Psychopharmacology

, Volume 174, Issue 1, pp 151–162 | Cite as

The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications

Review

Abstract

This paper puts the case for the hippocampus as being central to the neuropathology and pathophysiology of schizophrenia. The evidence comes from a range of approaches, both in vivo (neuropsychology, structural and functional imaging) and post mortem (histology, morphometry, gene expression, and neurochemistry). Neuropathologically, the main positive findings concern neuronal morphology, organisation, and presynaptic and dendritic parameters. The results are together suggestive of an altered synaptic circuitry or “wiring” within the hippocampus and its extrinsic connections, especially with the prefrontal cortex. These changes plausibly represent the anatomical component of the aberrant functional connectivity that underlies schizophrenia. Glutamatergic pathways are prominently but not exclusively affected. Changes appear somewhat greater in the left hippocampus than the right, and CA1 is relatively uninvolved compared to other subfields. Hippocampal pathology in schizophrenia may be due to genetic factors, aberrant neurodevelopment, and/or abnormal neural plasticity; it is not due to any recognised neurodegenerative process. Hippocampal involvement is likely to be associated with the neuropsychological impairments of schizophrenia rather than with its psychotic symptoms.

Keywords

Neuropathology Psychosis Connectivity Glutamate Hippocampal formation Medial temporal lobe 

References

  1. Akbarian S, Bunney WE Jr, Potkin SG, Wigal SB, Hagman JO, Sandman CA, Jones EG (1993a) Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbrances of cortical development. Arch Gen Psychiatry 50:169–177PubMedGoogle Scholar
  2. Akbarian S, Viňuela A, Kim JJ, Potkin SG, Bvunney WE, Jr, Jones EG (1993b) Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development. Arch Gen Psychiatry 50:178–187PubMedGoogle Scholar
  3. Akil M, Lewis D (1997) Cytoarchitecture of the entorhinal cortex in schizophrenia. Am J Psychiatry 154:1010–1012PubMedGoogle Scholar
  4. Altshuler LL, Conrad A, Kovelman JA, Scheibel AB (1987) Hippocampal pyramidal cell orientation in schizophrenia. A controlled neurohistologic study of the Yakovlev collection. Arch Gen Psychiatry 44:1094–1098PubMedGoogle Scholar
  5. Altshuler LL, Bartzokis G, Grieder T, Curran J, Jimenez T, Leight K, Wilkins J, Gerner R, Mintz J (2000) An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia. Biol Psychiatry 48:147–162CrossRefPubMedGoogle Scholar
  6. Amaral DG, Insausti R (1990) Hippocampal formation. In: Paxinos G (ed) The human nervous system. Academic Press, San Diego, pp 711–735Google Scholar
  7. Arnold SE (1997) The medial temporal lobe in schizophrenia. J Neuropsychiatr Clin Neurosci 9:460–470Google Scholar
  8. Arnold SE (2000) Hippocampal pathology. In: Harrison PJ, Roberts GW (eds) The neuropathology of schizophrenia. Progress and interpretation. Oxford University Press, Oxford, pp 57–80Google Scholar
  9. Arnold SE, Trojanowski JQ (1996) Cognitive impairment in elderly schizophrenia: a dementia (still) lacking distinctive histopathology. Schizophr Bull 22:5–9PubMedGoogle Scholar
  10. Arnold SE, Hyman BT, Van Hoesen GW, Damasio AR (1991a) Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia. Arch Gen Psychiatry 48:625–632PubMedGoogle Scholar
  11. Arnold SE, Lee VMY, Gur RE, Trojanowski JQ (1991b) Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia. Proc Natl Acad Sci USA 88:10850–10854PubMedGoogle Scholar
  12. Arnold SE, Franz B, Gur RC, Shapiro R, Moberg P, Trojanowski JQ (1995) Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. Am J Psychiatry 152:738–748PubMedGoogle Scholar
  13. Arnold SE, Franz BR, Trojanowski JQ, Moberg PJ, Gur RE (1996) Glial fibrillary acidic protein-immunoreactive astrocytosis in elderly patients with schizophrenia and dementia. Acta Neuropathol 91:269–277CrossRefPubMedGoogle Scholar
  14. Arnold SE, Ruscheinsky DD, Han LY (1997) Further evidence of abnormal cytoarchitecture of the entorhinal cortex in schizophrenia using spatial point pattern analyses. Biol Psychiatry 42:639–647PubMedGoogle Scholar
  15. Arnold SE, Trojanowski J, Gur RE, Blackwell P, Han L, Choi C (1998) Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 55:225–232CrossRefPubMedGoogle Scholar
  16. Atwood HL, Karunanithi S (2002). Diversification of synaptic strength: presynaptic elements. Nature Rev Neurosci 3:497–516CrossRefGoogle Scholar
  17. Baldessarini RJ, Hegarty JD, Bird ED, Benes FM (1997) Meta-analysis of postmortem studies of Alzheimer’s disease- like neuropathology in schizophrenia. Am J Psychiatry 154:861–863PubMedGoogle Scholar
  18. Barrera A, Jiménez- González A, Montiel J, Aboitiz F (2001) Dendritic structure of single hippocampal neurons according to sex and hemisphere or origin in middle-aged and elderly human subjects. Brain Res 906:31–37CrossRefPubMedGoogle Scholar
  19. Bartzokis G (2002) Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology 27:672–683CrossRefPubMedGoogle Scholar
  20. Benes FM (1999) Evidence for altered trisynaptic circuitry in schizophrenic hippocampus. Biol Psychiatry 46:589–599PubMedGoogle Scholar
  21. Benes FM, Davidson J, Bird ED (1986) Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch Gen Psychiatry 43:31–35Google Scholar
  22. Benes FM, Sorensen I, Bird ED (1991) Reduced neuronal size in posterior hippocampus of schizophrenic patients. Schizophr Bull 17:597–608PubMedGoogle Scholar
  23. Benes FM, Turtle M, Khan Y, Farol P (1994) Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood. Arch Gen Psychiatry 51:477–484.PubMedGoogle Scholar
  24. Benes FM, Khan Y, Vincent SL, Wickramasinghe R (1996) Differences in the subregional and cellular distribution of GABA, receptor binding in the hippocampal formation of schizophrenic brain. Synapse 22:338–349CrossRefPubMedGoogle Scholar
  25. Benes FM, Kwok EW, Vincent SL, Todtenkopf MS (1998) Reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 44:88–97Google Scholar
  26. Benes FM, Todtenkopf MS, Kostoulakos P (2001) GluR5,6,7 subunit immunoreactivity on apical pyramidal cell dendrites in hippocampus of schizophrenics and manic depressives. Hippocampus 11:482–491CrossRefPubMedGoogle Scholar
  27. Bernstein H-G, Krell D, Baumann B, Danos P, Falkai P, Diekmann S, Henning H, Bogerts B (1998) Morphometric studies of the entorhinal cortex in neuropsychiatric patients and controls: clusters of heterotopically displaced lamina II neurons are not indicative of schizophrenia. Schizophr Res 33:125–132CrossRefPubMedGoogle Scholar
  28. Bertolino A, Nawroz S, Mattay VS, Barnett AS, Duyn JH, Moonen CTW, Frank JA, Tedeschi G (1996) Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am J Psychiatry 153:1554–1563PubMedGoogle Scholar
  29. Bertolino A, Callicott JH, Elman I, Duyn JH, Tedeschi G, Frank JA et al. (1998) Regionally specific neurochemical pathology in untreated patients with schizophrenia: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatry 43:641–648CrossRefPubMedGoogle Scholar
  30. Blakemore CB, Falconer M (1967) Long term effects of anterior temporal lobectomy on certain cognitive functions. J Neurol Neurosurg Psychiatry 30:364–367PubMedGoogle Scholar
  31. Bogerts B, Meertz E, Schonfeldt-Bausch R (1985) Basal ganglia and limbic system pathology in schizophrenia. Arch Gen Psychiatry 42:784–791Google Scholar
  32. Bogerts B, Ashtari M, Degreef G, Alvir JMJ, Bilder RM, Lieberman JA (1990) Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Res 35:1–13CrossRefPubMedGoogle Scholar
  33. Bozikas VP, Kövari E, Bouras C, Karavatos A (2002) Neurofibillary tangles in elderly patients with late onset schizophrenia. Neurosci Lett 324:109–112CrossRefPubMedGoogle Scholar
  34. Brown R, Colter N, Corsellis JAN, Crow TJ, Frith CD, Jagoe R, Johnstone EC, Marsh L (1986) Postmortem evidence of structural brain changes in schizophrenia. Differences in brain weight, temporal horn area, and parahippocampal gyrus compared with affective disorder. Arch Gen Psychiatry 43:36–42PubMedGoogle Scholar
  35. Browning MD, Dudek EM, Rapier JL, Leonard S, Freedman R (1993) Significant reductions in synapsin but not synaptophysin specific activity in the brains of some schizophrenics. Biol Psychiatry 34:529–535CrossRefPubMedGoogle Scholar
  36. Bruton CJ, Crow TJ, Frith CD, Johnstone EC, Owens DGC, Roberts GW (1990) Schizophrenia and the brain: a prospective clinico-neuropathological study. Psychol Med 20:285–304PubMedGoogle Scholar
  37. Burnet PWJ, Eastwood SL, Harrison PJ (1996) 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially affected in schizophrenia. Neuropsychopharmacology 15:442–455PubMedGoogle Scholar
  38. Cannon TD, van Erp GM, Rosso IM, Huttunen M, Lönnqvist J, Pirkola T, Salonen O, Valanne L, Poutanen V-P, Standertskjö-Nordenstam C-G (2002) Fetal hypoxia and structural brain abnormalities in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry 59:35–41CrossRefPubMedGoogle Scholar
  39. Casanova MF, Rothberg B (2002) Shape distortion of the hippocampus: a possible explanation of the pyramidal cell disarray reported in schizophrenia. Schizophr Res 55:19–24CrossRefPubMedGoogle Scholar
  40. Casanova MF, Stevens JR, Brown R, Royston C, Bruton C (2002) Disentangling the pathology of schizophrenia and paraphrenia. Acta Neuropathol 103:313–320CrossRefPubMedGoogle Scholar
  41. Chambers JS, Thomas D, Saland L, Neve R, Perrone-Bizzozero NI (2003) GAP-43 and synaptophysin immunostaining reveal subtle alterations in the dentate gyrus of patients with schizophrenia [Abstract]. Schizophr Res 60:69CrossRefGoogle Scholar
  42. Christison GW, Casanova MF, Weinberger DR, Rawlings R, Kleinman JE (1989) A quantitative investigation of hippocampal pyramidal cell size, shape, and variability of orientation in schizophrenia. Arch Gen Psychiatry 46:1027–1032PubMedGoogle Scholar
  43. Conrad AJ, Abebe T, Austin R, Forsythe S, Scheibel AB (1991) Hippocampal pyramidal cell disarray in schizophrenia as a bilateral phenomenon. Arch Gen Psychiatry 48:413–417PubMedGoogle Scholar
  44. Cotter D, Kerwin R, Doshi B, Martin CS, Everall IP (1997) Alterations in hippocampal non-phosphorylated MAP2 protein expression in schizophrenia. Brain Res 765:238–246CrossRefPubMedGoogle Scholar
  45. Cotter D, Wilson S, Roberts E, Kerwin R, Everall IP (2000) Increased dendritic MAP2 expression in the hippocampus in schizophrenia. Schizophr Res 41:313–323CrossRefPubMedGoogle Scholar
  46. Cotter DR, Pariante CM, Everall IP (2001) Glial cell abnormalities in major psychiatric disorders: the evidence and implications. Brain Res Bull 55:585–595CrossRefPubMedGoogle Scholar
  47. Crow TJ (1990) Temporal lobe asymmetries as the key to the etiology of schizophrenia. Schizophr Bull 16:433–443PubMedGoogle Scholar
  48. Crow TJ, Ball J, Bloom SR, Brown R, Bruton CJ, Colter N, Frith CD, Johnstone EC, Owens DGC, Roberts GW (1989) Schizophrenia as an anomaly of development of cerebral asymmetry. Arch Gen Psychiatry 46:1145–1150PubMedGoogle Scholar
  49. Csernansky JG, Wang L, Jonmes D, Rastogi-Cruz D, Posener JA, Heydebrand G, Miller JP, Miller MI (2002) Hippocampal deformities in schizophrenia characterized by high dimensional brain mapping. Am J Psychiatry 159:2000–2006CrossRefPubMedGoogle Scholar
  50. Damadzic R, Biegelow L, Krimer LS, Goldenson DA, Saunders RC, Kleinman JE, Herman MM (2001) A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis. Brain Res Bull 55:611–618PubMedGoogle Scholar
  51. Damadzic R, Shuangshoti S, Givlen G, Herman MM (2002) Neuritic pathology is lacking in the entorhinal cortex subiculum and hippocampus in middle-aged adults with schizophrenia, bipolar disorder or unipolar depression. Acta Neuropathol 103:488–494CrossRefPubMedGoogle Scholar
  52. Davidsson P, Gottfries J, Bogdanovic N, Ekman R, Karlsson I, Gottfries CG, Blennow K (1999) The synaptic-vesicle-specific proteins rab3a and synaptophysin are reduced in thalamus and related cortical brain regions in schizophrenic brains. Schizophr Res 40:23–29CrossRefPubMedGoogle Scholar
  53. Davis, KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR, Buxbaum J, Haroutunian V (2003) White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry 60:443–456CrossRefPubMedGoogle Scholar
  54. Dean B, Scarr E, Bradbury R, Copolov D (1999) Decreased hippocampal (CA3) NMDA receptors in schizophrenia. Synapse 32:67–69CrossRefPubMedGoogle Scholar
  55. Deicken RF, Pegues M, Amend D (1999) Reduced hippocampal N-acetylaspartate without volume loss in schizophrenia. Schizophr Res 37:217–223PubMedGoogle Scholar
  56. DeKosky ST, Scheff SW, Styren SD (1996) Structural correlates of cognition in dementia: quantification and assessment of synaptic change. Neurodegeneration 5:417–421CrossRefPubMedGoogle Scholar
  57. DeLisi L (1997) Is schizophrenia a lifetime disorder of brain plasticity, growth and aging? Schizophr Res 23:119–129CrossRefPubMedGoogle Scholar
  58. De Toledo-Morrell L, Dickerson B, Sullivan MP, Spanovic C, Wilson R, Bennett DA (2000) Hemispheric differences in hippocampal volume predict verbal and spatial memory performance in patients with Alzheimer’s disease. Hippocampus 10:136–142CrossRefPubMedGoogle Scholar
  59. Dickey CC, McCarley RW, Shenton MR (2002) The brain in schizoptypal personality disorder: a review of structural MRI and CT findings. Harvard Rev Psychiatry 10:1–15Google Scholar
  60. Duvernoy HM (1998) The human hippocampus. Functional anatomy, vascularization and serial sections with MRI, 2nd edition. Springer, BerlinGoogle Scholar
  61. Dwork AJ (1997) Postmortem studies of the hippocampal formation in schizophrenia. Schizophr Bull 23:385–402PubMedGoogle Scholar
  62. East SZ, Burnet PWJ, Kerwin RW, Harrison PJ (2002) An RT-PCR study of 5-HT6 and 5-HT7 receptor mRNA expression in the hippocampal formation and dorsolateral prefrontal cortex in schizophrenia. Schizophr Res 57:15–26CrossRefPubMedGoogle Scholar
  63. Eastwood SL, Harrison PJ (1995) Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography. Neuroscience 69:339–343CrossRefPubMedGoogle Scholar
  64. Eastwood SL, Harrison PJ (1998) Hippocampal and cortical growth-associated protein-43 messenger RNA in schizophrenia. Neuroscience 86:437–448CrossRefPubMedGoogle Scholar
  65. Eastwood SL, Harrison PJ (1999) Detection and quantification of hippocampal synaptophysin messenger RNA in schizophrenia using autoclaved, formalin-fixed, paraffin wax-embedded sections. Neuroscience 93:99–106CrossRefPubMedGoogle Scholar
  66. Eastwood SL, Harrison PJ (2000) Hippocampal synaptic pathology in schizophrenia bipolar disorder and major depression: a study of complexin mRNAs. Mol Psychiatry 5:425–432CrossRefPubMedGoogle Scholar
  67. Eastwood SL, Harrison PJ (2004) 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 8:821–831CrossRefGoogle Scholar
  68. Eastwood SL, Burnet PWJ, McDonald B, Clinton J, Harrison PJ (1994) Synaptophysin gene expression in human brain: a quantitative in situ hybridization and immunocytochemical study. Neuroscience 59:881–892CrossRefPubMedGoogle Scholar
  69. Eastwood SL, Burnet PWJ, Harrison PJ (1995a) Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia. Neuroscience 66:309–319CrossRefPubMedGoogle Scholar
  70. Eastwood SL, McDonald B, Burnet PWJ, Beckwith JP, Kerwin RW, Harrison PJ (1995b) Decreased expression of mRNAs encoding non-NMDA glutamate receptors GluR1 and GluR2 in medial temporal lobe neurons in schizophrenia. Mol Brain Res 29:211–223CrossRefPubMedGoogle Scholar
  71. Eastwood SL, Burnet PWJ, Harrison PJ (1997a) GluR2 glutamate receptor subunit flip and flop isoforms are decreased in the hippocampal formation in schizophrenia: a reverse transcriptase-polymerase chain reaction (RT-PCR) study. Mol Brain Res 44:92–98CrossRefPubMedGoogle Scholar
  72. Eastwood SL, Kerwin RW, Harrison PJ (1997b) Immunoautoradiographic evidence for a loss of -amino-3-hydroxy-5-methyl-4 isoxazole propionate-preferring non-N-methyl-d-aspartate glutamate receptors within the medial temporal lobe in schizophrenia. Biol Psychiatry 41:636–643CrossRefPubMedGoogle Scholar
  73. Eastwood SL, Heffernan J, Harrison PJ (1997c) Chronic haloperidol differentially affects the expression of synaptic and neuronal plasticity-associated genes. Mol Psychiatry 2:322–329CrossRefPubMedGoogle Scholar
  74. Eastwood SL, Cairns NJ, Harrison PJ (2000a) Synaptophysin gene expression in schizophrenia: investigation of synaptic pathology in the cerebral cortex. Br J Psychiatry 176:236–242CrossRefPubMedGoogle Scholar
  75. Eastwood SL, Burnet PWJ, Harrison PJ (2000b) Expression of complexin I and II mRNAs and their regulation by antipsychotic drugs in the rat forebrain. Synapse 36:167–177CrossRefPubMedGoogle Scholar
  76. Eastwood SL, Law AJ, Everall IP, Harrison PJ (2003) The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology. Mol Psychiatry 8:148–155CrossRefPubMedGoogle Scholar
  77. Egan MF, Kojima M, Callicot JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function Cell 112:257–269Google Scholar
  78. Eichenbaum H, Otto T, Cohen NJ (1994) Two functional components of the hippocampal memory system. Behav Brain Sci 17:449–518Google Scholar
  79. Esiri MM, Pearson RCA (2000) Perspectives from other diseases and lesions. In: Harrison PJ, Roberts GW (eds) The neuropathology of schizophrenia. Progress and interpretation. Oxford University Press, Oxford, pp 257–276Google Scholar
  80. Falkai P, Bogerts B (1986) Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatr Neurol Sci 236:154–161Google Scholar
  81. Falkai P, Bogerts B, Rozumek M (1988) Limbic pathology in schizophrenia: the entorhinal region—a morphometric study. Biol Psychiatry 24:515–521CrossRefPubMedGoogle Scholar
  82. Falkai P, Honer WG, David S, Bogerts B, Majtenyi C, Bayer TA (1999) No evidence for astrogliosis in brains of schizophrenic patients. A post-mortem study. Neuropathol Appl Neurobiol 25:48–53CrossRefPubMedGoogle Scholar
  83. Falkai P, Schneider-Axmann T, Honer WG (2000) Entorhinal cortex pre-alpha cell clusters in schizophrenia: quantitative evidence of a developmental abnormality. Biol Psychiatry 47:937–943CrossRefPubMedGoogle Scholar
  84. Falkai PG, Kovalenko S, Schneider-Axmann T, Ovary I, Honer WG (2003) Second replication of disturbed pre-alpha-cell migration in the entorhinal cortex of schizophrenic patients [Abstract]. Schizophr Res 60:71CrossRefPubMedGoogle Scholar
  85. Fatemi SH, Earle JA, Stary JM, Lee S, Sedgewick J (2001) Altered levels of the synaptosomal associated protein SNAP-25 in hippocampus of subjects with mood disorders and schizophrenia. Neuroreport 12:3257–3262CrossRefPubMedGoogle Scholar
  86. Flor-Henry P (1969) The neuropathology of temporal lobe epilepsy. J Neuropathol Exp Neurol 52:433–443Google Scholar
  87. Freedman R, Adams Ce, Leonard S (2000) The 7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. J Chem Neuroanat 20:299–306CrossRefPubMedGoogle Scholar
  88. Friston KJ, Liddle PF, Frith CD, Hirsch SR, Frackowiak RSJ (1992) The left medial temporal region and schizophrenia. A PET study. Brain 115:367–382PubMedGoogle Scholar
  89. Gao XM, Sakai K, Roberts RC, Conley RR, Dean B, Tamminga CA (2000) Ionotropic glutamate receptors and expression of N-methyl-d-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. Am J Psychiatry 157:1141–1149CrossRefPubMedGoogle Scholar
  90. Goldberg TE, Torrey EF, Berman KF, Weinberger DR (1994) Relations between neuropsychological performance and brain morphological and physiological measures in monozygotic twins discordant for schizophrenia. Psychiatr Res Neuroimaging 55:51–61CrossRefGoogle Scholar
  91. Grace AA (2000) Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res Rev 31:330–341PubMedGoogle Scholar
  92. Gray JA, Feldon J, Rawlins JNP, Hemsley DR, Smith AD (1991) The neuropsychology of schizophrenia. Behav Brain Sci 14:1–84Google Scholar
  93. Greene JRT (1996) The subiculum: a potential site of action for novel antipsychotic drugs. Mol Psychiatry 1:380–387PubMedGoogle Scholar
  94. Gur RE, McGrathC, Chan RM, Schroeder L, Turner T, Turetsky BI, Kohler C, Alsop D, Maldjian J, Ragland JD, Gur RC (2002) A fMRI study of facial emotional processing I patients with schizophrenia. Am J Psychiatry 159:1992–1999CrossRefPubMedGoogle Scholar
  95. Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD et al. (2001) Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 98:4746–4751PubMedGoogle Scholar
  96. Harrison PJ (1995) On the neuropathology of schizophrenia and its dementia: neurodevelopmental, neurodegenerative, or both? Neurodegeneration 4:1–12CrossRefPubMedGoogle Scholar
  97. Harrison PJ (1997) Schizophrenia: a disorder of neurodevelopment? Curr Opin Neurobiol 7:285–289CrossRefPubMedGoogle Scholar
  98. Harrison PJ (1999a) The neuropathology of schizophrenia—a critical review of the data and their interpretation. Brain 122:593–624CrossRefPubMedGoogle Scholar
  99. Harrison PJ (1999b) The neuropathological effects of antipsychotic drugs. Schizophr Res 40:87–99Google Scholar
  100. Harrison PJ (2002) The neuropathology of primary mood disorder. Brain 125:1428–1449CrossRefPubMedGoogle Scholar
  101. Harrison PJ (2004) Schizophrenia and its dementia. In: Esiri MM, Trojanowski JQ, Lee V-MY (eds) The neuropathology of dementia, 2nd edn (in press)Google Scholar
  102. Harrison PJ, Eastwood SL (1998) Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia. Lancet 352:1669–1673CrossRefPubMedGoogle Scholar
  103. Harrison PJ, Eastwood SL (2001) Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus 11:508–519CrossRefPubMedGoogle Scholar
  104. Harrison PJ, Eastwood SL (2003) Vesicular glutamate transporter (VGLUT) gene expression provides further evidence for glutamatergic synaptic pathology in the hippocampus in schizophrenia [Abstract]. Schizophr Res 60:62–63CrossRefGoogle Scholar
  105. Harrison PJ, Kleinman JE (2000) Methodological issues. In: Harrison PJ, Roberts GW (eds) The neuropathology of schizophrenia. Progress and interpretation. Oxford University Press, Oxford, pp 339–350Google Scholar
  106. Harrison PJ, Lewis DA (2003) The neuropathology of schizophrenia. In: Hirsch SR, Weinberger D (eds) Schizophrenia, 2nd edition. Blackwell Science, Oxford, pp 306–317Google Scholar
  107. Harrison PJ, Owen MJ (2003) Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 361:417–419CrossRefPubMedGoogle Scholar
  108. Harrison PJ, Roberts (2000) The neuropathology of schizophrenia. Progress and interpretation. Oxford University Press, OxfordGoogle Scholar
  109. Harrison PJ, McLauglin D, Kerwin RW (1991) Decreased hippocampal expression of a glutamate receptor gene in schizophrenia. Lancet 337:450–452CrossRefPubMedGoogle Scholar
  110. Harrison PJ, Burnet PWJ, Falkai P, Bogerts B, Eastwood SL (1997) Gene expression and neuronal activity in schizophrenia: a study of polyadenylated mRNA in the hippocampal formation and cerebral cortex. Schizophr Res 26:93–102CrossRefPubMedGoogle Scholar
  111. Harrison PJ, Law AJ, Eastwood SL (2003) Glutamate receptors and transporters in the hippocampus in schizophrenia. Ann N Y Acad Sci 1003:94–101CrossRefPubMedGoogle Scholar
  112. Harvey PD, Silverman JM, Mohs RC, Parrella M, White L, Powchik P et al. (1999) Cognitive decline in late-life schizophrenia: a longitudinal study of geriatric chronically hospitalized patients. Biol Psychiatry 45:32–40Google Scholar
  113. Haydon PG (2001) Glia: listening and talking to the synapse. Nature Rev Neurosci 2:185–193CrossRefGoogle Scholar
  114. Heckers S (2001) Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 11:520–528CrossRefPubMedGoogle Scholar
  115. Heckers S, Konradi C (2002) Hippocampal neurons in schizophrenia. J Neural Transm 109:891–905CrossRefPubMedGoogle Scholar
  116. Heckers S, Heinsen H, Geiger B, Beckmann H (1991) Hippocampal neuron number in schizophrenia: a stereological study. Arch Gen Psychiatry 48:1002–1008PubMedGoogle Scholar
  117. Heckers S, Rauch SL, Goff DC, Savage CR, Schacter DL, Fischman AJ, Alpert NM (1998) Impaired recruitment of the hippocamps during conscious recollection in schizophrenia. Nat Neurosci 1:318–323CrossRefPubMedGoogle Scholar
  118. Heffernan JM, Eastwood SL, Nagy Z, Sanders MW, McDonald B, Harrison PJ (1998) Temporal cortex synaptophysin mRNA is reduced in Alzheimer’s disease and is negatively correlated with the severity of dementia. Exp Neurol 150:235–239CrossRefPubMedGoogle Scholar
  119. Hemby SE, Ginsberg SD, Brunk B, Arnold SE, Trojanowski, Eberwine JH (2002) Gene expression profile for schizophrenia. Arch Gen Psychiatry 59:631–640CrossRefPubMedGoogle Scholar
  120. Hof PR, Haroutunian V, Friedrich VL Jr, Byne W, Buitron C, Perl DP, Davis KL (2003) Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 53:1075–1085CrossRefPubMedGoogle Scholar
  121. Holinger DP, Galaburda AM, Harrison PJ (2000) Cerebral asymmetry. In: Harrison PJ, Roberts GW (eds) The neuropathology of schizophrenia. Progress and interpretation. Oxford University Press, Oxford, pp 151–171Google Scholar
  122. Honer WG, Young C, Falkai P (2000) Synaptic pathology. In Harrison PJ, Roberts GW, editors. The neuropathology of schizophrenia. Progress and interpretation. Oxford University Press, Oxford, pp 105–136Google Scholar
  123. Ince PG, Slade J, Chinnery RM, McKenzie J, Royston C, Roberts GW, Shaw PJ (1995) Quantitative study of synaptophysin immunoreactivity of cerebral cortex and spinal cord in motor neuron disease. J Neuropathol Exp Neurol 54:673–679PubMedGoogle Scholar
  124. Jakob H, Beckmann H (1986) Prenatal developmental disturbances in the limbic allocortex in schizophrenics. J Neural Transm 65:303–326PubMedGoogle Scholar
  125. Jellinger KA, Gabriel E (1999) No increased incidence of Alzheimer’s disease in elderly schizophrenics. Acta Neuropathol 97:165–169CrossRefPubMedGoogle Scholar
  126. Jessen F, Scheef L, Germeshausen L, Tawo Y, Kocklet M, Kuhn K-U, Maier W, Schild HH, Heun R (2003) Reduced hippocampal activation during encoding and recognition of words in schizophrenia patients. Am J Psychiatry 160:1305–1312CrossRefPubMedGoogle Scholar
  127. Jeste DV, Lohr JB (1989) Hippocampal pathologic findings in schizophrenia. A morphometric study. Arch Gen Psychiatry 46:1019–1024PubMedGoogle Scholar
  128. Jones PB, Done DJ (1997) From birth to onset: a developmental perspective of schizophrenia in two national birth cohorts. In: Keshavan MS, Murray RM (eds) Neurodevelopment and adult psychopathology. Cambridge University Press, Cambridge, pp 119–136Google Scholar
  129. Jonsson SAT, Luts A, Guldberg-Kjaer N, Brun A (1997) Hippocampal pyramidal cell disarray correlates negatively to cell number: implications for the pathogenesis of schizophrenia. Eur Arch Psychiatry Neurol Sci 247:120–127Google Scholar
  130. Joyal CC, Laakso MP, Tiihonen J, Syvälahti E, Vilkman H, Laakso A, Alakare B, Räkköläinen V, Raimo KR, Kietala S, Hietala J (2002) A volumetric MRI study of the entorhinal cortex in first episode neuroleptic-naïve schizophrenia. Biol Psychiatry 51:1005–1007CrossRefPubMedGoogle Scholar
  131. Joyce JN, Shane A, Lexow N, Winokur A, Casanova M, Kleinman JE (1993) Serotonin uptake sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology 8:315–336PubMedGoogle Scholar
  132. Kerwin RW, Patel S, Meldrum BS, Czudek C, Reynolds GP (1988) Asymmetrical loss of glutamate receptor subtype in left hippocampus in schizophrenia (letter). Lancet 1:583–584Google Scholar
  133. Kerwin R, Patel S, Meldrum B (1990) Quantitative autoradiographic analysis of glutamate binding sites in the hippocampal formation in normal and schizophrenic brain post mortem. Neuroscience 39:25–32CrossRefPubMedGoogle Scholar
  134. Keshavan MS, Anderson S, Pettegrew JW (1993) Is schizophrenia due to excessive synaptic pruning in the prefrontal cortex—the Feinberg hypothesis revisited. J Psychiatr Res 28:239–265CrossRefGoogle Scholar
  135. Koeppen AH, Dickson AC, Lamarche JB, Robitaille Y (1999) Synapses in the hereditary ataxias. J Neuropathol Exp Neurol 58:748–764PubMedGoogle Scholar
  136. Konradi C, Heckers S (2001) Antipsychotic drugs and neuroplasticity: insights into the treatment and neurobiology of schizophrenia. Biol Psychiatry 50:729–742CrossRefPubMedGoogle Scholar
  137. Kovelman JA, Scheibel A (1984) A neurohistological correlate of schizophrenia. Biol Psychiatry 19:1601–1621Google Scholar
  138. Krimer LS, Herman MM, Saunders RC, Boyd JC, Hyde TM, Carter JM, Kleinman JE, Weinberger DR (1997) A qualitative and quantitative analysis of the entorhinal cortex in schizophrenia. Cereb Cortex 7:732–739CrossRefPubMedGoogle Scholar
  139. Kuroki N, Matsushita M (1998) Pyramidal cell orientation and density in the hippocampus in schizophrenia. Neuropathology 18:235–241Google Scholar
  140. Lauer M, Beckmann H, Senitz D (2003) Increased frequency of dentate granule cells with basal dendrites in the hippocampal formation of schizophrenics. Psychiatry Res Neuroimaging 122:89–97CrossRefGoogle Scholar
  141. Law AJ, Deakin JFW (2001) Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses. NeuroRep 12:2971–2974CrossRefGoogle Scholar
  142. Law AJ, Shannon Weickert C, Hyde TM, Kleinman JE, Harrison PJ (2004) 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 (in press)Google Scholar
  143. Lawrie S, Abukmeil S (1998) Brain abnormality in schizophrenia. A systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry 172:110–120PubMedGoogle Scholar
  144. Lawrie SM, Whalley H, Kestelman JN, Abukmeil SS, Byrne M, Hodges A, Rimmington JE, Best JJK, Owens DGC, Johnstone EC (1999) Magnetic resonance imaging of brain in people at high risk of developing schizophrenia. Lancet 353:30–33CrossRefPubMedGoogle Scholar
  145. Lewis DA (2002) The human brain revisited: opportunities and challenges in postmortem studies of psychiatric disorders. Neuropsychopharmacology 26:143–154CrossRefPubMedGoogle Scholar
  146. Lewis DA (2004) PsychopharmacologyGoogle Scholar
  147. Lewis DA, Akil M (1997) Cortical dopamine in schizophrenia: strategies for postmortem studies. J Psychiatr Res 31:175–195CrossRefPubMedGoogle Scholar
  148. Lewis DA, Levitt P (2002) Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 25:409–432CrossRefPubMedGoogle Scholar
  149. Lieberman JA (1999) Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol Psychiatry 46:616–626PubMedGoogle Scholar
  150. Lipska BK, Weinberger DR (2000) To model a psychiatric disorder in animals: schizophrenia a a reality test. Neuropsychopharmacology 23:223–239PubMedGoogle Scholar
  151. Lipton AM, Cullum CM, Satumtira S, Sontag E, Hynan LS, White CL III, Bigio EH (2001) Contribution of asymmetric synapse loss to lateralizing clinical deficits in frontotemporal dementias. Ann Neurol 58:1233–1239CrossRefGoogle Scholar
  152. Maier M, Ron MA, Barker GJ, Tofts PS (1995) Proton magnetic resonance spectroscopy: an in vivo method of estimating hippocampal neuronal depletion in schizophrenia. Psychol Med 25:1201–1209PubMedGoogle Scholar
  153. Manns JR, Hopkins RO, Squire LR (2003) Semantic memory and the human hippocampus. Neuron 38:127–133PubMedGoogle Scholar
  154. Markovitsch HJ (1995) Anatomical basis of memory disorders. In: Gazzaniga MS (ed) The cognitive neurosciences. MIT Press, Cambridge, Mass., pp 765–779Google Scholar
  155. Martin RC, SawrieS, Hugg J, Gilliam F, Faught E, Kuzniecky R (1999) Cognitive correlates of ‘H MRSI-detected hippocampal abnormalities in temporal lobe epilepsy. Neurology 53:2052–2058PubMedGoogle Scholar
  156. Masliah E (1995) Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol Histopathol 10:509–519PubMedGoogle Scholar
  157. Masliah E, Terry RD (1993) The role of synaptic proteins in the pathogenesis of disorders of the central nervous system. Brain Pathol 3:77–86PubMedGoogle Scholar
  158. Masliah E, Terry RD, Alford M, DeTeresa R (1990) Quantitative immunohistochemistry of synaptophysin in human neocortex: an alternative method to estimate density of presynaptic terminals in paraffin sections. J Histochem Cytochem 38:837–844PubMedGoogle Scholar
  159. McBride T, Moberg PJ, Arnold SE, Mozley LH, Mahr RN, Giney M, Kumar A, Gur RE (2002) Neuropsychological functioning in elderly patients with schizophrenia and Alzheimer’s disease. Schizophr Res 55:217–227CrossRefPubMedGoogle Scholar
  160. McClure RK, Lieberman JA (2003) Neurodevelopmental and neurodegenerative hypotheses of schizophrenia: a review and critique. Curr Opin Psychiatry 16:S15–S28CrossRefGoogle Scholar
  161. McDonald B, Highley J, Walker M, Herron B, Cooper S, Esiri MM, Crow TJ (2000) Anomalous asymmetry of fusiform and parahippocampal gyrus gray matter in schizophrenia: a postmortem study. Am J Psychiatry 157:40–47PubMedGoogle Scholar
  162. McGlashan TH, Hoffman RE (2000) Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch Gen Psychiatry 57:637–648PubMedGoogle Scholar
  163. Medoff DR, Holbomb HH, Lahti AC, Tamminga CA (2001) Probing the human hippocampus using rCBF: contrasts in schizophrenia. Hippocampus 11:543–550CrossRefPubMedGoogle Scholar
  164. Milner B (1968) Visual recognition and recall after temporal lobe excision in man. Neuropsychologia 6:191–209CrossRefGoogle Scholar
  165. Mirnics K, Middleton FA, Lewis DA, Levitt P (2001) Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Trends Neurosci 24:479–486CrossRefPubMedGoogle Scholar
  166. Moises HW, Zoega T, Gottesman I (2002) The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. BMC Psychiatry 2:8CrossRefPubMedGoogle Scholar
  167. Murphy GM Jr, Lim KO, Wieneke M, Ellis WG, Forno LS, Hoff AL, Nordahl T (1998) No neuropathologic evidence for an increased frequency of Alzheimer’s disease among elderly schizophrenics. Biol Psychiatry 43:205–209PubMedGoogle Scholar
  168. Murray RM, Lewis S (1987) Is schizophrenia a neurodevelopmental disorder? BMJ 295:681–682PubMedGoogle Scholar
  169. Murthy VN, De Camilli P (2003) Cell biology of the presynaptic terminal. Annu Rev Neurosci 26:701–728CrossRefPubMedGoogle Scholar
  170. Nanko S (2002) Possible effect of the APOE 4 allele on the hippocampal volume and asymmetry in schizophrenia. Am J Med Genet 114:641–642CrossRefPubMedGoogle Scholar
  171. Narr KL, van-Erp TG, Cannon TD, Woods RP, Thompson PM, Jang S, Blanton R, Poutanen VP, Huttuen M, Lonnqvist J, Standerksjold-Nordenstam CG, Kaprio J, Mazziotta JC, Toga AW (2002) A twin study of genetic contributions to hippocampal morphology in schizophrenia. Neurobiol Dis 11:83–95CrossRefPubMedGoogle Scholar
  172. Nelson MD, Saykin AJ, Flashman LA, Riordan HJ (1998) Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging—a meta-analytic study. Arch Gen Psychiatry 55:433–440PubMedGoogle Scholar
  173. Novak G, Kim D, Seeman P, Tallerico T (2002) Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. Mol Brain Res 107:183–189CrossRefPubMedGoogle Scholar
  174. Novakowski C, Kaufmann WA, Adlassnig C, Maier H, Salim K, Jellinger KA, Marksteiner J (2002) Reduction of chromogranin B-like immunoreactivity in distinct subregions of the hippocampus from individuals with schizophrenia. Schizophr Res 58:43–53CrossRefPubMedGoogle Scholar
  175. Pakkenberg B (1990) Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch Gen Psychiatry 47:1023–1028PubMedGoogle Scholar
  176. Pantelis C, Velakoulis D, McGorry PD, Wood SJ, Suckling J, Phillips LJ, Yung AR, Bullmore ET, Brewer W, Soulsby B, Desmond P, McGuire PK (2003) Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 361:281–288CrossRefPubMedGoogle Scholar
  177. Petito CK, Feldmann E, Pulsinelli WA, Plum F (1987) Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology 37:1281–1286PubMedGoogle Scholar
  178. Port RL, Seybold KS (1995) Hippocampal synaptic plasticity as a biological substrate underlying episodic psychosis. Biol Psychiatry 37:318–324CrossRefPubMedGoogle Scholar
  179. Porter RHP, Eastwood SL, Harrison PJ (1997) Distribution of kainate receptor subunit mRNAs in human hippocampus, neocortex and cerebellum, and bilateral reduction of hippocampal GluR6 and KA2 transcripts in schizophrenia. Brain Res 751:217–231CrossRefPubMedGoogle Scholar
  180. Prohovnik I, Dwork AJ, Kaufman MA, Wilson N (1993) Alzheimer-type neuropathy in elderly schizophrenia patients. Schizophr Bull 19:805–816PubMedGoogle Scholar
  181. Purohit DP, Peri DP, Haroutunian V, Powchik P, Davidson M, Davies KL (1998) Alzheimer disease and related neurodegeneration diseases in elderly patients with schizophrenia—a postmortem neuropathologic study of 100 cases. Arch Gen Psychiatry 55:205–211PubMedGoogle Scholar
  182. Reynolds GP, Czudek C, Andrews HB (1990) Deficit and hemispheric asymmetry of GABA uptake sites in the hippocampus in schizophrenia. Biol Psychiatry 27:1038–1044CrossRefPubMedGoogle Scholar
  183. Religa D, Laudon H, Styczynska M, Winblad B, Näslund J, Haroutunian V (2003) Amyloid pathology in Alzheimer’s disease and schizophrenia. Am J Psychiatry 160:867–872CrossRefPubMedGoogle Scholar
  184. Roberts GW (1991) Schizophrenia: a neuropathological perspective. Br J Psychiatry 158:8–17PubMedGoogle Scholar
  185. Roberts GW, Harrison PJ (2000) Gliosis and its implications for the disease process. In: Harrison PJ, Roberts GW (eds) The neuropathology of schizophrenia. Progress and interpretation. Oxford University Press, Oxford, pp 137–150Google Scholar
  186. Roberts GW, Colter N, Lofthouse R, Bogerts B, Zech M, Crow TJ (1986) Gliosis in schizophrenia: a survey. Biol Psychiatry 21:1043–1050CrossRefPubMedGoogle Scholar
  187. Roberts GW, Colter N, Lofthouse R, Johnstone E, Crow TJ (1987) Is there gliosis in schizophrenia? Investigation of the temporal lobe. Biol Psychiatry 22:1459–1468CrossRefPubMedGoogle Scholar
  188. Roberts GW, Done DJ, Bruton C, Crow TJ (1990) A “mock up” of schizophrenia: temporal lobe epilepsy and schizophrenia-like psychosis. Biol Psychiatry 28:127–143CrossRefPubMedGoogle Scholar
  189. Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N, Hays AP, Dwork AJ (2000) Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders—preliminary findings. Arch Gen Psychiatry 57:349–356CrossRefPubMedGoogle Scholar
  190. Sachdev P (1998) Schizophrenia-like psychosis and epilepsy: the status of the association. Am J Psychiatry 155:325–336PubMedGoogle Scholar
  191. Sanfilipo M, Lafargue T, Rusinek H, Arena L, Lonergagan C, Lautin A, Rotrosen J, Wolkin A (2002) Cognitive performance in schizophrenia: relationship to regional brain volumes and psychiatric symptoms. Psychiatry Res 116:1–23CrossRefPubMedGoogle Scholar
  192. Sawada K, Barr AM, Takahashi S, Arima K, Falkai P, Phillips A, Honer WG (2003) Complexins I and II in hippocampus in schizophrenia [Abstract]. Schizophr Res 60:74–75CrossRefGoogle Scholar
  193. Saykin AJ, Shtasel DL, Gur RE, Kester DB, Mozley LH, Stafiniak P, Gur RC (1994) Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch Gen Psychiatry 51:124–131PubMedGoogle Scholar
  194. Schmajuk NA (2001) Hippocampal dysfunction in schizophrenia. Hippocampus 11:599–613CrossRefPubMedGoogle Scholar
  195. Schultze K, McDonald C, Frangou S, Sham P, Grech A, Toulopoulou T, Walshe M, Sharma T, Sigmundsson T, Taylor M, Murray RA (2003) Hippocampal volume in familial and nonfamilial schizophrenic probands and their unaffected relatives. Biol Psychiatry 53:562–570CrossRefPubMedGoogle Scholar
  196. Selemon LD, Rajkowska G, Goldman-Rakic PS (1995) Abnormally high neuronal density in the schizophrenic cortex—a morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 52:805–818PubMedGoogle Scholar
  197. Senitz D, Beckmann H (2003) Granule cells of the dentate gyrus with basal and recurrent dendrites in schizophrenic patients and controls. A comparative Golgi study. J Neural Transm 110:317–326PubMedGoogle Scholar
  198. Simpson MDC, Slater P, Deakin JFW (1998) Comparison of glutamate and gamma-aminobutyric acid uptake binding sites in frontal and temporal lobes in schizophrenia. Biol Psychiatry 44:423–427CrossRefPubMedGoogle Scholar
  199. Sokolov BP, Tcherepanov AA, Haroutunian V, Davis KL (2000) Levels of mRNAs encoding synaptic vesicle and synaptic plasma membrane proteins in the temporal cortex of elderly schizophrenic patients. Biol Psychiatry 48:184–196Google Scholar
  200. Stefanis N, Frangou S, Yakeley J, Sharma T, O’Connell P, Morgan K, Signmudsson T, Taylor M, Murray R (1999) Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications. Biol Psychiatry 46:697–702CrossRefPubMedGoogle Scholar
  201. Stevens JR (1982) Neuropathology of schizophrenia. Arch Gen Psychiatry 39:1131–1139PubMedGoogle Scholar
  202. Stevens JR (1992) Abnormal reinnervation as a basis for schizophrenia. Arch Gen Psychiatry 49:238–243PubMedGoogle Scholar
  203. Südhof TC (1995) The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature 375:645–653PubMedGoogle Scholar
  204. Sze C-I, Bi H, Kleinschmidt-DeMasters B, Filley CM, Martin LJ (2000) Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer’s disease brains. J Neurol Sci 175:81–90CrossRefPubMedGoogle Scholar
  205. Szeszko PR, Strous RD, Goldman RS, Ashtari M, Knuth KH, Lieberman JA, Bilder RM (2002) Neuropsychological correlates of hippocampal volumes in patients experiencing a first episode of schizophrenia. Am J Psychiatry 159:217–226CrossRefPubMedGoogle Scholar
  206. Takahashi S, Yamamoto H, Matsuda Z, Ogawa M, Yagyu K, Taniguchi T, Miyata T, Kaba H, Higuchi T, Okutani F, Fujimoto S (1995) Identification of two highly homologous presynaptic proteins distinctly localized at the dendritic and somatic synapses. FEBS Lett 368:455–460CrossRefPubMedGoogle Scholar
  207. Takahashi S, Ujihara H, Huang GZ, Yagyu K, Sanbo M, Kaba H, Yagi T (1999) Reduced hippocampal LTP in mice lacking a presynaptic protein, complexin II. Eur J Neurosci 11:2359–2366CrossRefPubMedGoogle Scholar
  208. Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase TN, Carpenter WT (1992) Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome. Arch Gen Psychiatry 49:522–530PubMedGoogle Scholar
  209. Tarsa L, Goda Y (2002) Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci USA 99:1012–1016CrossRefPubMedGoogle Scholar
  210. Tcherepanov AA, Sokolov BP (1997) Age-related abnormalities in expression of mRNAs encoding synapsin 1A, synapsin 1B, and synaptophysin in the temporal cortex of schizophrenics. J Neurosci 49:639–644CrossRefGoogle Scholar
  211. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580Google Scholar
  212. Thompson PM, Egbufoama S, Vawter MP (2003) SNAP-25 reduction in the hippocampus of patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:411–417CrossRefPubMedGoogle Scholar
  213. Todtenkopf MS, Benes F (1998) Distribution of glutamate decarboxylase65 immunoreactive puncta on pyramidal and nonpyramidal neurons in hippocampus of schizophrenic brain. Synapse 29:323–332CrossRefPubMedGoogle Scholar
  214. Torrey EF, Peterson MR (1974) Schizophrenia and the limbic system. Lancet 2:942–946PubMedGoogle Scholar
  215. Tsai G, Passani LA, Slusher BS, Carter R, Baer L, Kleinman J, Coyle JT (1995) Abnormal excitatory transmitter metabolism in schizophrenia brains. Arch Gen Psychiatry 52:829–836PubMedGoogle Scholar
  216. Ullian EM, Sapperstein SK, Christopherson KA, Barres BA (2001) Control of synapse number by glia. Science 291:657–661CrossRefPubMedGoogle Scholar
  217. Van Erp TGM, Saleh PA, Rosso IM, Huttunen M, Lnnqvist J, Pirkila T, Solonen O, Valanne L, Poutanen VP, Standertskjld-Nordenstam CG, Cannon TD (2002) Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers. Am J Psychiatry 159:1514–1520CrossRefPubMedGoogle Scholar
  218. Van Hoesen GW, Augustinack JC, Redman SJ (1999) Ventromedial temporal lobe pathology in dementia, brain trauma, and schizophrenia. Ann N Y Acad Sci 877:575–594PubMedGoogle Scholar
  219. Vawter MP, Hyde TM, Kleinman JE, Freed WJ (1999) Alterations of hippocampal secreted N-CAM in bipolar disorder and synaptophysin in schizophrenia. Mol Psychiatry 4:467–475CrossRefPubMedGoogle Scholar
  220. Vawter MP, Thatcher L, Usen N, Hyde TM, Kleinman JE, Freed WJ (2002) Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia. Mol Psychiatry 7:571–579CrossRefPubMedGoogle Scholar
  221. Velakoulis D, Pantelis C, McGorry PD, Dudgeon P, Brewer W, Cook M, Desmond P, Bridle N, Tierney P, Murrie V, Singh B, Copolov D (1999) Hippocampal volume in first-episode psychoses and chronic schizophrenia. Arch Gen Psychiatry 56:133–141PubMedGoogle Scholar
  222. Venables PH (1992) Hippocampal function and schizophrenia: experimental psychological evidence. Ann N Y Acad Sci 658:111–127PubMedGoogle Scholar
  223. Walker MA, Highley JR, Esiri MM, McDonald B, Roberts HC, Evans SP, Crow TJ (2002) Estimated neuronal populations and volumes of the hippocampus and its subfields in schizophrenia. Am J Psychiatry 159:821–828CrossRefPubMedGoogle Scholar
  224. Webster MJ, Weickert CS, Herman MM, Hyde TM, Kleinman JE (2001) Synaptophysin and GAP-43 mRNA levels in the hippocampus of subjects with schizophrenia. Schizophr Res 49:89–98CrossRefPubMedGoogle Scholar
  225. Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660–689PubMedGoogle Scholar
  226. Weinberger DR (1995) From neuropathology to neurodevelopment. Lancet 346:552–557PubMedGoogle Scholar
  227. Weinberger DR (1999) Cell biology of the hippocampal formation in schizophrenia. Biol Psychiatry 45:395–402CrossRefPubMedGoogle Scholar
  228. Weinberger DR, McClure RK (2002) Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain? Arch Gen Psychiatry 59:553–558CrossRefPubMedGoogle Scholar
  229. Weiss AP, Schacter DL, Goff DC, Rauch SL, Alpert NM, Fischman AJ, Heckers S (2003) Impaired hippocampal recruitment during normal modulation of memory performance in schizophrenia. Biol Psychiatry 53:4855CrossRefGoogle Scholar
  230. West MJ, Coleman PD, Floord DG, Troncoso JC (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344:769–772PubMedGoogle Scholar
  231. Wisniewski HM, Constantinidis J, Wegiel J, Bobinkski M, Tarnawski M (1994) Neurofibrillary pathology in brains of elderly schizophrenics treated with neuroleptics. Alz Dis Assoc Disord 8:211–227Google Scholar
  232. Woods BT (1998) Is schizophrenia a progressive neurodevelopmental disorder? Toward a unitary pathogenetic mechanism. Am J Psychiatry 155:1661–1670PubMedGoogle Scholar
  233. Wright IC, Rabe-Hesketh S, Woodruff PWR, David AS, Murray RM, Bullmore ET (2000) Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 157:16–25PubMedGoogle Scholar
  234. Yao PJ, Zhu M, Pyrun EI, Brooks AI, Therianos S, Meyers VE et al. (2003) Defects in expression of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer’s disease. Neurobiol Dis 12:97–109CrossRefPubMedGoogle Scholar
  235. Young CE, Arima K, Xie J, Hu L, Beach TG, Falkai P, Honer WG (1998) SNAP-25 deficit and hippocampal connectivity in schizophrenia. Cereb Cortex 8:261–268CrossRefPubMedGoogle Scholar
  236. Zaidel DW, Esiri MM, Eastwood SL, Harrison PJ (1995) Asymmetrical hippocampal circuitry and schizophrenia. Lancet 345:656–657CrossRefGoogle Scholar
  237. Zaidel DW, Esiri M, Harrison PJ (1997a) Size, shape, and orientation of neurons in the left and right hippo- campus: Investigation of normal asymmetries and alterations in schizophrenia. Am J Psychiatry 154:812–818PubMedGoogle Scholar
  238. Zaidel DW, Esiri MM, Harrison PJ (1997b) The hippocampus in schizophrenia: lateralized increase in neuronal density and altered cytoarchitectural asymmetry. Psychol Med 27:703–713PubMedGoogle Scholar
  239. Zakzanis KK, Andrikopoulos J, Young DA, Campbell Z, Sethian T (2003) Neuropsychological differentiation of late-onset schizophrenia and dementia of the Alzheimer’s type. Appl Neuropsychol 10:105–114CrossRefPubMedGoogle Scholar
  240. Zhang ZJ, Reynolds GP (2002) A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 55:1–10CrossRefPubMedGoogle Scholar
  241. Zhang B, Koh YH, Beckstead RB, Budnik V, Ganetzky B, Bellen HJ (1998) Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis. Neuron 21:1465–1475PubMedGoogle Scholar
  242. Zola-Morgan S, Squire LR (1993) Neuroanatomy of memory. Annu Rev Neurosci 16:547–563PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Department of Psychiatry, Neurosciences Building, Warneford HospitalUniversity of OxfordOxfordUK

Personalised recommendations