Skip to main content
PMC home page
Postgraduate Medical Journal logoLink to Postgraduate Medical Journal
. 2002 Mar;78(917):142–148. doi: 10.1136/pmj.78.917.142

Understanding the pathology of schizophrenia: recent advances from the study of the molecular architecture of postmortem CNS tissue

B Dean 1
PMCID: PMC1742312  PMID: 11884695

Abstract

The use of central nervous system (CNS) tissue obtained postmortem has long underpinned efforts to understand the neurobiology of schizophrenia, but the ability to use such tissue in conjunction with a wide variety of methodologies has seen a renaissance of interest in this area of research. Recent findings have shown changes in markers in a number of neurotransmitter systems in the brains of subjects with schizophrenia which include the dopaminergic, serotonergic, cholinergic, glutamatergic, and GABAergic systems of the CNS. Many of these changes also appear to be regionally specific, and abnormalities in non-neurotransmitter specific pathways have been found in schizophrenia. Changes in the neurotransmitter release pathways in schizophrenia may be important in the pathology of the illness, and recent findings suggest that abnormalities in the Wnt pathway, which controls transcription selectivity in cells, may be involved. Studies using CNS material obtained postmortem clearly show that the pathology of schizophrenia is complex while the polygenetic nature of the illness may be adding to this complexity.

Full Text

The Full Text of this article is available as a PDF (109.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aparicio-Legarza M. I., Davis B., Hutson P. H., Reynolds G. P. Increased density of glutamate/N-methyl-D-aspartate receptors in putamen from schizophrenic patients. Neurosci Lett. 1998 Jan 30;241(2-3):143–146. doi: 10.1016/s0304-3940(98)00017-2. [DOI] [PubMed] [Google Scholar]
  2. Beasley C., Cotter D., Khan N., Pollard C., Sheppard P., Varndell I., Lovestone S., Anderton B., Everall I. Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia. Neurosci Lett. 2001 Apr 20;302(2-3):117–120. doi: 10.1016/s0304-3940(01)01688-3. [DOI] [PubMed] [Google Scholar]
  3. Breese C. R., Lee M. J., Adams C. E., Sullivan B., Logel J., Gillen K. M., Marks M. J., Collins A. C., Leonard S. Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology. 2000 Oct;23(4):351–364. doi: 10.1016/S0893-133X(00)00121-4. [DOI] [PubMed] [Google Scholar]
  4. Court J. A., Piggott M. A., Lloyd S., Cookson N., Ballard C. G., McKeith I. G., Perry R. H., Perry E. K. Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease and in relation to neuroleptic medication. Neuroscience. 2000;98(1):79–87. doi: 10.1016/s0306-4522(00)00071-3. [DOI] [PubMed] [Google Scholar]
  5. Crook J. M., Dean B., Pavey G., Copolov D. The binding of [3H]AF-DX 384 is reduced in the caudate-putamen of subjects with schizophrenia. Life Sci. 1999;64(19):1761–1771. doi: 10.1016/s0024-3205(99)00114-9. [DOI] [PubMed] [Google Scholar]
  6. Crook J. M., Tomaskovic-Crook E., Copolov D. L., Dean B. Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. Biol Psychiatry. 2000 Sep 1;48(5):381–388. doi: 10.1016/s0006-3223(00)00918-5. [DOI] [PubMed] [Google Scholar]
  7. Dale T. C. Signal transduction by the Wnt family of ligands. Biochem J. 1998 Jan 15;329(Pt 2):209–223. doi: 10.1042/bj3290209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dale T. C. Signal transduction by the Wnt family of ligands. Biochem J. 1998 Jan 15;329(Pt 2):209–223. doi: 10.1042/bj3290209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Davidsson P., Gottfries J., Bogdanovic N., Ekman R., Karlsson I., Gottfries C. G., Blennow K. The synaptic-vesicle-specific proteins rab3a and synaptophysin are reduced in thalamus and related cortical brain regions in schizophrenic brains. Schizophr Res. 1999 Nov 9;40(1):23–29. doi: 10.1016/s0920-9964(99)00037-7. [DOI] [PubMed] [Google Scholar]
  10. Dean B., Crook J. M., Opeskin K., Hill C., Keks N., Copolov D. L. The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia. Mol Psychiatry. 1996 Mar;1(1):54–58. [PubMed] [Google Scholar]
  11. Dean B., Crook J. M., Pavey G., Opeskin K., Copolov D. L. Muscarinic1 and 2 receptor mRNA in the human caudate-putamen: no change in m1 mRNA in schizophrenia. Mol Psychiatry. 2000 Mar;5(2):203–207. doi: 10.1038/sj.mp.4000684. [DOI] [PubMed] [Google Scholar]
  12. Dean B., Hayes W., Hill C., Copolov D. Decreased serotonin2A receptors in Brodmann's area 9 from schizophrenic subjects. A pathological or pharmacological phenomenon? Mol Chem Neuropathol. 1998 Jun-Aug;34(2-3):133–145. doi: 10.1007/BF02815075. [DOI] [PubMed] [Google Scholar]
  13. Dean B., Hussain T., Hayes W., Scarr E., Kitsoulis S., Hill C., Opeskin K., Copolov D. L. Changes in serotonin2A and GABA(A) receptors in schizophrenia: studies on the human dorsolateral prefrontal cortex. J Neurochem. 1999 Apr;72(4):1593–1599. doi: 10.1046/j.1471-4159.1999.721593.x. [DOI] [PubMed] [Google Scholar]
  14. Dean B., Pavey G., McLeod M., Opeskin K., Keks N., Copolov D. A change in the density of [(3)H]flumazenil, but not [(3)H]muscimol binding, in Brodmann's Area 9 from subjects with bipolar disorder. J Affect Disord. 2001 Oct;66(2-3):147–158. doi: 10.1016/s0165-0327(00)00294-9. [DOI] [PubMed] [Google Scholar]
  15. Dean B., Scarr E., Bradbury R., Copolov D. Decreased hippocampal (CA3) NMDA receptors in schizophrenia. Synapse. 1999 Apr;32(1):67–69. doi: 10.1002/(SICI)1098-2396(199904)32:1<67::AID-SYN9>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  16. Dean B. Signal transmission, rather than reception, is the underlying neurochemical abnormality in schizophrenia. Aust N Z J Psychiatry. 2000 Aug;34(4):560–569. doi: 10.1080/j.1440-1614.2000.00747.x. [DOI] [PubMed] [Google Scholar]
  17. Dean B. Signal transmission, rather than reception, is the underlying neurochemical abnormality in schizophrenia. Aust N Z J Psychiatry. 2000 Aug;34(4):560–569. doi: 10.1080/j.1440-1614.2000.00747.x. [DOI] [PubMed] [Google Scholar]
  18. Dean B., Sundram S., Bradbury R., Scarr E., Copolov D. Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience. 2001;103(1):9–15. doi: 10.1016/s0306-4522(00)00552-2. [DOI] [PubMed] [Google Scholar]
  19. Dean B., Tomaskovic-Crook E., Opeskin K., Keks N., Copolov D. No change in the density of the serotonin1A receptor, the serotonin4 receptor or the serotonin transporter in the dorsolateral prefrontal cortex from subjects with schizophrenia. Neurochem Int. 1999 Feb;34(2):109–115. doi: 10.1016/s0197-0186(98)00074-6. [DOI] [PubMed] [Google Scholar]
  20. Deutsch S. I., Mastropaolo J., Schwartz B. L., Rosse R. B., Morihisa J. M. A "glutamatergic hypothesis" of schizophrenia. Rationale for pharmacotherapy with glycine. Clin Neuropharmacol. 1989 Feb;12(1):1–13. [PubMed] [Google Scholar]
  21. Durany N., Zöchling R., Boissl K. W., Paulus W., Ransmayr G., Tatschner T., Danielczyk W., Jellinger K., Deckert J., Riederer P. Human post-mortem striatal alpha4beta2 nicotinic acetylcholine receptor density in schizophrenia and Parkinson's syndrome. Neurosci Lett. 2000 Jun 23;287(2):109–112. doi: 10.1016/s0304-3940(00)01144-7. [DOI] [PubMed] [Google Scholar]
  22. Eastwood S. L., Cairns N. J., Harrison P. J. Synaptophysin gene expression in schizophrenia. Investigation of synaptic pathology in the cerebral cortex. Br J Psychiatry. 2000 Mar;176:236–242. doi: 10.1192/bjp.176.3.236. [DOI] [PubMed] [Google Scholar]
  23. Gao X. M., Sakai K., Roberts R. C., Conley R. R., Dean B., Tamminga C. A. Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. Am J Psychiatry. 2000 Jul;157(7):1141–1149. doi: 10.1176/appi.ajp.157.7.1141. [DOI] [PubMed] [Google Scholar]
  24. Glantz L. A., Austin M. C., Lewis D. A. Normal cellular levels of synaptophysin mRNA expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry. 2000 Sep 1;48(5):389–397. doi: 10.1016/s0006-3223(00)00923-9. [DOI] [PubMed] [Google Scholar]
  25. Goodman A. B., Pardee A. B. Meeting report; "Molecular neurobiological mechanisms in schizophrenia: seeking a synthesis," April 11-14, 1999. Biol Psychiatry. 2000 Aug 1;48(3):173–183. doi: 10.1016/s0006-3223(00)00904-5. [DOI] [PubMed] [Google Scholar]
  26. Healy D. J., Haroutunian V., Powchik P., Davidson M., Davis K. L., Watson S. J., Meador-Woodruff J. H. AMPA receptor binding and subunit mRNA expression in prefrontal cortex and striatum of elderly schizophrenics. Neuropsychopharmacology. 1998 Oct;19(4):278–286. doi: 10.1016/S0893-133X(98)00014-1. [DOI] [PubMed] [Google Scholar]
  27. Hernandez I., Sokolov B. P. Abnormalities in 5-HT2A receptor mRNA expression in frontal cortex of chronic elderly schizophrenics with varying histories of neuroleptic treatment. J Neurosci Res. 2000 Jan 15;59(2):218–225. [PubMed] [Google Scholar]
  28. Honer W. G., Falkai P., Chen C., Arango V., Mann J. J., Dwork A. J. Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness. Neuroscience. 1999;91(4):1247–1255. doi: 10.1016/s0306-4522(98)00679-4. [DOI] [PubMed] [Google Scholar]
  29. Huntsman M. M., Tran B. V., Potkin S. G., Bunney W. E., Jr, Jones E. G. Altered ratios of alternatively spliced long and short gamma2 subunit mRNAs of the gamma-amino butyrate type A receptor in prefrontal cortex of schizophrenics. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):15066–15071. doi: 10.1073/pnas.95.25.15066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Huttunen M. The evolution of the serotonin-dopamine antagonist concept. J Clin Psychopharmacol. 1995 Feb;15(1 Suppl 1):4S–10S. doi: 10.1097/00004714-199502001-00002. [DOI] [PubMed] [Google Scholar]
  31. Ibrahim H. M., Hogg A. J., Jr, Healy D. J., Haroutunian V., Davis K. L., Meador-Woodruff J. H. Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia. Am J Psychiatry. 2000 Nov;157(11):1811–1823. doi: 10.1176/appi.ajp.157.11.1811. [DOI] [PubMed] [Google Scholar]
  32. Impagnatiello F., Guidotti A. R., Pesold C., Dwivedi Y., Caruncho H., Pisu M. G., Uzunov D. P., Smalheiser N. R., Davis J. M., Pandey G. N. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15718–15723. doi: 10.1073/pnas.95.26.15718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Jarskog L. F., Gilmore J. H., Selinger E. S., Lieberman J. A. Cortical bcl-2 protein expression and apoptotic regulation in schizophrenia. Biol Psychiatry. 2000 Oct 1;48(7):641–650. doi: 10.1016/s0006-3223(00)00988-4. [DOI] [PubMed] [Google Scholar]
  34. Kouzmenko A. P., Hayes W. L., Pereira A. M., Dean B., Burnet P. W., Harrison P. J. 5-HT2A receptor polymorphism and steady state receptor expression in schizophrenia. Lancet. 1997 Jun 21;349(9068):1815–1815. doi: 10.1016/S0140-6736(05)61695-9. [DOI] [PubMed] [Google Scholar]
  35. Kouzmenko A. P., Scaffidi A., Pereira A. M., Hayes W. L., Copolov D. L., Dean B. No correlation between A(-1438)G polymorphism in 5-HT2A receptor gene promoter and the density of frontal cortical 5-HT2A receptors in schizophrenia. Hum Hered. 1999 Mar;49(2):103–105. doi: 10.1159/000022853. [DOI] [PubMed] [Google Scholar]
  36. Kozlovsky N., Belmaker R. H., Agam G. Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry. 2000 May;157(5):831–833. doi: 10.1176/appi.ajp.157.5.831. [DOI] [PubMed] [Google Scholar]
  37. Kühl M., Sheldahl L. C., Park M., Miller J. R., Moon R. T. The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet. 2000 Jul;16(7):279–283. doi: 10.1016/s0168-9525(00)02028-x. [DOI] [PubMed] [Google Scholar]
  38. Landén M., Davidsson P., Gottfries C. G., Grenfeldt B., Stridsberg M., Blennow K. Reduction of the small synaptic vesicle protein synaptophysin but not the large dense core chromogranins in the left thalamus of subjects with schizophrenia. Biol Psychiatry. 1999 Dec 15;46(12):1698–1702. doi: 10.1016/s0006-3223(99)00160-2. [DOI] [PubMed] [Google Scholar]
  39. Masters C. L., Beyreuther K. The Worster-Drought syndrome and other syndromes of dementia with spastic paraparesis: the paradox of molecular pathology. J Neuropathol Exp Neurol. 2001 Apr;60(4):317–319. doi: 10.1093/jnen/60.4.317. [DOI] [PubMed] [Google Scholar]
  40. Meltzer H. Y. Biochemical studies in schizophrenia. Schizophr Bull. 1976;2(1):10–18. doi: 10.1093/schbul/2.1.10. [DOI] [PubMed] [Google Scholar]
  41. Meltzer H. Y. Biochemical studies in schizophrenia. Schizophr Bull. 1976;2(1):10–18. doi: 10.1093/schbul/2.1.10. [DOI] [PubMed] [Google Scholar]
  42. Miyaoka T., Seno H., Ishino H. Increased expression of Wnt-1 in schizophrenic brains. Schizophr Res. 1999 Jul 27;38(1):1–6. doi: 10.1016/s0920-9964(98)00179-0. [DOI] [PubMed] [Google Scholar]
  43. Ohnuma T., Augood S. J., Arai H., McKenna P. J., Emson P. C. Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia. Brain Res Mol Brain Res. 1998 May;56(1-2):207–217. doi: 10.1016/s0169-328x(98)00063-1. [DOI] [PubMed] [Google Scholar]
  44. Ohnuma T., Augood S. J., Arai H., McKenna P. J., Emson P. C. 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(2):441–448. doi: 10.1016/s0306-4522(99)00189-x. [DOI] [PubMed] [Google Scholar]
  45. Pralong D., Tomaskovic-Crook E., Opeskin K., Copolov D., Dean B. Serotonin(2A) receptors are reduced in the planum temporale from subjects with schizophrenia. Schizophr Res. 2000 Jul 7;44(1):35–45. doi: 10.1016/s0920-9964(99)00150-4. [DOI] [PubMed] [Google Scholar]
  46. Richardson-Burns S. M., Haroutunian V., Davis K. L., Watson S. J., Meador-Woodruff J. H. Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus. Biol Psychiatry. 2000 Jan 1;47(1):22–28. doi: 10.1016/s0006-3223(99)00207-3. [DOI] [PubMed] [Google Scholar]
  47. Riley B. P., McGuffin P. Linkage and associated studies of schizophrenia. Am J Med Genet. 2000 Spring;97(1):23–44. doi: 10.1002/(sici)1096-8628(200021)97:1<23::aid-ajmg5>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  48. Riley B. P., McGuffin P. Linkage and associated studies of schizophrenia. Am J Med Genet. 2000 Spring;97(1):23–44. doi: 10.1002/(sici)1096-8628(200021)97:1<23::aid-ajmg5>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  49. Seeburg P. H. The TINS/TiPS Lecture. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci. 1993 Sep;16(9):359–365. doi: 10.1016/0166-2236(93)90093-2. [DOI] [PubMed] [Google Scholar]
  50. Selkoe D. J. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741–766. doi: 10.1152/physrev.2001.81.2.741. [DOI] [PubMed] [Google Scholar]
  51. Sokolov B. P. Expression of NMDAR1, GluR1, GluR7, and KA1 glutamate receptor mRNAs is decreased in frontal cortex of "neuroleptic-free" schizophrenics: evidence on reversible up-regulation by typical neuroleptics. J Neurochem. 1998 Dec;71(6):2454–2464. doi: 10.1046/j.1471-4159.1998.71062454.x. [DOI] [PubMed] [Google Scholar]
  52. Sokolov B. P., Tcherepanov A. A., Haroutunian V., Davis K. L. Levels of mRNAs encoding synaptic vesicle and synaptic plasma membrane proteins in the temporal cortex of elderly schizophrenic patients. Biol Psychiatry. 2000 Aug 1;48(3):184–196. doi: 10.1016/s0006-3223(00)00875-1. [DOI] [PubMed] [Google Scholar]
  53. Stefanis N. C., Bresnick J. N., Kerwin R. W., Schofield W. N., McAllister G. Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain. Brain Res Mol Brain Res. 1998 Jan;53(1-2):112–119. doi: 10.1016/s0169-328x(97)00285-4. [DOI] [PubMed] [Google Scholar]
  54. Tallerico T., Novak G., Liu I. S., Ulpian C., Seeman P. Schizophrenia: elevated mRNA for dopamine D2(Longer) receptors in frontal cortex. Brain Res Mol Brain Res. 2001 Mar 5;87(2):160–165. doi: 10.1016/s0169-328x(00)00293-x. [DOI] [PubMed] [Google Scholar]
  55. Tandon R. Cholinergic aspects of schizophrenia. Br J Psychiatry Suppl. 1999;(37):7–11. [PubMed] [Google Scholar]
  56. Thomas E. A., Dean B., Pavey G., Sutcliffe J. G. Increased CNS levels of apolipoprotein D in schizophrenic and bipolar subjects: implications for the pathophysiology of psychiatric disorders. Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4066–4071. doi: 10.1073/pnas.071056198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Thompson P. M., Sower A. C., Perrone-Bizzozero N. I. Altered levels of the synaptosomal associated protein SNAP-25 in schizophrenia. Biol Psychiatry. 1998 Feb 15;43(4):239–243. doi: 10.1016/S0006-3223(97)00204-7. [DOI] [PubMed] [Google Scholar]
  58. Turner K. M., Burgoyne R. D., Morgan A. Protein phosphorylation and the regulation of synaptic membrane traffic. Trends Neurosci. 1999 Oct;22(10):459–464. doi: 10.1016/s0166-2236(99)01436-8. [DOI] [PubMed] [Google Scholar]
  59. Turner K. M., Burgoyne R. D., Morgan A. Protein phosphorylation and the regulation of synaptic membrane traffic. Trends Neurosci. 1999 Oct;22(10):459–464. doi: 10.1016/s0166-2236(99)01436-8. [DOI] [PubMed] [Google Scholar]
  60. 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 Feb;158(2):256–265. doi: 10.1176/appi.ajp.158.2.256. [DOI] [PubMed] [Google Scholar]
  61. Webster M. J., Shannon Weickert C., Herman M. M., Hyde T. M., Kleinman J. E. Synaptophysin and GAP-43 mRNA levels in the hippocampus of subjects with schizophrenia. Schizophr Res. 2001 Apr 15;49(1-2):89–98. doi: 10.1016/s0920-9964(00)00052-9. [DOI] [PubMed] [Google Scholar]
  62. Young C. E., Arima K., Xie J., Hu L., Beach T. G., Falkai P., Honer W. G. SNAP-25 deficit and hippocampal connectivity in schizophrenia. Cereb Cortex. 1998 Apr-May;8(3):261–268. doi: 10.1093/cercor/8.3.261. [DOI] [PubMed] [Google Scholar]
  63. de Leon J., Dadvand M., Canuso C., White A. O., Stanilla J. K., Simpson G. M. Schizophrenia and smoking: an epidemiological survey in a state hospital. Am J Psychiatry. 1995 Mar;152(3):453–455. doi: 10.1176/ajp.152.3.453. [DOI] [PubMed] [Google Scholar]

Articles from Postgraduate Medical Journal are provided here courtesy of BMJ Publishing Group

RESOURCES