Top

Published in:

Open Access 01-04-2009 | Original Paper

Stereologic investigation of the posterior part of the hippocampus in schizophrenia

Authors: Andrea Schmitt, Corinna Steyskal, Hans-Gert Bernstein, Thomas Schneider-Axmann, Eleni Parlapani, Evelin L. Schaeffer, Wagner F. Gattaz, Bernhard Bogerts, Christoph Schmitz, Peter Falkai

Published in: Acta Neuropathologica | Issue 4/2009

Abstract

Structural magnetic resonance imaging and postmortem studies showed volume loss in the hippocampus in schizophrenia. The noted tissue reduction in the posterior section suggests that some cellular subfractions within this structure might be reduced in schizophrenia. To address this, we investigated numbers and densities of neurons, oligodendrocytes and astrocytes in the posterior hippocampal subregions in postmortem brains from ten patients with schizophrenia and ten matched controls using design-based stereology performed on Nissl-stained sections. Compared to the controls, the patients with schizophrenia showed a significant decrease in the mean number of oligodendrocytes in the left and right CA4. This is the first finding of reduced numbers of oligodendrocytes in CA4 of the posterior part of the hippocampus in schizophrenia. Our results are in line with earlier findings in the literature concerning decreased numbers of oligodendrocytes in the prefrontal cortex in schizophrenia. Our results may indicate disturbed connectivity of the CA4 of the posterior part of the hippocampus in schizophrenia and, thus, contribute to the growing number of studies showing the involvement of posterior hippocampal pathology in the pathophysiology of schizophrenia.

Available only for authorised users

Amaral D, Lavanex P (2007) Hippocampal neuroanatomy. In: Andersen P, Morris R, Amaral D, Bliss T, O’Keefe J (eds) The hippocampus book. Oxford University Press, Oxford, pp 37–114

Andrade JP, Madeira MD, Paula-Barbosa MM (2000) Sexual dimorphism in the subiculum of the rat hippocampal formation. Brain Res 875:125–137. doi:10.1016/S0006-8993(00)02605-6 PubMedCrossRef

Arnold SE, Franz BR, Gur RC et al (1995) Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical–hippocampal interactions. Am J Psychiatry 152:738–748PubMed

Arnone D, McIntosh AM, Tan GM et al (2008) Meta-analysis of magnetic resonance imaging studies of the corpus callosum in schizophrenia. Schizophr Res 101:124–132. doi:10.1016/j.schres.2008.01.005 PubMedCrossRef

Bartzokis G, Nuechterlein KH, Lu PH et al (2003) Dysregulated brain development in adult men with schizophrenia: a magnetic resonance imaging study. Biol Psychiatry 53:412–421. doi:10.1016/S0006-3223(02)01835-8 PubMedCrossRef

Becker T, Elmer K, Schneider F et al (1996) Confirmation of reduced temporal limbic structure volume on magnetic resonance imaging in male patients with schizophrenia. Psychiatry Res 67:135–143. doi:10.1016/0925-4927(96)03002-8 PubMedCrossRef

Benes FM (1991) Evidence for neurodevelopment disturbances in anterior cingulate cortex of post-mortem schizophrenic brain. Schizophr Res 5:187–188. doi:10.1016/0920-9964(91)90063-W PubMedCrossRef

Benes FM (1989) Myelination of cortical-hippocampal relays during late adolescence. Schizophr Bull 15:585–593PubMed

Benes FM, Kwok EW, Vincent SL et al (1998) A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 44:88–97. doi:10.1016/S0006-3223(98)00138-3 PubMedCrossRef

10.

Benes FM, Sorensen I, Bird ED (1991) Reduced neuronal size in posterior hippocampus of schizophrenic patients. Schizophr Bull 17:597–608PubMed

11.

Benes FM, Turtle M, Khan Y et al (1994) Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood. Arch Gen Psychiatry 51:477–484PubMed

12.

Bogerts B (1997) The temporolimbic system theory of positive schizophrenic symptoms. Schizophr Bull 23:423–435PubMed

13.

Bogerts B, Falkai P, Haupts M et al (1990) Post-mortem volume measurements of limbic system and basal ganglia structures in chronic schizophrenics. Initial results from a new brain collection. Schizophr Res 3:295–301. doi:10.1016/0920-9964(90)90013-W PubMedCrossRef

14.

Bogerts B, Lieberman JA, Ashtari M et al (1993) Hippocampus-amygdala volumes and psychopathology in chronic schizophrenia. Biol Psychiatry 33:236–246. doi:10.1016/0006-3223(93)90289-P PubMedCrossRef

15.

Bullmore ET, Frangou S, Murray RM (1997) The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia. Schizophr Res 28:143–156. doi:10.1016/S0920-9964(97)00114-X PubMedCrossRef

16.

Byne W, Kidkardnee S, Tatusov A et al (2006) Schizophrenia-associated reduction of neuronal and oligodendrocyte numbers in the anterior principal thalamic nucleus. Schizophr Res 85:245–253. doi:10.1016/j.schres.2006.03.029 PubMedCrossRef

17.

Casanova MF, Stevens JR, Kleinman JE (1990) Astrocytosis in the molecular layer of the dentate gyrus: a study in Alzheimer’s disease and schizophrenia. Psychiatry Res 35:149–166. doi:10.1016/0165-1781(90)90157-Z PubMedCrossRef

18.

Corfas G, Roy K, Buxbaum JD (2004) Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. Nat Neurosci 7:575–580. doi:10.1038/nn1258 PubMedCrossRef

19.

Dracheva S, Davis KL, Chin B et al (2006) Myelin-associated mRNA and protein expression deficits in the anterior cingulate cortex and hippocampus in elderly schizophrenia patients. Neurobiol Dis 21:531–540. doi:10.1016/j.nbd.2005.08.012 PubMedCrossRef

20.

Dwork AJ (1997) Postmortem studies of the hippocampal formation in schizophrenia. Schizophr Bull 23:385–402PubMed

21.

Ellison-Wright I, Glahn DC, Laird AR et al (2008) The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am J Psychiatry 165:1015–1023. doi:10.1176/appi.ajp.2008.07101562 PubMedCrossRef

22.

Eyler LT, Jeste DV, Brown GG (2008) Brain response abnormalities during verbal learning among patients with schizophrenia. Psychiatry Res 162:11–25. doi:10.1016/j.pscychresns.2007.03.009 PubMedCrossRef

23.

Falkai P, Bogerts B (1986) Cell loss in the hippocampus of schizophrenics. Eur Arch Psychiatry Neurol Sci 236:154–161. doi:10.1007/BF00380943 PubMedCrossRef

24.

Falkai P, Honer WG, David S et al (1999) No evidence for astrogliosis in brains of schizophrenic patients. A post-mortem study. Neuropathol Appl Neurobiol 25:48–53. doi:10.1046/j.1365-2990.1999.00162.x PubMedCrossRef

25.

Goldman-Rakic PS, Selemon LD, Schwartz ML (1984) Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey. Neuroscience 12:719–743. doi:10.1016/0306-4522(84)90166-0 PubMedCrossRef

26.

Gundersen HJ, Bagger P, Bendtsen TF et al (1988) The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 96:857–881PubMedCrossRef

27.

Halim ND, Weickert CS, McClintock BW et al (2004) Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus. Neuropsychopharmacology 29:1063–1069. doi:10.1038/sj.npp.1300422 PubMedCrossRef

28.

Harrison PJ (2004) The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl) 174:151–162. doi:10.1007/s00213-003-1761-y CrossRef

29.

Harrison PJ (1999) The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122(Pt 4):593–624. doi:10.1093/brain/122.4.593 PubMedCrossRef

30.

Harrison PJ, Eastwood SL (2001) Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus 11:508–519. doi:10.1002/hipo.1067 PubMedCrossRef

31.

Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10:40–68 image 45PubMedCrossRef

32.

Heckers S (2001) Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 11:520–528. doi:10.1002/hipo.1068 PubMedCrossRef

33.

Heckers S, Heinsen H, Geiger B et al (1991) Hippocampal neuron number in schizophrenia. A stereological study. Arch Gen Psychiatry 48:1002–1008PubMed

34.

Heckers S, Konradi C (2002) Hippocampal neurons in schizophrenia. J Neural Transm 109:891–905. doi:10.1007/s007020200073 PubMedCrossRef

35.

Highley JR, Walker MA, McDonald B et al (2003) Size of hippocampal pyramidal neurons in schizophrenia. Br J Psychiatry 183:414–417. doi:10.1192/bjp.183.5.414 PubMedCrossRef

36.

Hirayasu Y, Shenton ME, Salisbury DF et al (1998) Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. Am J Psychiatry 155:1384–1391PubMed

37.

Hof PR, Haroutunian V, Copland C et al (2002) Molecular and cellular evidence for an oligodendrocyte abnormality in schizophrenia. Neurochem Res 27:1193–1200. doi:10.1023/A:1020981510759 PubMedCrossRef

38.

Hof PR, Haroutunian V, Friedrich VL Jr et al (2003) Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 53:1075–1085. doi:10.1016/S0006-3223(03)00237-3 PubMedCrossRef

39.

Honea R, Crow TJ, Passingham D et al (2005) Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. Am J Psychiatry 162:2233–2245. doi:10.1176/appi.ajp.162.12.2233 PubMedCrossRef

40.

Hurlemann R, Tepest R, Maier W et al (2005) Intact hippocampal gray matter in schizophrenia as revealed by automatized image analysis postmortem. Anat Embryol (Berl) 210:513–517. doi:10.1007/s00429-005-0035-3 CrossRef

41.

Kalus P, Buri C, Slotboom J et al (2004) Volumetry and diffusion tensor imaging of hippocampal subregions in schizophrenia. Neuroreport 15:867–871. doi:10.1097/00001756-200404090-00027 PubMedCrossRef

42.

Katsel P, Davis KL, Haroutunian V (2005) Variations in myelin and oligodendrocyte-related gene expression across multiple brain regions in schizophrenia: a gene ontology study. Schizophr Res 79:157–173. doi:10.1016/j.schres.2005.06.007 PubMedCrossRef

43.

Kodama M, Fujioka T, Duman RS (2004) Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry 56:570–580. doi:10.1016/j.biopsych.2004.07.008 PubMedCrossRef

44.

Konopaske GT, Dorph-Petersen KA, Pierri JN et al (2007) Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology 32:1216–1223. doi:10.1038/sj.npp.1301233 PubMedCrossRef

45.

Konopaske GT, Dorph-Petersen KA, Sweet RA et al (2008) Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry 63:759–765. doi:10.1016/j.biopsych.2007.08.018 PubMedCrossRef

46.

Kreczmanski P, Heinsen H, Mantua V et al (2007) Volume, neuron density and total neuron number in five subcortical regions in schizophrenia. Brain 130:678–692. doi:10.1093/brain/awl386 PubMedCrossRef

47.

Kuroki N, Kubicki M, Nestor PG et al (2006) Fornix integrity and hippocampal volume in male schizophrenic patients. Biol Psychiatry 60:22–31. doi:10.1016/j.biopsych.2005.09.021 PubMedCrossRef

48.

Lim KO, Ardekani BA, Nierenberg J et al (2006) Voxelwise correlational analyses of white matter integrity in multiple cognitive domains in schizophrenia. Am J Psychiatry 163:2008–2010. doi:10.1176/appi.ajp.163.11.2008 PubMedCrossRef

49.

Long JM, Mouton PR, Jucker M et al (1999) What counts in brain aging? Design-based stereological analysis of cell number. J Gerontol 54:B407–B417

50.

Mouton PR, Long JM, Lei DL et al (2002) Age and gender effects on microglia and astrocyte numbers in brains of mice. Brain Res 956:30–35. doi:10.1016/S0006-8993(02)03475-3 PubMedCrossRef

51.

Narr KL, Thompson PM, Sharma T et al (2001) Three-dimensional mapping of temporo-limbic regions and the lateral ventricles in schizophrenia: gender effects. Biol Psychiatry 50:84–97. doi:10.1016/S0006-3223(00)01120-3 PubMedCrossRef

52.

Newton SS, Duman RS (2007) Neurogenic actions of atypical antipsychotic drugs and therapeutic implications. CNS Drugs 21:715–725. doi:10.2165/00023210-200721090-00002 PubMedCrossRef

53.

Pakkenberg B, Pelvig D, Marner L et al (2003) Aging and the human neocortex. Exp Gerontol 38:95–99. doi:10.1016/S0531-5565(02)00151-1 PubMedCrossRef

54.

Pegues MP, Rogers LJ, Amend D et al (2003) Anterior hippocampal volume reduction in male patients with schizophrenia. Schizophr Res 60:105–115. doi:10.1016/S0920-9964(02)00288-8 PubMedCrossRef

55.

Price JL, Ko AI, Wade MJ et al (2001) Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 58:1395–1402. doi:10.1001/archneur.58.9.1395 PubMedCrossRef

56.

Rajarethinam R, DeQuardo JR, Miedler J et al (2001) Hippocampus and amygdala in schizophrenia: assessment of the relationship of neuroanatomy to psychopathology. Psychiatry Res 108:79–87. doi:10.1016/S0925-4927(01)00120-2 PubMedCrossRef

57.

Rametti G, Segarra N, Junque C et al (2007) Left posterior hippocampal density reduction using VBM and stereological MRI procedures in schizophrenia. Schizophr Res 96:62–71. doi:10.1016/j.schres.2007.04.034 PubMedCrossRef

58.

Schmitz C (1998) Variation of fractionator estimates and its prediction. Anat Embryol (Berl) 198:371–397. doi:10.1007/s004290050191 CrossRef

59.

Schmitz C, Hof PR (2005) Design-based stereology in neuroscience. Neuroscience 130:813–831. doi:10.1016/j.neuroscience.2004.08.050 PubMedCrossRef

60.

Schmitz C, Hof PR (2000) Recommendations for straightforward and rigorous methods of counting neurons based on a computer simulation approach. J Chem Neuroanat 20:93–114. doi:10.1016/S0891-0618(00)00066-1 PubMedCrossRef

61.

Segal D, Koschnick JR, Slegers LH et al (2007) Oligodendrocyte pathophysiology: a new view of schizophrenia. Int J Neuropsychopharmacol 10:503–511. doi:10.1017/S146114570600722X PubMedCrossRef

62.

Selemon LD, Mrzljak J, Kleinman JE et al (2003) Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca’s area 44 and area 9. Arch Gen Psychiatry 60:69–77PubMedCrossRef

63.

Stark AK, Toft MH, Pakkenberg H et al (2007) The effect of age and gender on the volume and size distribution of neocortical neurons. Neuroscience 150:121–130. doi:10.1016/j.neuroscience.2007.06.062 PubMedCrossRef

64.

Stark AK, Uylings HB, Sanz-Arigita E et al (2004) Glial cell loss in the anterior cingulate cortex, a subregion of the prefrontal cortex, in subjects with schizophrenia. Am J Psychiatry 161:882–888. doi:10.1176/appi.ajp.161.5.882 PubMedCrossRef

65.

Steiner J, Bernstein HG, Bielau H et al (2008) S100B-immunopositive glia is elevated in paranoid as compared to residual schizophrenia: a morphometric study. J Psychiatr Res 42:868–876. doi:10.1016/j.jpsychires.2007.10.001 PubMedCrossRef

66.

Sterio DC (1984) The unbiased estimation of number and sizes of arbitrary particles using the disector. J Microsc 134:127–136PubMed

67.

Szeszko PR, Goldberg E, Gunduz-Bruce H et al (2003) Smaller anterior hippocampal formation volume in antipsychotic-naive patients with first-episode schizophrenia. Am J Psychiatry 160:2190–2197. doi:10.1176/appi.ajp.160.12.2190 PubMedCrossRef

68.

Tkachev D, Mimmack ML, Ryan MM et al (2003) Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362:798–805. doi:10.1016/S0140-6736(03)14289-4 PubMedCrossRef

69.

Tregellas JR, Tanabe JL, Miller DE et al (2004) Neurobiology of smooth pursuit eye movement deficits in schizophrenia: an fMRI study. Am J Psychiatry 161:315–321. doi:10.1176/appi.ajp.161.2.315 PubMedCrossRef

70.

Uranova NA, Vostrikov VM, Orlovskaya DD et al (2004) Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res 67:269–275. doi:10.1016/S0920-9964(03)00181-6 PubMedCrossRef

71.

Uranova NA, Vostrikov VM, Vikhreva OV et al (2007) The role of oligodendrocyte pathology in schizophrenia. Int J Neuropsychopharmacol 10:537–545. doi:10.1017/S1461145707007626 PubMedCrossRef

72.

van Kooten IA, Palmen SJ, von Cappeln P et al (2008) Neurons in the fusiform gyrus are fewer and smaller in autism. Brain 131:987–999. doi:10.1093/brain/awn033 PubMedCrossRef

73.

Velakoulis D, Stuart GW, Wood SJ et al (2001) Selective bilateral hippocampal volume loss in chronic schizophrenia. Biol Psychiatry 50:531–539. doi:10.1016/S0006-3223(01)01121-0 PubMedCrossRef

74.

Vostrikov V, Orlovskaya D, Uranova N (2008) Deficit of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenia. World J Biol Psychiatry 9:34–42. doi:10.1080/15622970701210247 PubMedCrossRef

75.

Walker MA, Highley JR, Esiri MM et al (2002) Estimated neuronal populations and volumes of the hippocampus and its subfields in schizophrenia. Am J Psychiatry 159:821–828. doi:10.1176/appi.ajp.159.5.821 PubMedCrossRef

76.

West MJ, Coleman PD, Flood DG et al (1994) Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344:769–772. doi:10.1016/S0140-6736(94)92338-8 PubMedCrossRef

77.

West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497. doi:10.1002/ar.1092310411 PubMedCrossRef

78.

White T, Kendi AT, Lehericy S et al (2007) Disruption of hippocampal connectivity in children and adolescents with schizophrenia—a voxel-based diffusion tensor imaging study. Schizophr Res 90:302–307. doi:10.1016/j.schres.2006.09.032 PubMedCrossRef

79.

Williams RW, Rakic P (1988) Three-dimensional counting: an accurate and direct method to estimate numbers of cells in sectioned material. J Comp Neurol 278:344–352. doi:10.1002/cne.902780305 PubMedCrossRef

80.

Wright IC, Rabe-Hesketh S, Woodruff PW et al (2000) Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 157:16–25PubMed

81.

Yakovlev PI, Lecours AR (1967) The myelogenetic cycles of regional maturation of the brain. Blackwell Scientific Publications, Oxford, pp 3–70

82.

Yamasue H, Iwanami A, Hirayasu Y et al (2004) Localized volume reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: an MRI parcellation study. Psychiatry Res 131:195–207. doi:10.1016/j.pscychresns.2004.05.004 PubMedCrossRef

83.

Zaidel DW, Esiri MM, Harrison PJ (1997) Size, shape, and orientation of neurons in the left and right hippocampus: investigation of normal asymmetries and alterations in schizophrenia. Am J Psychiatry 154:812–818PubMed

84.

Zhang Z, Sun J, Reynolds GP (2002) A selective reduction in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia patients. Chin Med J 115:819–823PubMed

85.

Zhou Y, Shu N, Liu Y et al (2008) Altered resting-state functional connectivity and anatomical connectivity of hippocampus in schizophrenia. Schizophr Res 100:120–132. doi:10.1016/j.schres.2007.11.039 PubMedCrossRef

Title: Stereologic investigation of the posterior part of the hippocampus in schizophrenia
Authors: Andrea Schmitt
Corinna Steyskal
Hans-Gert Bernstein
Thomas Schneider-Axmann
Eleni Parlapani
Evelin L. Schaeffer
Wagner F. Gattaz
Bernhard Bogerts
Christoph Schmitz
Peter Falkai
Publication date: 01-04-2009
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 4/2009
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-008-0430-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Stereologic investigation of the posterior part of the hippocampus in schizophrenia

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2009

Kurt Jellinger Prize 2009 for Outstanding Scientific Writing in Neuropathology

The quantitative neuropathology of schizophrenia

Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation

Spatial distribution and density of oligodendrocytes in the cingulum bundle are unaltered in schizophrenia

Volume and neuron number of the lateral geniculate nucleus in schizophrenia and mood disorders

Lewy body/α-synucleinopathy in schizophrenia and depression: a preliminary neuropathological study