Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P=0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2A and 5HT1B receptors, and dopamine D5 receptors.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory
Acta Neuropathologica Open Access 25 June 2021
Associations between different dimensions of prenatal distress, neonatal hippocampal connectivity, and infant memory
Neuropsychopharmacology Open Access 18 April 2020
Psychopharmacology Open Access 22 February 2020
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Torrey EF, Webster M, Knable MB, Johnston N, Yolken RH . The Stanley Foundation Brain Collection and Neuropathology Consortium. Schizophr Res. 2000; 44: 151–155.
Knable MB, Barci BM, Bartko JJ, Webster MJ, Torrey EF . Molecular abnormalities in the major psychiatric illnesses: classification and regression tree analysis of postmortem prefrontal markers. Mol Psychiatry 2002; 7: 392–404.
Knable MB, Barci BM, Bartko JJ, Webster MJ, Torrey EF . Abnormalities in the cingulate gyrus in bipolar disorder and other severe psychiatric illnesses: postmortem findings from the Stanley Foundation Neuropathology Consortium and literature review. Clin Neurosci Res. 2002; 2: 171–181.
Weinberger DR . Cell biology of the hippocampal formation in schizophrenia. Biol Psychiatry 1999; 45: 395–402.
Manji HK, Duman RS . Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. Psychopharmacol Bull 2001; 35: 5–49.
McEwen BS . Plasticity of the hippocampus: adaptation to chronic stress and allostatic load. Ann NY Acad Sci 2001; 933: 265–277.
Eyles D, McGrath J, Reynolds G . Neuronal calcium-binding proteins and schizophrenia. Schizophr Res. 2002; 57: 27.
Zhang ZJ, Reynolds GP . A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res. 2002; 55: 1–10.
Benes FM, Kwok EW, Vincent SL, Todtenkopf MS . A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 1998; 44: 88–97.
Todtenkopf MS, Benes FM . Distribution of glutamate decarboxylase 65 immunoreactive puncta on pyramidal and nonpyramidal neurons in hippocampus of schizophrenic brain. Synapse 1998; 29: 323–332.
Benes FM, Todtenkopf MS . Effect of age and neuroleptics on tyrosine hydroxylase-IR in sector CA2 of schizophrenic brain. Neuroreport 1999; 10: 3527–3530.
Benes FM, Todtenkopf MS, Kostoulakos P . GluR5,6,7 subunit reactivity on apical pyramidal cell dendrites in hippocampus of schizophrenics and manic depressives. Hippocampus 2001; 11: 482–491.
Heckers S, Konradi C . Hippocampal neurons in schizophrenia. J Neural Transmission 2002; 109: 891–905.
Arnold SE, Trojanowski JQ . Human fetal hippocampal development. 1. Cytoarchitecture, myeloarchitecture, and neuronal morphologic features. J Comp Neurol 1996; 367: 274–292.
Harrison PJ, Eastwood SL . Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus 2001; 11: 508–519.
Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N et al. Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders-preliminary findings. Arch Gen Psychiatry 2000; 57: 349–356.
Beasley CL, Zhang ZJ, Patten I, Reynolds GP . Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Biol Psychiatry 2002; 52: 708–715.
Cotter D, Landau S, Beasley C, Stevenson R, Chana G, MacMillan L et al. The density and spatial distribution of GABAergic neurons, labeled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia. Biol Psychiatry 2002; 51: 377–386.
Ritzler JM, Sawhney R, Geurts van Kessel AHM, Grzeschik K-H, Schinzel A, Berchtold MW . The genes for the highly homologous Ca (2+) binding proteins oncomodulin and parvalbumin are not linked in the human genome. Genomics 1992; 12: 567–572.
Badner JA, Gershon ES . Meta-analysis of whole genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7: 405–411.
D'Arcangelo G, Miao GG, Chen S-C, Soares HD, Morgan JI, Curran T . A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 1995; 374: 719–723.
Fatemi SH, Earle JA, McMenomy T . Reduction in reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Molecular Psychiatry 2000; 5: 654–663.
Guidotti A, Auta J, Davis JM, Gerevini VD, Dwivedi Y, Grayson DR et al. Decrease in reelin and glutamic acid decarboxylase 67 expression in schizophrenia and bipolar disorder. Arch Gen Psychiatry 2000; 57: 1061–1069.
Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci USA 1998; 95: 15718–15723.
Eastwood SL, Law AJ, Everall IP, Harrison PJ . axonal chemorepellant semaphoring 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology. Mol Psychiatry 2003; 8: 148–155.
Fatemi SH, Kroll JL, Stary JM . Altered levels of reelin and its isoforms in schizophrenia and mood disorders. Neuroreport 2001; 12: 3209–3215.
Chen ML, Chen SY, Huang CH, Chen CH . Identification of a single nucleotide polymorphism at the 5' promoter region of the human reelin gene and association study with schizophrenia. Mol Psychiatry 2002; 7: 447–448.
Akahane A, Kunugi H, Tanaka H, Nanko S . Association analysis of polymorphic CGG repeat in 5′ UTR of the reelin and VLDLR genes with schizophrenia. Schizophr Res 2002; 58: 37–41.
Haas CA, Dudeck O, Kirsch M, Huszka C, Kann G, Pollack S et al. Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J Neuroscience 2002; 22: 5797–5802.
Thom M, Sisodiya SM, Beckett A, Martinian L, Lin WR, Harkness W et al. Cytoarchitectural abnormalities in hippocampal sclerosis. J Neuropathol Exp Neurol 2002; 61: 510–519.
Drakew A, Deller T, Heimrich B, Gebhardt C, Del Turco D, Tielsch A et al. Dentate granule cells in reeler mutants and VLDLR and ApoER2 knockout mice. Exp Neurol 2002; 176: 12–24.
Eastwood SL, Harrison PJ . Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs. Mol Psychiatry 2000; 5: 425–432.
Webster MJ, Knable MB, O'Grady J, Weickert CS . Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders. Mol Psychiatry 2002; 7: 985–994.
Law AJ, Deakin JF . Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses. Neuroreport 2001; 12: 2971–2974.
Fatemi SH, Earle JA, Stary JM, Lee S, Sedgewick J . Altered levels of the synaptosomal associated protein SNAP-25 in hippocampus of subjects with mood disorders and schizophrenia. Neuroreport 2001; 12: 3257–3262.
Aloe L, Iannitelli A, Angelucci F, Bersani G, Fiore M . Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia -like disorders. Behav Pharmacol 2000; 11: 235–242.
Bersani G, Iannitelli A, Maselli, Pancheri P, Aloe L, Angelucci F et al. Low nerve growth facto plasma levels in schizophrenic patients: a preliminary study. Schizophr Res 1999; 37: 201–203.
Chen B, Dowlatshahi D, MacQueen GM, Wang J-F, Young LT . Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 2001; 50: 260–265.
Bayer TA, Schramm M, Feldmann N, Knable MB, Falkai P . Antidepressant drug exposure is associated with mRNA levels of tyrosine receptor kinase B in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2000; 24: 881–888.
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.
Angelucci F, Mathe AA, Aloe L . Brain-derived neurotrophic factor and tyrosine receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. J Neurosci Res 2000; 60: 783–794.
Wassink TH, Nelson JJ, Crowe RR, Andreasen NC . Heritability of BDNF alleles and their effect on brain morphology in schizophrenia. Am J Med Genet 1999; 88: 724–728.
Ritter LM, Meador-Woodruff JH . Antipsychotic regulation of hippocampal dopamine receptor messenger RNA expression. Biol Psychiatry 1997; 42: 155–164.
Muir WJ, Thomson ML, McKeon P, Mynett-Johnson L, Whitton C, Evans KL et al. Markers close to the dopamine D% receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder. Am J Med Genet 2001; 105: 152–158.
Williams NM, Cardno AG, Murphy KC, Jones LA, Asherson P, McGuffin P et al. Association between schizophrenia and a microsatellite polymorphism at the dopamine D5 receptor gene. Psychiatr Genet 1997; 7: 83–85.
Kalsi G, Sherrington R, Mankoo BS, Brynjolfsson J, Sigmundsson T, Curtis D, Read T, Murphy P et al. Linkage study of the D5 dopamine receptor gene in multiplex Icelandic and English schizophrenia pedigrees. Am J Psychiatry 1996; 153: 107–109.
Rosel P, Arranz B, San L, Vallejo J, Crespo JM, Urretavizcaya M et al. Altered 5-HT2a binding site and second messenger inositol triphosphate levels in hippocampus but not in frontal cortex from depressed suicide victims. Psychiatry Res 2000; 99: 173–181.
Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Pandy SC, Pesold C et al. Higher expression of serotonin 5HT2A receptors in the postmortem brains of teenage suicide victims. Am J Psychiatry 2002; 159: 419–429.
Marazziti D, Giannaccini G, Giromella A, Betti L, Pesce D, Nardi I et al. 3H-ketanserin binding sites in different psychiatric disorders. Neurochem Int 2003; 42: 511–516.
Ngan ET, Yatham LN, Ruth TJ, Liddle PF . Decreased serotonin 2A receptor densities in neuroleptic naïve patients with schizophrenia: A PET study using 18-F-setoperone. Am J Psychiatry 2000; 157: 1016–1018.
Dean B, Hayes W . Decreased frontal cortical serotonin 2A receptors in schizophrenia. Schizophr Res 1996; 21: 133–139.
About this article
Cite this article
Knable, M., Barci, B., Webster, M. et al. Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. Mol Psychiatry 9, 609–620 (2004). https://doi.org/10.1038/sj.mp.4001471
- bipolar disorder
- post mortem
This article is cited by
Schizophrenia in the genetic era: a review from development history, clinical features and genomic research approaches to insights of susceptibility genes
Metabolic Brain Disease (2023)
Enkephalin release from VIP interneurons in the hippocampal CA2/3a region mediates heterosynaptic plasticity and social memory
Molecular Psychiatry (2022)
Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory
Acta Neuropathologica (2021)
Reduced GluN1 in mouse dentate gyrus is associated with CA3 hyperactivity and psychosis-like behaviors
Molecular Psychiatry (2020)