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Pharmacopsychiatry 2007; 40: S40-S44
DOI: 10.1055/s-2007-992811
Original Paper

© Georg Thieme Verlag KG Stuttgart · New York

Systems Neurobiology of the Dysfunctional Brain: Schizophrenia

J. Gallinat 1 , K. Obermayer 2 , A. Heinz 1
  • 1Klinik für Psychiatrie und Psychotherapie, Charité Universitätsmedizin Berlin, Campus Mitte, Germany
  • 2Berlin University of Technology, Berlin, Germany
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Publication History

Publication Date:
17 December 2007 (online)

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Abstract

Systems biology tries to reconstruct living systems beyond bioinformatics or statistical approaches where known databases are analysed. An advantage is the dynamic variation in the model for instance by the addition of the factor time, which enables the researcher to simulate complex processes related to psychiatric diseases (systems neurobiology). Dynamic models of a patients' individual pathophysiology may be constructed employing multimodal brain imaging data of current neurotransmission and brain activation. From the clinical point of view, individual models of pathophysiology are preconditions for a personalised pharmacotherapy and may be suitable to predict adverse events, course of the disease and outcome. This review discusses the potential role of systems neurobiology in schizophrenia and focuses on evidence for a dysfunction of the dopamine and glutamate system.

Key words

system biology - computational neuroscience - schizophrenia - dopamine - glutamate

References

  • 1 Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Heertum R Van, Gorman JM, Laruelle M. Prefrontal dopamine D1 receptors and working memory in schizophrenia.  J Neurosci. 2002;  , May 1; 22 ((9)) 3708-3719
    Google Scholar
  • 2 Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Heertum RL Van, Gorman JM, Laruelle M. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.  Proc Natl Acad Sci USA. 2000;  , Jul 5; 97 ((14)) 8104-8109
    Google Scholar
  • 3 Alberghina LR, Rossi R, Porro D, Vanoni M. In: Alberghino L, Westerhoff HV eds., Systems Biology, Definitions and Perspectives. Springer Verlag
  • 4 Andras P, Wennekers T. Cortical activity pattern computation.  Biosystems. 2007;  , Feb; 87 ((2-3)) 179-185
    Google Scholar
  • 5 Beckmann H, Jakob H. Prenatal developmental disorders of brain structures in schizophrenic psychoses Nervenarzt.  1994;  , Jul; 65 ((7)) 454-463
    Google Scholar
  • 6 Bender W, Albus M, Moller HJ, Tretter F. Towards systemic theories in biological psychiatry.  Pharmacopsychiatry. 2006;  , Feb; 39 (Suppl) 1 S4-S9
    Google Scholar
  • 7 Bertolino A, Breier A, Callicott JH, Adler C, Mattay VS, Shapiro M, Frank JA, Pickar D, Weinberger DR. The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia.  Neuropsychopharmacology. 2000;  , Feb; 22 ((2)) 125-132
    Google Scholar
  • 8 Bosl WJ. Systems biology by the rules: hybrid intelligent systems for pathway modeling and discovery.  BMC Syst Biol. 2007;  , Feb 15; 1 13
    Google Scholar
  • 9 Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain.  Acta Pharmacol Toxicol (Copenh). 1963;  20 140-144
    Google Scholar
  • 10 Carlsson A, Waters N, Carlsson ML. Neurotransmitter interactions in schizophrenia-therapeutic implications.  Biol Psychiatry. 1999;  , Nov 15; 46 ((10)) 1388-1395
    Google Scholar
  • 11 Carlsson A. The neurochemical circuitry of schizophrenia.  Pharmacopsychiatry. 2006;  , Feb; 39 (Suppl 1) S10-S14
    Google Scholar
  • 12 Cohen JD, Braver TS, Brown JW. Computational perspectives on dopamine function in prefrontal cortex.  Curr Opin Neurobiol. 2002;  , Apr; 12 ((2)) 223-229
    Google Scholar
  • 13 Contreras-Vidal JL, Schultz W. A predictive reinforcement model of dopamine neurons for learning approach behavior.  J Comput Neurosci. 1999;  , May-Jun; 6 ((3)) 191-214
    Google Scholar
  • 14 Daniel DG, Weinberger DR, Jones DW, Zigun JR, Coppola R, Handel S, Bigelow LB, Goldberg TE, Berman KF, Kleinman JE. The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia.  J Neurosci. 1991;  , Jul; 11 ((7)) 1907-1917
    Google Scholar
  • 15 Durstewitz D. A few important points about dopamine's role in neural network dynamics.  Pharmacopsychiatry. 2006;  , Feb; 39 (Suppl 1) S72-S75
    Google Scholar
  • 16 Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.  Proc Natl Acad Sci USA. 2001;  , Jun 5; 98 ((12)) 6917-6922
    Google Scholar
  • 17 Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence?.  J Psychiatr Res. 1982-1983;  17 ((4)) 319-334
    Google Scholar
  • 18 Frank MJ, Seeberger LC, O'reilly RC. By carrot or by stick: cognitive reinforcement learning in parkinsonism.  Science. 2004;  , Dec 10 ; 306 ((5703)) 1940-1943
    Google Scholar
  • 19 Gallinat J, Bajbouj M, Sander T, Schlattmann P, Xu K, Ferro EF, Goldman D, Winterer G. Association of the G1947A COMT (Val(108/158)Met) gene polymorphism with prefrontal P300 during information processing.  Biol Psychiatry. 2003;  , Jul 1; 54 ((1)) 40-48
    Google Scholar
  • 20 Gallinat J, Gotz T, Kalus P, Bajbouj M, Sander T, Winterer G. Genetic variations of the NR3A subunit of the NMDA receptor modulate prefrontal cerebral activity in humans.  J Cogn Neurosci. 2007;  , Jan; 19 ((1)) 59-68
    Google Scholar
  • 21 Gallinat J, Heinz A. Combination of multimodal imaging and molecular genetic information to investigate complex psychiatric disorders.  Pharmacopsychiatry. 2006;  , Feb; 39 (Suppl 1) S76-S79
    Google Scholar
  • 22 Gallinat J, Kunz D, Lang UE, Neu P, Kassim N, Kienast T, Seifert F, Schubert F, Bajbouj M. Association between cerebral glutamate and human behaviour: the sensation seeking personality trait.  Neuroimage. 2007;  , Jan 15; 34 ((2)) 671-678
    Google Scholar
  • 23 Gallinat J, Winterer G, Herrmann CS, Senkowski D. Reduced oscillatory gamma-band responses in unmedicated schizophrenic patients indicate impaired frontal network processing.  Clin Neurophysiol. 2004;  , Aug; 115 ((8)) 1863-1874
    Google Scholar
  • 24 Goldman-Rakic PS, Leranth C, Williams SM, Mons N, Geffard M. Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex.  Proc Natl Acad Sci USA. 1989;  , Nov; 86 ((22)) 9015-9019
    Google Scholar
  • 25 Grace AA, Moore H, O'Donnell P. The modulation of corticoaccumbens transmission by limbic afferents and dopamine: a model for the pathophysiology of schizophrenia.  Adv Pharmacol. 1998;  42 721-724
    Google Scholar
  • 26 Grace AA. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia.  Neuroscience. 1991;  41 ((1)) 1-24
    Google Scholar
  • 27 Grant SG. Systems biology in neuroscience: bridging genes to cognition.  Curr Opin Neurobiol. 2003;  , Oct; 13 ((5)) 577-582
    Google Scholar
  • 28 Haber SN, Fudge JL. The primate substantia nigra and VTA: integrative circuitry and function.  Crit Rev Neurobiol. 1997;  11 ((4)) 323-342
    Google Scholar
  • 29 Heimer L, Zahm DS, Alheid GG. Basal ganglia. In Paxinos, G., ed. The Rat Nervous System. San Diego, CA: Academic Press 1995: 579-628
    Google Scholar
  • 30 Heinz A, Saunders RC, Kolachana BS, Jones DW, Gorey JG, Bachevalier J, Weinberger DR. Striatal dopamine receptors and transporters in monkeys with neonatal temporal limbic damage.  Synapse. 1999;  , May; 32 ((2)) 71-79
    Google Scholar
  • 31 Heinz A. Dopaminergic dysfunction in alcoholism and schizophrenia-psychopathological and behavioral correlates.  Eur Psychiatry. 2002;  , Mar; 17 ((1)) 9-16
    Google Scholar
  • 32 Jentsch JD, Taylor JR, Roth RH. Subchronic phencyclidine administration increases mesolimbic dopaminergic system responsivity and augments stress- and psychostimulant-induced hyperlocomotion.  Neuropsychopharmacology. 1998;  , Aug; 19 ((2)) 105-113
    Google Scholar
  • 33 Juckel G, Schlagenhauf F, Koslowski M, Filonov D, Wustenberg T, Villringer A, Knutson B, Kienast T, Gallinat J, Wrase J, Heinz A. Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics.  Psychopharmacology (Berl). 2006b;  , Aug; 187 ((2)) 222-228
    Google Scholar
  • 34 Juckel G, Schlagenhauf F, Koslowski M, Wustenberg T, Villringer A, Knutson B, Wrase J, Heinz A. Dysfunction of ventral striatal reward prediction in schizophrenia.  Neuroimage. 2006a;  , Jan 15; 29 ((2)) 409-416 , Epub 2005 Sep 1.
    Google Scholar
  • 35 Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Heertum RL Van, Cooper TB, Carlsson A, Laruelle M. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia.  Biol Psychiatry. 2000;  , Oct 1; 48 ((7)) 627-640
    Google Scholar
  • 36 Kolachana BS, Saunders RC, Weinberger DR. Augmentation of prefrontal cortical monoaminergic activity inhibits dopamine release in the caudate nucleus: an in vivo neurochemical assessment in the rhesus monkey.  Neuroscience. 1995;  , Dec; 69 ((3)) 859-868
    Google Scholar
  • 37 Krystal JH, Perry  Jr  EB, Gueorguieva R, Belger A, Madonick SH, Abi-Dargham A, Cooper TB, Macdougall L, Abi-Saab W, D'Souza DC. Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function.  Arch Gen Psychiatry. 2005;  , Sep; 62 ((9)) 985-994
    Google Scholar
  • 38 Laruelle M, Abi-Dargham A. Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies.  J Psychopharmacol. 1999;  , Dec; 13 ((4)) 358-371
    Google Scholar
  • 39 Lipska BK, Jaskiw GE, Weinberger DR. Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia.  Neuropsychopharmacology. 1993;  , Aug; 9 ((1)) 67-75
    Google Scholar
  • 40 Lipska BK, Weinberger DR. Prefrontal cortical and hippocampal modulation of dopamine-mediated effects.  Adv Pharmacol. 1998;  42 806-809
    Google Scholar
  • 41 Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine.  Proc Natl Acad Sci USA. 2003;  , May 13; 100 ((10)) 6186-6191
    Google Scholar
  • 42 Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia.  Nat Neurosci. 2002;  , Mar; 5 ((3)) 267-271
    Google Scholar
  • 43 Miller DW, Abercrombie ED. Effects of MK-801 on spontaneous and amphetamine-stimulated dopamine release in striatum measured with in vivo microdialysis in awake rats.  Brain Res Bull. 1996;  40 ((1)) 57-62
    Google Scholar
  • 44 Montag C, Heinz A, Kunz D, Gallinat J. Self-reported empathic abilities in schizophrenia.  Schizophr Res. 2007;  , May; 92 ((1-3)) 85-89
    Google Scholar
  • 45 Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial.  Nat Med. 2007;  , Oct; 13 ((9)) 1102-1107
    Google Scholar
  • 46 Pearlson GD. Psychiatric and medical syndromes associated with phencyclidine (PCP) abuse.  Johns Hopkins Med J. 1981;  , Jan; 148 ((1)) 25-33
    Google Scholar
  • 47 Pycock CJ, Kerwin RW, Carter CJ. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats.  Nature. 1980;  , Jul 3; 286 ((5768)) 74-76
    Google Scholar
  • 48 Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward.  Science. 1997;  , Mar 14; 275 ((5306)) 1593-1599
    Google Scholar
  • 49 Sesack SR, Carr DB, Omelchenko N, Pinto A. Anatomical substrates for glutamate-dopamine interactions: evidence for specificity of connections and extrasynaptic actions.  Ann NY Acad Sci. 2003;  , Nov; 1003 36-52
    Google Scholar
  • 50 Thompson JL, Pogue-Geile MF, Grace AA. Developmental pathology, dopamine, and stress: a model for the age of onset of schizophrenia symptoms.  Schizophr Bull. 2004;  30 ((4)) 875-900
    Google Scholar
  • 51 Tretter F, Scherer J. Schizophrenia, neurobiology and the methodology of systemic modeling.  Pharmacopsychiatry. 2006;  , Feb; 39 (Suppl 1) S26-S35
    Google Scholar
  • 52 Wang XJ. Toward a prefrontal microcircuit model for cognitive defi-cits in schizophrenia.  Pharmacopsychiatry. 2006;  , Feb; 39 (Suppl 1) S80-S87
    Google Scholar
  • 53 Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia.  Arch Gen Psychiatry. 1987;  , Jul; 44 ((7)) 660-669
    Google Scholar
  • 54 Wennekers T, Ay N, Andras P. High-resolution multiple-unit EEG in cat auditory cortex reveals large spatio-temporal stochastic interactions.  Biosystems. 2007;  , May-Jun; 89 ((1-3)) 190-197
    Google Scholar
  • 55 West AR, Grace AA. Opposite influences of endogenous dopamine D1 and D2 receptor activation on activity states and electrophysiological properties of striatal neurons: studies combining in vivo intracellular recordings and reverse microdialysis.  J Neurosci. 2002;  , Jan 1; 22 ((1)) 294-304
    Google Scholar
  • 56 Willner P. The dopamine hypothesis of schizophrenia: current status, future prospects.  Int Clin Psychopharmacol. 1997;  , Nov; 12 ((6)) 297-308
    Google Scholar
  • 57 Zangen A, Hyodo K. Transcranial magnetic stimulation induces increases in extracellular levels of dopamine and glutamate in the nucleus accumbens.  Neuroreport. 2002;  , Dec 20; 13 ((18)) 2401-2405
    Google Scholar

Correspondence

PD Dr. J. Gallinat

Klinik für Psychiatrie und Psychotherapie

Charité Universitätsmedizin Berlin

Charité Campus Mitte

Charitéplatz 1

10117 Berlin

Germany

Phone: +49/30/450 517 07 0

Fax: +49/30/450 517 96 2

Email: juergen.gallinat@charite.de