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European Archives of Psychiatry and Clinical Neuroscience

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01.06.2014 | Original Paper

Neuropathological changes in the substantia nigra in schizophrenia but not depression

verfasst von: M. R. Williams, K. Galvin, B. O’Sullivan, C. D. MacDonald, E. W. K. Ching, F. Turkheimer, O. D. Howes, R. K. B. Pearce, S. R. Hirsch, M. Maier

Erschienen in: European Archives of Psychiatry and Clinical Neuroscience | Ausgabe 4/2014

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Abstract

Schizophrenia is a chronic, disabling neuropsychiatric disorder characterised by positive, negative and cognitive symptoms. The aetiology is not known, although genetic, imaging and pathological studies have implicated both neurodevelopmental and neurodegenerative processes. The substantia nigra is a basal ganglia nucleus responsible for the production of dopamine and projection of dopaminergic neurons to the striatum. The substantia nigra is implicated in schizophrenia as dopamine has been heavily implicated in the dopamine hypothesis of schizophrenia and the prevalent psychotic symptoms and the monoamine theory of depression, and is a target for the development of new therapies. Studies into the major dopamine delivery pathways in the brain will therefore provide a strong base in improving knowledge of these psychiatric disorders. This post-mortem study examines the cytoarchitecture of dopaminergic neurons of the substantia nigra in schizophrenia (n = 12) and depression (n = 13) compared to matched controls (n = 13). Measures of nucleolar volume, nuclear length and nuclear area were taken in patients with chronic schizophrenia and major depressive disorder against matched controls. Astrocyte density was decreased in schizophrenia compared to controls (p = 0.030), with no change in oligodendrocyte density observed. Significantly increased nuclear cross-sectional area (p = 0.017) and length (p = 0.021), and increased nucleolar volume (p = 0.037) in dopaminergic neurons were observed in schizophrenia patients compared with controls, suggesting nuclear pleomorphic changes. No changes were observed in depression cases compared to control group. These changes may reflect pathological alterations in gene expression, neuronal structure and function in schizophrenia.

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Abi-Dargham A, Rodenhiser J, Printz D et al (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 97:8104–8109PubMedCentralPubMedCrossRef

Agid O, Mamo D, Ginovart N, Vitcu I, Wilson AA, Zipursky RB, Kapur S (2007) Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response-a double-blind PET study in schizophrenia. Neuropsychopharmacology 32:1209–1215PubMedCrossRef

Anamizu Y, Seichi A, Tsuzuki N, Nakamura K (2006) Age-related changes in histogram pattern of anterior horn cells in human cervical spinal cord. Neuropathology 26:533–539PubMedCrossRef

Bachus SE, Hyde TM, Akil M, Weickert CS, Vawter MP, Kleinman JE (1997) Neuropathology of suicide. A review and an approach. Ann N Y Acad Sci 836:201–219PubMedCrossRef

Baquet ZC, Williams D, Brody J, Smeyne RJ (2009) A comparison of model-based (2D) and design-based (3D) stereological methods for estimating cell number in the substantia nigra pars compacta (SNpc) of the C57BL/6 J mouse. Neuroscience 161:1082–1090PubMedCentralPubMedCrossRef

Baumeister AA, Francis JL (2002) Historical development of the dopamine hypothesis of schizophrenia. J Hist Neurosci 11:265–277PubMedCrossRef

Berciano MT, Novell M, Villagra NT, Casafont I, Bengoechea R, Val-Bernal JF, Lafarga M (2007) Cajal body number and nucleolar size correlate with the cell body mass in human sensory ganglia neurons. J Struct Biol 158:410–420PubMedCrossRef

Beskow J, Gotffries CG, Winblad B (1976) Determination of monoamine and monoamine metabolites in the human brain: postmortem studies in a group of suicides and in a control group. Acta Psychiatr Scand 53:7–20PubMedCrossRef

Breier A, Su TP, Saunders R et al (1997) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 94:2569–2574PubMedCentralPubMedCrossRef

10.

Brown R, Colter N, Corsellis JA et al (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 43:36–42PubMedCrossRef

11.

Bustos G, Abarca J, Campusano J, Bustoc V, Noriega V, Aliaga E (2004) Functional interactions between somatodendritic dopamine release, glutamate receptors and brain-derived neurotrophic factor expression in mesencephalic structures of the brain. Brain Res Rev 47:126–144PubMedCrossRef

12.

Clausius N, Born C, Grunze H (2009) The relevance of dopamine agonists in the treatment of depression. Neuropsychiatrie 23:15–25PubMed

13.

D’Haenen HA, Bossuyt A (1994) Dopamine D2 receptors in depression measured with single photon emission computed tomography. Biol Psychiatry 35:128–132PubMedCrossRef

14.

Davis KL, Kahn RS, Ko G, Davidson M (1991) Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148:1474–1486PubMed

15.

Dunlop BW, Nemeroff CB (2007) The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64:327–337PubMedCrossRef

16.

Fleming TM, Scott V, Naskar K, Joe N, Brown CH, Stern JE (2011) State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signalling in neurosecretory neurons. J Physiol 589:3929–3941PubMedCentralPubMed

17.

Fusar-Poli P, Perez J, Broome M et al (2007) Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis. Neurosci Biobehav Rev 31:465–484PubMedCrossRef

18.

Hajos M, Greenfield SA (1994) Synaptic connections between pars compacta and pars reticulata neurones: electrophysiological evidence for functional modules within the substantia nigra. Brain Res 660:216–224PubMedCrossRef

19.

Harrison PJ (1999) The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain 122:593–624PubMedCrossRef

20.

Hietala J, Syvalahti E, Vilkman H et al (1999) Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia. Schizophr Res 35:41–50PubMedCrossRef

21.

Howes OD, Egerton A, Allan V, McGuire P, Stokes P, Kapur S (2009) Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging. Curr Pharm Des 15:2550–2559PubMedCentralPubMedCrossRef

22.

Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35:549–562PubMedCentralPubMedCrossRef

23.

Howes OD, Montgomery AJ, Asselin MC, Murray RM, Grasby PM, McGuire PK (2006) The pre-synaptic dopaminergic system before and after the onset of psychosis: initial results from an ongoing [18F]fluoro-dopa PET study. Schizophr Res 86(Suppl 1):S11CrossRef

24.

Huttunen J, Heinimaa M, Svirskis T et al (2008) Striatal dopamine synthesis in first-degree relatives of patients with schizophrenia. Biol Psychiatry 63:114–117PubMedCrossRef

25.

Jamieson SM, Liu JJ, Connor B, Dragunow M, McKeage MJ (2007) Nucleolar enlargement, nuclear eccentricity and altered cell body immunostaining characteristics of large-sized sensory neurons following treatment of rats with paclitaxel. Neurotoxicology 28:1092–1098PubMedCrossRef

26.

Jentsch JD, Taylor JR, Roth RH (1998) Subchronic phencyclidine administration increases mesolimbic dopaminergic system responsivity and augments stress-and psychostimulant-induced hyperlocomotion. Neuropsychopharmacology 19:105–113PubMedCrossRef

27.

Kasper BS, Taylor DC, Janz D, Kasper EM, Maier M, Williams MR, Crow TJ (2010) Neuropathology of epilepsy and psychosis: the contributions of J.A.N. Corsellis. Brain 133:3795–3805PubMedCrossRef

28.

Keck ME, Welt T, Muller MB et al (2002) Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system. Neuropharmacology 43:101–109PubMedCrossRef

29.

Kegeles LS, Abi-Dargham A, Frankle WG et al (2010) Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 67:231–239PubMedCrossRef

30.

Kessler RM, Woodward ND, Riccardi P et al (2009) Dopamine D2 Receptor Levels in striatum, thalamus, substantia nigra, limbic regions, and cortex in schizophrenic subjects. Biol Psychiatry 65:1024–1031PubMedCentralPubMedCrossRef

31.

Kestler LP, Walker E, Vega EM (2001) Dopamine receptors in the brain of schizophrenia patients: a meta-analysis of the findings. Behav Pharmacol 12:355–371PubMedCrossRef

32.

Klimek V, Schenck JE, Han H, Stockmeier CA, Ordway GA (2002) Dopaminergic abnormalities in amygdaloid nucleus in major depression: a postmortem study. Biol Psychiatry 52:740–748PubMedCrossRef

33.

Laruelle M, Kegeles LS, Abi-Dargham A (2003) Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. Ann N Y Acad Sci 1003:138–158PubMedCrossRef

34.

Lawrie SM, Abukmeil SS (1998) Brain abnormality in schizophrenia: a systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry 172:110–120PubMedCrossRef

35.

Lindstrom LH, Gefvert O, Hagberg G, Lundberg T, Bergstrom M, Hartvig P, Langstrom B (1999) Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(β-11C) DOPA and PET. Biol Psychiatry 46:681–688PubMedCrossRef

36.

Lopez Leon S, Croes EA, Sayed-Tabatabaei FA, Claes S, Van Broeckhoven C, van Duijn CM (2005) The dopamine D4 receptor gene 48-base-pair-repeat polymorphism and mood disorders: a meta-analysis. Biol Psychiatry 57:999–1003PubMedCrossRef

37.

Mamah D, Wang L, Barch D, de Erausquin GA, Gado M, Csernansky JG (2007) Structural analysis of the basal ganglia in schizophrenia. Schizophr Res 89:59–71PubMedCentralPubMedCrossRef

38.

Martinot M, Bragulat V, Artiges E, Dolle F, Hinnen F, Jouvent R, Martinot J (2001) Decreased presynaptic dopamine function in the left caudate of depressed patients with affective flattening and psychomotor retardation. Am J Psychiatry 158:314–316PubMedCrossRef

39.

McIlwain DL, Hoke VB (2005) The role of the cytoskeleton in cell body enlargement, increased nuclear eccentricity and chromatolysis in axotomized spinal motor neurons. BMC Neurosci 6:19PubMedCentralPubMedCrossRef

40.

Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G et al (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5:267–271PubMedCrossRef

41.

Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC (2009) Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry 66:811–822PubMedCentralPubMedCrossRef

42.

Mitterauer BJ (2011) Possible role of glia in cognitive impairment in schizophrenia. CNS Neurosci Ther 17:333–344PubMedCrossRef

43.

Mizrahi R, Agid O, Borlido C, Suridjan I, Rusjan P, Houle S, Remington G, Wilson AA, Kapur S (2011) Effects of antipsychotics on D3 receptors: a clinical PET study in first episode antipsychotic naive patients with schizophrenia using [11C]-(+)-PHNO. Schizophr Res 131:63–68PubMedCrossRef

44.

Mueller HT, Haroutunian V, Davis KL, Meador-Woodruff JH (2004) Expression of the ionotropic glutamate receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in schizophrenia. Brain research. Mol Brain Res 121:60–69PubMedCrossRef

45.

Murray GK, Corlett PR, Clark L et al (2008) Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. Mol Psychiatry 239:267–276CrossRef

46.

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 55:433–440PubMedCrossRef

47.

Öngür D, Drevets WC, Price JL (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. PNAS USA 95:13290–13295PubMedCentralPubMedCrossRef

48.

Owen R, Owen F, Poulter M, Crow TJ (1984) Dopamine D2 receptors in substantia nigra in schizophrenia. Brain Res 299:152–154PubMedCrossRef

49.

Pakkenberg B (1987) Post-mortem study of chronic schizophrenic brains. Br J Psychiatry 151:744–752PubMedCrossRef

50.

Park SK, Nguyen MD, Fischer A et al (2005) Par-4 links dopamine signaling and depression. Cell 122:275–287PubMedCrossRef

51.

Parsey RV, Oquendo MA, Zea-Ponce Y et al (2001) Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression. Biol Psychiatry 50:313–322PubMedCrossRef

52.

Pena E, Berciano MT, Fernandez R, Ojeda JL, Lafarga M (2001) Neuronal body size correlates with the number of nucleoli and cajal bodies, and with the organization of the splicing machinery in rat trigeminal ganglion neurons. J Comp Neurol 430:250–263PubMedCrossRef

53.

Rajkowska G, Miguel-Hidalgo JJ, Makkos Z, Meltzer H, Overholser J, Stockmeier C (2002) Layer-specific reductions in GFAP-reactive astroglia in the dorsolateral prefrontal cortex in schizophrenia. Schizophr Res 57:127–138. Erratum in: Schizophr Res 2003 60:103

54.

Rajkowska G, Selemon LD, Goldman-Rakic PS (1998) Neuronal and glial somal size in the prefrontal cortex: a post-mortem morphometric study of schizophrenia and Huntington disease. Arc Gen Psychiatry 55:215–224CrossRef

55.

Rajkowska G (1997) Morphometric methods for studying the prefrontal cortex in suicide victims and psychiatric patients. Ann N Y Acad Sci 29(836):253–268CrossRef

56.

Rampello L, Nicoletti G, Raffaele R (1991) Dopaminergic hypothesis for retarded depression: a symptom profile for predicting therapeutical responses. Acta Psychiatr Scand 84:552–554PubMedCrossRef

57.

Rey MJ, Schulz P, Costa C, Dick P, Tissot R (1989) Guidelines for the dosage of neuroleptics. I: chlorpromazine equivalents of orally administered neuroleptics. Int Clin Psychopharmacol 4:95–104PubMedCrossRef

58.

Rothermundt M, Ahn JN, Jörgens S (2009) S100B in schizophrenia: an update. Gen Physiol Biophys 28:F76–F81PubMed

59.

Schmitt A, Steyskal C, Bernstein HG, Schneider-Axmann T, Parlapani E, Schaeffer EL, Gattaz WF, Bogerts B, Schmitz C, Falkai P (2009) Stereologic investigation of the posterior part of the hippocampus in schizophrenia. Acta Neuropathol 117:395–407PubMedCrossRef

60.

Seeman P, Lee T (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188:1217–1219PubMedCrossRef

61.

Segal D, Schmitz C, Hof PR (2009) Spatial distribution and density of oligodendrocytes in the cingulum bundle are unaltered in schizophrenia. Acta Neuropathol 117:385–394PubMedCentralPubMedCrossRef

62.

Selemon LD, Rajkowska G (2002) Two-dimensional versus three-dimensional cell counting correspondence. Biol Psychiatry 51:838–846PubMedCrossRef

63.

Smieskova R, Fusar-Poli P, Allen P et al (2009) The effects of antipsychotics on the brain: what have we learnt from structural imaging of schizophrenia?—a systematic review. Curr Pharm Des 15:2535–2549PubMedCrossRef

64.

Strafella AP, Paus T, Fraraccio M, Dagher A (2003) Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain 126:2609–2615PubMedCrossRef

65.

Sullivan PF, Neale MC, Kendler KS (2000) Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157:1552–1562PubMedCrossRef

66.

Swaab DF, Bao AM, Lucassen PJ (2005) The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 4(2):141–194PubMedCrossRef

67.

Tanaka S (2010) Model-based parametric study of frontostriatal abnormalities in schizophrenia patients. BMC Psychiatry 27:10–17

68.

Tepper JM, Lee CR (2007) GABAergic control of substantia nigra dopaminergic neurons. Prog Brain Res 160:189–208PubMedCrossRef

69.

Thompson PM, Vidal C, Giedd JN et al (2001) Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci USA 98:11650–11655PubMedCentralPubMedCrossRef

70.

Todtenkopf MS, Vincent SL, Benes FM (2005) A cross-study meta-analysis and three-dimensional comparison of cell counting in the anterior cingulate cortex of schizophrenic and bipolar brain. Schizophr Res 73:79–89PubMedCrossRef

71.

Toru M, Watanabe S, Shibuya H et al (1988) Neurotransmitters, receptors and neuropeptides in post-mortem brains of chronic schizophrenic patients. Acta Psychiatr Scand 78:121–137PubMedCrossRef

72.

Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI (2004) Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley neuropathology consortium. Schizophr Res 67:269–275PubMedCrossRef

73.

van Berckel BN, Kegeles LS, Waterhouse R et al (2006) Modulation of amphetamine-induced dopamine release by group II metabotropic glutamate receptor agonist LY354740 in non-human primates studied with positron emission tomography. Neuropsychopharmacology 31:967–977PubMedCrossRef

74.

van Haren NE, Cahn W, Hulshoff Pol HE, Kahn RS (2008) Schizophrenia as a progressive brain disease. Eur Psychiatry 23:245–254PubMedCrossRef

75.

von Bartheld C (2002) Counting particles in tissue sections: choices of methods and importance of calibration to minimize biases. Histol Histopathol 17:639–648

76.

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

77.

Wang L, Mamah D, Harms MP et al (2008) Progressive deformation of deep brain nuclei and hippocampal-amygdala formation in schizophrenia. Biol Psychiatry 64:1060–1068PubMedCentralPubMedCrossRef

78.

Williams MR, Hampton T, Pearce RKB, Hirsch SR, Ansorge O, Thom M, Maier M (2013) Astrocyte decrease in the subgenual cingulate and callosal genu in schizophrenia. Eur Arch Psychiatry clin Neurosci 263:41–52PubMedCrossRef

79.

Williams MR, Marsh R, Jain J, Pearce RKB, Hirsch SR, Gentleman S, Thom M, Maier M (2011) Examination of glial and neuronal changes in the Nucleus Basalis in schizophrenia and recurrent depression. Int Clin Psychopharmacol 26:e68CrossRef

80.

Williams MR, Pearce RKB, Hirsch SR, Ansorge O, Thom M, Maier M (2006) Astrocytes abnormalities differentiate schizophrenia from affective disorders in post-mortem brain. Schizophr Res 81:72

81.

Woodruff PW, McManus IC, David AS (1995) Meta-analysis of corpus callosum size in schizophrenia. J Neurol Neurosurg Psychiatry 58:457–461PubMedCentralPubMedCrossRef

82.

Woods SW (2003) Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry 64:663–667PubMedCrossRef

83.

Zaborszky L, Vadasz C (2001) The midbrain dopaminergic system: anatomy and genetic variation in dopamine neuron number of inbred mouse strains. Behav Genet 31:47–59PubMedCrossRef

84.

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 27:703–713

85.

Zakzanis KK, Hansen KT (1998) Dopamine D2 densities and the schizophrenic brain. Schizophr Res 32:201–206PubMedCrossRef

Titel: Neuropathological changes in the substantia nigra in schizophrenia but not depression
verfasst von: M. R. Williams
K. Galvin
B. O’Sullivan
C. D. MacDonald
E. W. K. Ching
F. Turkheimer
O. D. Howes
R. K. B. Pearce
S. R. Hirsch
M. Maier
Publikationsdatum: 01.06.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: European Archives of Psychiatry and Clinical Neuroscience / Ausgabe 4/2014
Print ISSN: 0940-1334
Elektronische ISSN: 1433-8491
DOI: https://doi.org/10.1007/s00406-013-0479-z

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Neuropathological changes in the substantia nigra in schizophrenia but not depression

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