-25 (SNAP-25) as a novel presynaptic marker. Neuroscience 1990; 38: 515–525.PubMedCrossRefGoogle Scholar
  24. Glantz LA, Austin MC, Lewis DA. Normal cellular levels of synaptophysin mRNA expression in the prefrontal cortex of subjects with schizophrenia Biol Psychiatry 2000; 48: 389–397.Google Scholar
  25. Glantz LA, Lewis DA. Synaptophysin and not rab3A is specifically reduced in the prefrontal cortex of schizophrenic subjects. Soc Neurosci Abstr 1993; 20: 622.Google Scholar
  26. Glantz LA, Lewis DA. Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia: regional and diagnstic specificity. Arch Gen Psychiatry 1997; 54: 943–952.PubMedCrossRefGoogle Scholar
  27. Hamos JE, DeGennaro LJ, Drachman DA. Synaptic loss in Alzheimer’s disease and other dementias. Neurology 1989; 39: 355–361.PubMedCrossRefGoogle Scholar
  28. Harrison PJ. The neuropathological effects of antipsychotic drugs. Schizophr Res 1999; 40: 8799.CrossRefGoogle Scholar
  29. Harrison PJ, Eastwood SL. Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia. Lancet 1998; 352: 1669–1673.PubMedCrossRefGoogle Scholar
  30. Heindel WC, Jernigan TL, Archibald SL, Achim CL, Masliah E, Wiley CA. The relationship of quantitative brain magnetic resonance imaging measures to neuropathologie indices of human immunodeficiency virus infection. Arch Neurology 1994; 51: 1129–1135.CrossRefGoogle Scholar
  31. Helme-Guizon A, Davis S, Israel M, et al. Increase in syntaxin IB and glutamate release in mossy fibre terminals following induction of LTP in the dentate gyrus: a candidate molecular mechanism underlying transsynaptic plasticity. Eur J Neurosci 1998; 10: 2231 2237.Google Scholar
  32. Hicks A, Davis S, Rodger J, Helme-Guizon A, Laroche S, Mallet J. Synapsin I and syntaxin 1B: key elements in the control of neurotransmitter release are regulated by neuronal activation and long-term potentiation in vivo. Neuroscience 1997; 79: 329–340.PubMedCrossRefGoogle Scholar
  33. Honer WG, Falkai P, Bayer TA, et al. Abnormalities of SNARE mechanism proteins in anterior frontal cortex in severe mental illness. Cerebral Cortex 2001; (submitted).Google Scholar
  34. Honer WG, Falkai P, Chen C, Arango V, Mann JJ, Dwork M. Synaptic and plasticity associated proteins in anterior frontal cortex in severe mental illness. Neuroscience 1999; 91: 1247–1255.PubMedCrossRefGoogle Scholar
  35. Honer WG, Falkai P, Young C, et al. Cingulate cortex synaptic terminal proteins and neural cell adhesion molecule in schizophrenia Neuroscience 1997; 78: 99–110.Google Scholar
  36. Honer WG, Young C, Falkai P. Synaptic pathology. In: Harrison PJ, Roberts GW (eds). The Neuropathology of Schizophrenia Oxford University Press, Oxford, 2000; pp 105–136.Google Scholar
  37. Jorgensen OS, Riederer P. Increased synaptic markers in hippocampus of depressed patients. J Neural Transmission 1985; 64: 55–66.CrossRefGoogle Scholar
  38. Kamphuis W, Smirnova T, Hicks A, Hendriksen H, Mallet J, Lopes da Silva FH. The expression of syntaxin 1B/GR33 mRNA is enhanced in the hippocampal kindling model of epileptogenesis. J Neurochem 1995; 65: 1974–1980.PubMedCrossRefGoogle Scholar
  39. Karson CN, Mrak RE, Schluterman KO, Stumer WQ, Sheng JG, Griffin WST. Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for ‘hypofrontality’. Molec Psychiatry 1999; 4: 39–45.CrossRefGoogle Scholar
  40. Kroesen S, Marksteiner J, Mahata SK, et al. Effects of haloperidol, clozapine and citalopram on messenger RNA levels of chromogranins A and B and secretogranin II in various regions of rat brain. Neuroscience 1995; 69: 881–891.PubMedCrossRefGoogle Scholar
  41. Lidow MS, Song Z-M, Castner SA, Allen PB, Greengard P, Goldman-Rakic PS. Antipsychotic treatment induces alterations in dendrite-and spine-associated proteins in dopamine-rich areas of the primate cerebral cortex. Biol Psychiatry 2001; 49: 1–12.PubMedCrossRefGoogle Scholar
  42. Liu D, Diorio J, Day JC, Francis DD, Meaney MJ. Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nature Neurosci 2000; 3: 799–806.PubMedCrossRefGoogle Scholar
  43. Loessner B, Bullock S, Rose SPR. 411B: a monoclonal postsynaptic marker for modulations of synaptic connectivity in the rat brain. J Neurochem 1988; 51: 385–390.PubMedCrossRefGoogle Scholar
  44. Lue L-F, Brachova L, Civin WH, Rogers J. Inflammation, Ab deposition, and neurofibrillary tangle formation as correlates of Alzheimer’s disease neurodegeneration. Journal of Neuropathology and Experimental Neurology 1996; 55: 1083–1088.PubMedGoogle Scholar
  45. Lynch MA, Voss KL, Rodriguez J, Bliss TVP. Increase in synaptic vesicle proteins accompanies long-term potentiation in the dentate gyms. Neuroscience 1994; 60: 1–5.PubMedCrossRefGoogle Scholar
  46. Marin C, Tolosa E. Striatal synaptophysin levels are not indicative of dopaminergic supersensitivity. Neuropharmacol 1997; 36: 1115–1117.CrossRefGoogle Scholar
  47. Masliah E, Ellisman M, Carragher B, et al. Three-dimensional analysis of the relationship between synaptic pathology and neuropil threads in Alzheimer disease. J Neuropathol Exp Neurol 1992; 51: 404–414.PubMedCrossRefGoogle Scholar
  48. Masliah E, Fagan AM, Terry RD, DeTeresa R, Mallory M, Gage FH. Reactive synaptogenesis assessed by synaptophysin immunoreactivity is associated with GAP-43 in the dentate gyrus of the adult rat. Exp Neurol 1991; 113: 131–142.PubMedCrossRefGoogle Scholar
  49. Masliah E, Terry RD, DeTeresa RM, Hansen LA. Inununohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci Lett 1989; 103: 234–239.PubMedCrossRefGoogle Scholar
  50. McGlashan TH, Hoffman RE. Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch Gen Psychiatry 2000; 57: 637–648.PubMedCrossRefGoogle Scholar
  51. Melloni RH, Hemmendinger LM, Hamos JE, DeGennnaro LJ. Synapsin I gene expression in the adult rat brain with comparative analysis of mRNA and protein in the hippocampus. J Comp Neurol 1993; 327: 507–520.PubMedCrossRefGoogle Scholar
  52. Minger SL, Honer WG, Esiri MM, et al. Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer’s disease. J Neuropath Exp Neurol 2001 (in press).Google Scholar
  53. Mimics K, Middleton FA, Marquez A, Lewis DA, Levitt P. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 2000; 28: 53–67.CrossRefGoogle Scholar
  54. Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, et al. Staging of cytoskeletal and b-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer’s disease. Am J Pathol 2000; 157: 623–636.PubMedCrossRefGoogle Scholar
  55. Mullany PM, Lynch MA. Evidence for a role for synaptophysin in expression of long-term potentiation in rat dentate gyrus. NeuroReport 1998; 9: 2489–2494.Google Scholar
  56. Nakahara T, Motomura K, Hashimoto K, et al. Long-term treatment with haloperidol decreases the mRNA levels of complexin I, but not complexin II, in rat prefrontal cortex, nucleus acumbens and ventral tegmental area. Neurosci Lett 2000; 290: 29–32.PubMedCrossRefGoogle Scholar
  57. Nakahara T, Nakamura K, Tsutsumi T, et al. Effect of chronic haloperidol treatment on synaptic protein mRNAs in the rat brain. Molec Brain Res 1998; 61: 238–242.PubMedCrossRefGoogle Scholar
  58. Patanow CM, Day JR, Billingsley ML. Alterations in hippocampal expression of SNAP-25, GAP-43, stannin and glial fibrillary acidic protein following mechanical and trimethyltininduced injury in the rat. Neuroscience 1997; 76: 187–202.PubMedCrossRefGoogle Scholar
  59. Perrone-Bizzozero NI, Sower AC, Bird ED, Benowitz LI, Ivins KJ, Neve RL. Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. Proc Nat Acad Sci U.S.A. 1996; 93: 14182–14187.CrossRefGoogle Scholar
  60. Poltorak M, Herranz AS, Williams J, Lauretti L, Freed WJ. Effects of frontal cortical lesions on mouse striatum: reorganizationof cell recognition molecule, glial fiber, and synaptic protein expression in the dorsomedial striatum. J Neurosci 1993; 13: 2217–2223.PubMedGoogle Scholar
  61. Richter-Levin G, Thomas KL, Hunt SP, Bliss TVP. Dissociation between genes activated in long-term potentiation and in spatial learning in the rat. Neurosci Lett 1998; 251: 41–44.PubMedCrossRefGoogle Scholar
  62. Roberts LA, Morris BJ, O’Shaughnessey CT. Involvement of two isoforms of SNAP-25 in the expression of long-term potentiation in the rat hippocampus. NeuroReport 1998; 9: 33–36.Google Scholar
  63. Rodger J, Davis S, Laroche S, Mallet J, Hicks A. Induction of long-term potentiation in vivo regulates alternate splicing to alter syntaxin 3 isoform expression in rat dentate gyros. J Neurochem 1998; 71: 666–675.PubMedCrossRefGoogle Scholar
  64. Sawada K, Takahashi S, Dwork AJ, Li H-Y, Hu L, Falkai P. Complexins I and II in anterior frontal cortex in schizophrenia. Schizophr Res 2001; (in press).Google Scholar
  65. Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 1999; 45: 17–25.PubMedCrossRefGoogle Scholar
  66. Sokolov BP, Tcherepanov AA, Haroutunian V, Davis KL. Levels of mRNAs encoding synaptic vesicle and synaptic plasma membrane proteins in the temporal cortex of elderly schizophrenic patients. Biol Psychiatry 2000; 48: 184–196.PubMedCrossRefGoogle Scholar
  67. Stefan MD, Horton K, Johnston P, Bruton CJ, Roberts GW, Royston MC. Synaptic pathology in schizophrenia: abnormalities of the prefrontal cortex. Schizophr Res 1995; 15: 32.CrossRefGoogle Scholar
  68. Tcherepanov AA, Sokolov BP. Age-related abnormalities in expression of mRNAs encoding synapsin IA, synapsin I B, and synaptophysin in temporal cortex of schizophrenics. J Neurosci Res 1997; 49: 639–644.PubMedCrossRefGoogle Scholar
  69. Terry RD, Masliah E, Salmon DP, 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.PubMedCrossRefGoogle Scholar
  70. Thompson PM, Sower AC, Perrone-Bizzozero NI. Altered levels of the synaptosomal associated protein SNAP-25 in schizophrenia. Biol Psychiatry 1998; 43: 239–243.PubMedCrossRefGoogle Scholar
  71. Vawter MP, Cannon-Spoor HE, Hemperly JJ, et al. Abnormal expression of cell recognition molecules in schizophrenia. Exp Neurol 1998; 149: 424–432.PubMedCrossRefGoogle Scholar
  72. Vawter MP, Howard AL, Hyde TM, Kleinman JE, Freed WJ. Alterations of hippocampal secreted N-CAM in bipolar disorder and synaptophysin in schizophrenia. Molec Psychiatry 1999; 4: 467–475.CrossRefGoogle Scholar
  73. Walaas SI, Jahn R, Greengard P. Quantitation of nerve terminal populations: synaptic vesicleasociated proteins as markers for synaptic density in the rat neostriatum. Synapse 1988; 2: 516–520.PubMedCrossRefGoogle Scholar
  74. 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: 61–70.CrossRefGoogle Scholar
  75. Weickert CS, Webster MJ, Hyde TM, et al. Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia. Cereb Cortex 2001; 11: 136–147.PubMedCrossRefGoogle Scholar
  76. Young CE, Arima K, Xie J, et al. SNAP-25 deficit and hippocampal connectivity in schizophrenia. Cereb Cortex 1998; 8: 261–268.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2002

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  • William G. Honer

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