Journal of Neural Transmission

, Volume 104, Issue 11–12, pp 1371–1381 | Cite as

Changes in protein kinase C and adenylate cyclase in the temporal lobe from subjects with schizophrenia

  • B. Dean
  • K. Opeskin
  • G. Pavey
  • C. Hill
  • N. Keks
Biological Psychiatry

Summary

Changes in G-protein linked neurotransmitter receptors have been reported in a number of regions of the brain of schizophrenic subjects. These changes, if functional, could cause a change in proteins such as protein kinase C (PKC) and adenylate cyclase (AC) which are important components of the G-protein linked second messenger cascades. We therefore used autoradiography to measure the distribution and density of [3H]phorbol ester binding to PKC and [3H]forskolin binding to AC in tissue obtained at autopsy from schizophrenic and non-schizophrenic subjects (Controls). There were significant decreases in the density of PKC in the parahippocampal gyrus (687 ± 60 vs. 885 ± 51fmol/mg TE; mean ± SEM; p < 0.01) and in AC in the dentate gyrus (75 ± 4.9 vs. 92 ± 6.5, p < 0.05) from the schizophrenic subjects. These data could indicate that changes in neurotransmitter receptors in the hippocampus from subjects with schizophrenia could have resulted in a change in their associated second messenger systems.

Keywords

Schizophrenia protein kinase C adenylate cyclase hippocampus frontal cortex human brain 

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References

  1. Altshuler LL, Casanova MF, Goldberg TE, Kleinman JE (1990) The hippocampus and parahippocampus in schizophrenic, suicide and control brains. Arch Gen Psychiatry 47: 1029–1034Google Scholar
  2. American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders, 3rd edn, rev. American Psychiatric Association, Washington DCGoogle Scholar
  3. Appel NM, Robbins JD, De Souza EB, Seamon KB (1992) [125I]-labelled forskolin analogs which discriminate adenlyl cyclase and a glucose transporter: pharmacological characterization of binding sites in rat brain by in vitro receptor autoradiography. J Pharmacol Exp Ther 263: 1415–1423Google Scholar
  4. Arnold SE, Franz BR, Gur RC, Gur RE, Shapiro RM, Moberg PJ, Trojanowski JQ (1995) Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. Am J Psychiatry 152: 738–748Google Scholar
  5. Arora RC, Meltzer HY (1991) Serotonin2 (5-HT2) receptor binding in the frontal cortex of schizophrenic patients. J Neural Transm [Gen Sect] 85: 19–29Google Scholar
  6. Conrad AJ, Abede T, Austin R, Forsythe S, Scheibel AB (1991) Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon. Arch Gen Psychiatry 48: 413–417Google Scholar
  7. Dean B, Hayes W (1996) Decreased frontal cortical serotonin2Areceptors in subjects with schizophrenia. Schizophr Res 21: 133–139Google Scholar
  8. Dean B, Opeskin K, Pavey G, Naylor L, Hill C, Keks NA, Copolov DL (1995) [3H]paroxetine binding is altered in the hippocampus but not the frontal cortex or caudate nucleus from subjects with schizophrenia. J Neurochem 64: 1197–1202Google Scholar
  9. Freedman R, Hall M, Adler LE, Leonard S (1995) Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38: 22–33Google Scholar
  10. Gehlert D, Dawson T, Yamamura H, Wamsley J (1985) Quantitative autoradiography of [3H]Forskolin binding sites in the rat brain. Brain Res 361: 351–360Google Scholar
  11. Giambalvo CT, Wagner RL (1994) Activation of D1 and D2 dopamine receptors inhibits protein kinase C activity in striatal synaptoneurosomes. J Neurochem 63: 169–176Google Scholar
  12. Glatt CE, Snyder SH (1993) Cloning and expression of an adenylyl cyclase localized to the corpus striatum. Nature 361: 536–538Google Scholar
  13. Hashimoto T, Kitamura N, Kajimoto Y, Shirai Y, Shirakawa O, Mita T, Nishino N, Tanaka C (1993) Differential changes in serotonin 5-HT1A and 5-HT2 receptor binding in patients with chronic schizophrenia. Psychopharmacology (Berl) 112: S35-S39Google Scholar
  14. Heckers S, Heinsen H, Beckmann H (1991) Hippocampal neuron number in schizophrenia. Arch Gen Psychiatry 48: 1002–1008Google Scholar
  15. Hill C, Keks NA, Roberts S, Opeskin K, Dean B, Copolov DL (1996) Postmortem brain studies in schizophrenia: the problems of diagnosis. Am J Psychiatry 153: 533–537Google Scholar
  16. Horsburgh K, Dewar D, Graham DI, McCulloch J (1991) Autoradiographic imaging of [3H]phorbol 12,13-dibutyrate binding to protein kinase C in Alzheimers disease. J Neurochem 56: 1121–1129Google Scholar
  17. Jeste DV, Lohr JB (1989) Hippocampal pathologic findings in schizophrenia. Arch Gen Psychiatry 46: 1019–1024Google Scholar
  18. Joyce JN, Shane A, Lexow N, Winokur A, Casanova MF, Kleinman JE (1993) Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology 8: 315–336Google Scholar
  19. Julius D (1991) Molecular biology of serotonin receptors. Ann Rev Neurosci 14: 335–360Google Scholar
  20. Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277: 93–96Google Scholar
  21. Kerwin RW, Beats BC (1990) Increased forskolin binding in the left parahippocampal gyrus and CA1 region in post mortem schizophrenic brain determined by quantitative autoradiography. Neurosci Lett 118: 164–168Google Scholar
  22. Kerwin RW, Patel S, Meldrum BS, Czudek C, Reynolds GP (1988) Asymmetrical loss of glutamate receptor subtype in left hippocampus in schizophrenia. Lancet i: 583–584Google Scholar
  23. Kikkawa U, Nishizuka Y (1986) The role of protein kinase C in transmembrane signalling. Annu Rev Cell Biol 2: 149–178Google Scholar
  24. Luchins DJ (1990) A possible role of hippocampal dysfunction in schizophrenic symptomatology. Biol Psychiatry 28: 87–91Google Scholar
  25. Nishino N, Kitamura N, Hashimoto T, Kajimoto Y, Shirai Y, Murakami N, Nakai T, Komure O, Shirakaea O, Mita T, Nakai H (1993) Increase in [3H]cAMP binding sites and decrease in Gia and Goa immunoreactivities in left temporal cortices from patients with schizophrenia. Brain Res 615: 41–49Google Scholar
  26. Nishizuka Y (1988) The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334: 661–665Google Scholar
  27. Opeskin K, Dean B, Pavey G, Hill C, Keks NA, Copolov DL (1996) Neither levels of protein kinase C nor adenylate cyclase are altered in the caudate putamen from subjects with schizophrenia. Schizophr Res 22: 159–164Google Scholar
  28. Pantelis C, Barnes TRE, Nelson HE (1992) Is the concept of frontal-subcortical dementia relevant to schizophrenia. Br J Psychiatry 160: 442–460Google Scholar
  29. Pearce RKB, Seeman P, Jellinger K, Tourtellotte WW (1990) Dopamine uptake sites and dopamine receptors in Parkinson's disease and schizophrenia. Eur Neurol 30 [Suppl 1]: 9–14Google Scholar
  30. Reynolds GP, Czudek C, Andrews HB (1990) Deficit and hemispheric asymmetry of GABA uptake sites in hippocampus in schizophrenia. Biol Psychiatry 27: 1038–1044Google Scholar
  31. Rolls ET, O'Mara S (1993) Neurophysiological and theoretical analysis of how the primate hippocampus functions in memory. In: Ono T, Squire LR, Raichle ME, Perrett DI, Fukuda M (eds) Brain mechanisms of perception and memory: from neuron to behaviour. Oxford University Press, New York, pp 276–300Google Scholar
  32. Sibley DR, Monsma FJ (1992) Molecular biology of dopamine receptors. Trends Pharmacol Sci 13: 61–69Google Scholar
  33. Sujzuki T (1993) Characterisation of protein kinase C activities in postsynaptic density fractions prepared from cerebral cortex, hippocampus and cerebellum. Brain Res 619: 69–75Google Scholar
  34. Wan DC, Pavey G, Dean B, Copolov DL (1996) Chronic treatment with haloperidol or clozapine causes differential changes in dopamine receptors but not levels of adenylate cyclase or protein kinase in rat forebrain. Life Sci 59: 2001–2008Google Scholar
  35. Weinberger DR, Berman KF, Zec RF (1986) Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. Arch Gen Psychiatry 43: 114–124Google Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • B. Dean
    • 1
  • K. Opeskin
    • 2
  • G. Pavey
    • 1
  • C. Hill
    • 1
  • N. Keks
    • 1
  1. 1.The Mental Health Research Institute of VictoriaParkville
  2. 2.The Victorian Institute of Forensic MedicineSouth MelbourneAustralia

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