Abstract
Previous work from our laboratory showed deficits in tyrosine hydroxylase protein expression within the substantia nigra/ventral tegmental area (SN/VTA) in schizophrenia. However, little is known about the nature and specific location of these deficits within the SN/VTA. The present study had two aims: (1) test if tyrosine hydroxylase deficits could be explained as the result of neuronal loss; (2) assess if deficits in tyrosine hydroxylase are sub-region specific within the SN/VTA, and thus, could affect specific dopaminergic pathways. To achieve these objectives: (1) we obtained estimates of the number of dopaminergic neurons, total number of neurons, and their ratio in matched SN/VTA schizophrenia and control samples; (2) we performed a qualitative assessment in SN/VTA schizophrenia and control matched samples that were processed simultaneously for tyrosine hydroxylase immunohistochemistry. We did not find any significant differences in the total number of neurons, dopaminergic neurons, or their ratio. Our qualitative study of TH expression showed a conspicuous decrease in labeling of neuronal processes and cell bodies within the SN/VTA, which was sub-region specific. Dorsal diencephalic dopaminergic populations of the SN/VTA presented the most conspicuous decrease in TH labeling. These data support the existence of pathway-specific dopaminergic deficits that would affect the dopamine input to the cortex without significant neuronal loss. Interestingly, these findings support earlier reports of decreases in tyrosine hydroxylase labeling in the target areas for this dopaminergic input in the prefrontal and entorhinal cortex. Finally, our findings support that tyrosine hydroxylase deficits could contribute to the hypodopaminergic state observed in cortical areas in schizophrenia.
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References
Abi-Dargham A, Silstein M, Kegeles L, Laruelle M (2010) Dopamine dysfunction in schizophrenia. In: Iversen LL, Iversen SD, Dunnett SB, Bjorklund A (eds) Dopamine Handbook. Oxford University Press, Oxford, pp 511–519
Akil M, Pierri JN, Whitehead RE, Edgar CL, Mohila C, Sampson AR, Lewis DA (1999) Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry 156:1580–1589
Akil M, Edgar CL, Pierri JN, Casali S, Lewis DA (2000) Decreased density of tyrosine hydroxylase-immunoreactive axons in the entorhinal cortex of schizophrenic subjects. Biol Psychiatry 47:361–370
Bergman O, Hakansson A, Westberg L, Nordenstrom K, Carmine Belin A, Sydow O, Olson L, Holmberg B, Eriksson E, Nissbrandt H (2010) PITX3 polymorphism is associated with early onset Parkinson’s disease. Neurobiol Aging 31:114–117
Bogerts B, Hantsch J, Herzer M (1983) A morphometric study of the dopamine-containing cell groups in the mesencephalon of normals, Parkinson patients, and schizophrenics. Biol Psychiatry 18:951–969
Carlsson A, Lindqvist M (1963) Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 20:140–144
Carlsson A, Lindqvist M, Magnusson T (1957) 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180:1200
Chung CY, Seo H, Sonntag KC, Brooks A, Lin L, Isacson O (2005) Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Hum Mol Genet 14:1709–1725
Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483
Damier P, Hirsch EC, Agid Y, Graybiel AM (1999a) The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28 K) immunohistochemistry. Brain 122:1421–1436
Damier P, Hirsch EC, Agid Y, Graybiel AM (1999b) The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 122:1437–1448
Davis KL, Kahn RS, Ko G, Davidson M (1991) Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148:1474–1486
Fallon JH, Loughlin SE (1987) Monoamine innervation of cerebral cortex and a theory of the role of monoamines in cerebral cortex and basal ganglia. In: Jones EG, Peters A (eds) cerebral cortex. Plenum Press, New York, pp 41–109
Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114:2283–2301
Finlay JM (2001) Mesoprefrontal dopamine neurons and schizophrenia: role of developmental abnormalities. Schizophr Bull 27:431–442
Floresco SB, Magyar O (2006) Mesocortical dopamine modulation of executive functions: beyond working memory. Psychopharmacology 188:567–585
Frankle WG, Laruelle M (2002) Neuroreceptor imaging in psychiatric disorders. Ann Nucl Med 16:437–446
Fuchs J, Mueller JC, Lichtner P, Schulte C, Munz M, Berg D, Wullner U, Illig T, Sharma M, Gasser T (2009) The transcription factor PITX3 is associated with sporadic Parkinson’s disease. Neurobiol Aging 30:731–738
Gaspar P, Stepniewska I, Kaas JH (1992) Topography and collateralization of the dopaminergic projections to motor and lateral prefrontal cortex in owl monkeys. J Comp Neurol 325:1–21
Gibb WR, Lees AJ (1991) Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson’s disease. J Neurol Neurosurg Psychiatry 54:388–396
Goldman-Rakic PS (1996) Regional and cellular fractionation of working memory. Proc Natl Acad Sci USA 93:13473–13480
Grimm J, Mueller A, Hefti F, Rosenthal A (2004) Molecular basis for catecholaminergic neuron diversity. Proc Natl Acad Sci USA 101:13891–13896
Grunblatt E, Mandel S, Maor G, Youdim MB (2001) Gene expression analysis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice model of Parkinson’s disease using cDNA microarray: effect of R-apomorphine. J Neurochem 78:1–12
Guillin O, Abi-Dargham A, Laurelle M (2007) Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol 78:1–39
Haber SN, Fudge JL (1997) The primate substantia nigra and VTA: integrative circuitry and function. Crit Rev Neurobiol 11:323–342
Haber SN, Gdowski MJ (2004) The basal ganglia. In: Paxinos G, Mai JK (eds) The Human Nervous System. Elsevier Academic Press, London, pp 676–738
Haber SN, Ryoo H, Cox C, Lu W (1995) Subsets of midbrain dopaminergic neurons in monkeys are distinguished by different levels of mRNA for the dopamine transporter: comparison with the mRNA for the D2 receptor, tyrosine hydroxylase and calbindin immunoreactivity. J Comp Neurol 362:400–410
Hauser MA, Li YJ, Xu H, Noureddine MA, Shao YS, Gullans SR, Scherzer CR, Jensen RV, McLaurin AC, Gibson JR, Scott BL, Jewett RM, Stenger JE, Schmechel DE, Hulette CM, Vance JM (2005) Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism. Arch Neurol 62:917–921
Hirsch E, Graybiel AM, Agid AM (1988) Melanized dopaminergic neurons are differentially susceptible to degradation in Parkinson’s disease. Nature 334:345–348
Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III–the final common pathway. Schizophr Bull 35:549–562
Howes OD, Williams M, Ibrahim K, Leung G, Egerton A, McGuire PK, Turkheimer F (2013) Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study. Brain 136:3242–3251
Ichinose H, Ohye T, Fujita K, Pantucek F, Lange K, Riederer P, Nagatsu T (1994) Quantification of mRNA of tyrosine hydroxylase and aromatic l-aminoacid decarboxylase in the substantia nigra in Parkinson’s disease and schizophrenia. J Neural Transm Park Dis Dement Sect 8:149–158
Kaalund SS, Newburn EN, Ye T, Tao R, Li C, Deep-Soboslay A, Herman MM, Hyde TM, Winberger DR, Lipska BK, Kleinman JE (2013) Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia. Mol Psychiatry. doi:10.1038/mp.2013.165
Keshavan MS, Nasrallah HA, Tandon R (2011) Schizophrenia, “Just the Facts” 6. Moving ahead with the schizophrenia concept: from the elephant to the mouse. Schizophr Res 127:3–13
Kubis N, Faucheux BA, Ransmayr G, Damier P, Duyckaerts C, Henin D, Forette B, Le Charpentier Y, Hauw JJ, Agid Y, Hirsch EC (2000) Preservation of midbrain catecholaminergic neurons in very old human subjects. Brain 123:366–373
Lopez-Garcia P, Young Espinoza L, Molero Santos P, Marin J, Ortuno Sanchez-Pedreno F (2013) Impact of COMT genotype on cognition in schizophrenia spectrum patients and their relatives. Psychiatry Res 208:118–124
Luk KC, Rymar VV, van den Munckhof P, Nicolau S, Steriade C, Bifsha P, Drouin J, Sadikot AF (2013) The transcription factor Pitx3 is expressed selectively in midbrain dopaminergic neurons susceptible to neurodegenerative stress. J Neurochem 125:932–943
Meyer-Lindenberg A (2010) Imaging genetics of schizophrenia. Dialogues Clin Neurosci 12:449–456
Mizoguchi K, Shoji H, Tanaka Y, Maruyama W, Tabira T (2009) Age-related spatial working memory impairment is caused by prefrontal cortical dopaminergic dysfunction in rats. Neuroscience 162:1192–1201
Motulsky HJ (2010) Intuitive biostatistics: A nonmathematical guide to statistical thinking. Oxford University Press, New York
Motulsky HJ, Brown RE (2006) Detecting outliers when fitting data with nonlinear regression-a new method based on robust nonlinear regression and the false discovery rate. BMC Bioinformatics 7:123
Mueller HT, Haroutunian V, Davis KL, Meador-Woodruff JH (2004) Expression of ionotropic gluatamate receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in schizophrenia. Brain Res Mol Brain Res 121:60–69
Nasrallah H, Tandon R, Keshavan M (2011) Beyond the facts in schizophrenia: closing the gaps in diagnosis, pathophysiology, and treatment. Epidemiol Psychiatr Sci 20:317–327
Nelander J, Hebsgaard JB, Parmar M (2009) Organization of the human embryonic ventral mesencephalon. Gene Expr Patterns 9:555–561
Nieuwenhuys R, Voogd J, van Huijzen C (2008) Topography of spinal cord, brain stem and cerebellum. In: Nieuwenhuys R, Voogd J, van Huijzen C (eds) The human central nervous system. Springer, Berlin, pp 177–246
Paxinos G, Huang XF (1995) Atlas of the human brainstem. Academic Press, San Diego
Perez-Costas E, Melendez-Ferro M, Roberts RC (2010) Basal ganglia pathology in schizophrenia: dopamine connections and anomalies. J Neurochem 113:287–302
Perez-Costas E, Melendez-Ferro M, Rice MW, Conley RR, Roberts RC (2012a) Dopamine pathology in schizophrenia: analysis of total and phosphorylated tyrosine hydroxylase in the substantia nigra. Front Psychiatry 3:31
Perez-Costas E, Rodriguez-Pallares J, Roberts RC, Labandeira-Garcia JL, Melendez-Ferro M (2012b) Poly-c-binding proteins in schizophrenia: a possible mechanism for tyrosine hydroxylase pathology. Program No. 452.11. 2012. Neuroscience Meeting Planner. New Orleans, LA: Society for Neuroscience, 2012
Puelles L, Verney C (1998) Early neuromeric distribution of tyrosine-hydroxylase-immunoreactive neurons in human embryos. J Comp Neurol 394:283–308
Raznahan A, Greenstein D, Lee Y, Long R, Clasen L, Gochman P, Addington A, Giedd JN, Rapoport JL, Gogtay N (2011) Catechol-o-methyl transferase (COMT) val158met polymorphism and adolescent cortical development in patients with childhood-onset schizophrenia, their non-psychotic siblings, and healthy controls. Neuroimage 57:1517–1523
Remington G, Agid O, Foussias G (2011) Schizophrenia as a disorder of too little dopamine: implications for symptoms and treatment. Expert Rev Neurother 11:589–607
Rice MW, Smith KL, Roberts RC, Perez-Costas E, Melendez-Ferro M (2014) Assessment of cytochrome c oxidase dysfunction in the substantia nigra/ventral tegmental area in schizophrenia. PLoS One 9(6):e100054. doi:10.1371/journal.pone.0100054
Rudow G, O’Brien R, Savonenko AV, Resnick SM, Zonderman AB, Pletnikova O, Marsh L, Dawson TM, Crain BJ, West MJ, Troncoso JC (2008) Morphometry of the human substantia nigra in ageing and Parkinson’s disease. Acta Neuropathol 115:461–470
Seamans JK, Yang CR (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74:1–58
Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–152
Seeman P, Lee T (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188:1217–1219
Seeman P, Lee T, Chau-Wong M, Wong K (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–719
Smidt MP, Burbach JP (2007) How to make a mesodiencephalic dopaminergic neuron. Nat Rev Neurosci 8:21–32
Smits SM, Burbach JP, Smidt MP (2006) Developmental origin and fate of meso-diencephalic dopamine neurons. Prog Neurobiol 78:1–16
Smits SM, von Oerthel L, Hoekstra EJ, Burbach JP, Smidt MP (2013) Molecular marker differences relate to developmental position and subsets of meso-diencephalic dopaminergic neurons. PLoS One 8(10):e76037
Spitzer RL, Williams JB, Gibbon M, First MB (1992) The Structured Clinical Interview for DSM-III-R (SCID). I: history, rationale, and description. Arch Gen Psychiatry 49:624–629
Surmeier DJ, Guzman JN, Sanchez-Padilla J, Goldberg JA (2010) What causes the death of dopaminergic neurons in Parkinson’s disease? Prog Brain Res 183:59–77
Tan HY, Callicott JH, Weinberger DR (2007) Dysfunctional and compensatory prefrontal cortical systems, genes and the pathogenesis of schizophrenia. Cereb Cortex 17:171–181
Tanaka S (2006) Dopaminergic control of working memory and its relevance to schizophrenia: a circuit dynamics perspective. Neuroscience 139:153–171
Thuret S, Bhatt L, O’Leary DD, Simon HH (2004) Identification and developmental analysis of genes expressed by dopaminergic neurons of the substantia nigra pars compacta. Mol Cell Neurosci 25:394–405
Toda M, Abi-Dargham A (2007) Dopamine hypothesis of schizophrenia: making sense of it all. Curr Psychiatry Rep 9:329–336
Tost H, Hakimi S, Meyer-Lindenberg A (2010) Dopamine dysfunction in schizophrenia: from genetic susceptibility to cognitive impairment. In: Iversen LL, Iversen SD, Dunnett SB, Bjorklund A (eds) Dopamine Handbook. Oxford University Press, Oxford, pp 558–571
van den Heuvel DM, Pasterkamp RJ (2008) Getting connected in the dopamine system. Prog Neurobiol 85:75–93
van Domburg PH, ten Donkelaar HJ (1991) The human substantia nigra and ventral tegmental area. A neuroanatomical study with notes on aging and aging diseases. Adv Anat Embryol Cell Biol 121:1–132
van Os J, Kapur S (2009) Schizophrenia. Lancet 374:635–645
Verney C (1999) Distribution of the catecholaminergic neurons in the central nervous system of human embryos and fetuses. Microsc Res Tech 46:24–47
Verney C, Zecevic N, Puelles L (2001) Structure of longitudinal brain zones that provide the origin for the substantia nigra and ventral tegmental area in human embryos, as revealed by cytoarchitecture and tyrosine hydroxylase, calretinin, calbindin and GABA immunoreactions. J Comp Neurol 429:22–44
Watson RE Jr, Wiegand SJ, Clough RW, Hoffman GE (1986) Use of cryoprotectant to maintain long-term peptide immunoreactivity and tissue morphology. Peptides 7:155–159
Williams MR, Galvin K, O’Sullivan B, Macdonald CD, Ching EW, Turkheimer F, Howes OD, Pearce RK, Hirsch SR and Maier M (2013) Neuropathological changes in the substantia nigra in schizophrenia but not depression. Eur Arch Psychiatry Clin Neurosci (In press)
Winter S, Dieckmann M, Schwabe K (2009) Dopamine in the prefrontal cortex regulates rats behavioral flexibility to changing reward value. Behav Brain Res 198:206–213
Zecevic N, Verney C (1995) Development of the catecholamine neurons in human embryos and fetuses, with special emphasis on the innervation of the cerebral cortex. J Comp Neurol 351:509–535
Acknowledgments
The authors wish to thank the Maryland Brain Collection, University of Maryland School of Medicine for providing the samples used in this study. This work was supported by the National Institutes of Health (USA) grant R01MH066123-09 awarded to MMF, EPC and RCR.
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Rice, M.W., Roberts, R.C., Melendez-Ferro, M. et al. Mapping dopaminergic deficiencies in the substantia nigra/ventral tegmental area in schizophrenia. Brain Struct Funct 221, 185–201 (2016). https://doi.org/10.1007/s00429-014-0901-y
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DOI: https://doi.org/10.1007/s00429-014-0901-y