Mental Illness, Synapses and the Brain – Behavioral Disorders by a System of Molecules within a System of Neurons?

F. Tretter

doi:10.1055/s-0030-1253365

Pharmacopsychiatry, Inhaltsverzeichnis

Pharmacopsychiatry 2010; 43: S9-S20
DOI: 10.1055/s-0030-1253365

Review

Mental Illness, Synapses and the Brain – Behavioral Disorders by a System of Molecules within a System of Neurons?

F. Tretter¹

¹Department of Addiction, Isar-Amper-Clinics, Haar/Munich, Germany

Abstract

The multi-level systems view conceiving the brain as a “network of networks of neurons” rises the question how it could be possible to understand this complex system with respect to mental functions and dysfunctions. One crucial issue is related to the analysis of the connectivity of these networks by the study of synapses. Also synapses are complex dynamical molecular systems that can only be understood by computer-based methodologies in order to analyze complex data sets and for modeling complex molecular networks. Many data are available but there is a lack models that capture the dynamic features of synapses that are involved in psychiatric disorders and psychopharmaceutical treatment. One strategy of research could be offered by Systems Biology. Here some challenges for modeling synapses in mental disorders are discussed.

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Referenzen

References

1 Abbot LF. Balancing homeostasis and learning in neural circuits. Zoology. 2003; 106 (4) 365-371
2 Abbott LF, Regehr WG. Synaptic computation. Nature. 2004; 431 (7010) 796
3 Abbott LF, Varela J, Sen K. et al . Synaptic depression and cortical gain control. Science. 1997; 275 220-224
4 Aghajanian GK, Marek GJ. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Rev. 2000; 31 (2–3) 302-312
5 Alon U. Systems Biology – Design principles of biological circuits.. New York: Chapman & Hall; 2007
6 Bender W, Albus M, Möller HJ. et al . Towards systemic theories in biological psychiatry. Pharmacopsychiatry. 2006; 39 (S 01) S4-S9
7 Benes FM. Neural circuitry models of schizophrenia: is it dopamine, GABA, glutamate or something else?. Biol Psychiatry. 2009; 65 1003-1005
8 Benoit-Marand M, Borrelli E, Gonomn F. Inhibition of dopamine release via presynaptic D2 receptors: time course asnd functional characteristics in vivo. J Neurosci. 2001; 21 9134-9141
9 Bertram R, Sherman A, Stanley EF. Single-domain/bound calcium hypothesis of transmitter release and facilitation. J Neurophysiol. 1996; 75 1919-1931
10 Best JA, Nijhout HF, Reed MC. Homeostatic mechanisms in dopamine synthesis and release: a mathematical model. Theoretical Biology and Medical Modelling. 2009; 6 21 DOI: doi:10.1186/1742-4682-6-21
11 Brunel N, Wang X-J. Effects of neuromodulation in a cortical network model of object working memory dominated by recurrent inhibition. J Comput Neurosci. 2001; 11 63-85
12 Carlsson A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology. 1988; 1 179-186
13 Carlsson A. The neurochemical circuitry of schizophrenia. Pharamcopsychiatry. 2006; 39 (Suppl. 1) S10-S14
14 Carlsson M, Carlsson A. Interactions between glutamatergic and monoaminergic systems within the basal ganglia – implications for schizophrenia and Parkinson's disease. Trends Neurosci. 1990; 13 272-276
15 Carlsson A, Waters N, Carlsson ML. Neurotransmitter interactions in schizophrenia- therapeutic implications. Eur Arch Psychiat Clin Neurosci. 1999; 249 (S 04) 37-43
16 Carlsson A, Waters N, Holm-Waters S. et al . Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol. 2001; 41 237-260
17 Chavas J, Marty A. Coexistence of Excitatory and Inhibitory GABA Synapses in the Cerebellar Interneuron Network. J Neurosci. 2003; 23 (6) 2019-2031
18 Clements JD. Transmitter timecourse in the synaptic cleft: its role in central synaptic function, Trends. Neurosci. 1996; 19 (5) 163-171
19 Cohen JD, Servan-Schreiber D. A theory of dopamine function and its role in cognitive deficits in schizophrenia. Schizophr Bull. 1993; 19 85-104
20 Cooper JR, Bloom FE, Roth RH. The Biochemical Basis of Neuropharmacology.. 8th ed., New York: Oxford University Press; 2004
21 Cragg SJ, Rice ME. Dancing past the DAT at a DA synapse. Trends Neurosci. 2004; 27 (5) 270-277
22 Dayan P, Abbott LF. Theoretical Neuroscience Computational and mathematical modeling of neural systems.. Cambridge, MA: MIT Press; 2005
23 Durstewitz D. A few important points about dopamine's role in neural network dynamics. Pharmacopsychiatry. 2006; 39 (S 01) S72-S75
24 Durstewitz D, Seamans JK. The computational role of dopamine D1 receptors in working memory. Neural Netw. 2002; 15 (4–6) 561-572 Review
25 Durstewitz D, Seamans JK, Sejnowski TJ. Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex. J Neurophysiol. 2000; 83 1733-1750
26 Fernandez E, Schiappa R, Giraul JA. et al . DARPP-32 is a robust integrator of dopamine and glutamate signals. PLoS Comput Biol. 2006; 2 (12) e176
27 Fishwick PE. ed Handbook of dynamic system modeling.. New York: Chapman & Hall; 2007
28 von Foerster H. Understanding Understanding: Essays on Cybernetics and Cognition.. Berlin: Springer; 2002
29 Freeman WJ. Neurodynamics: An exploration in mesoscopic brain dynamics.. Berlin: Springer; 2000
30 Gallinat J, Obermayer K, Heinz A. Systems Neurobiology of the dysfunctional brain. Pharmacopsychiatry. 2007; 40 (S 01) S40-S44
31 Gao W-J, Goldman-Rakic PS. Selective modulation of excitatory and inhibitory microcircuits by dopamine. PNAS. 2003; 100 (5) 2836-2841
32 Gebicke-Haerter P. Systems Biology in Molecular Psychiatry. Pharmacopsychiatry. 2008; 41 (S 01) S19-S27
33 Giuditta A, Chun JT, Eyman M. et al . Local gene expression in axons and nerve endings:the glia-neuronunit. Physiol Rev. 2008; 89 515-555
34 Goldman-Rakic PS. Cellular basis of working memory. Neuron. 1995; 14 477-485
35 Goldman-Rakic PS. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol Psychiatry. 1999; 456 650-661
36 Goldman-Rakic SP, Muly III EC, Williams GV. D1 receptors in prefrontal cells and circuits. Brain Research Rev. 2000; 31 295-301
37 Grace AA. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neurosci. 1991; 41 1-24
38 Grace AA, Bunney BS. Electrophysiological Properties of Midbrain Dopamine Neurons: Psychopharmacology – 4^th Generation of Progress. 2000;
39 Grant SGN. Systems biology in neuroscience: bridging genes to cognition. Curr Opin Neurobiol. 2003; 13 (5) 577-582
40 Haken H. Brain dynamics.. Berlin: Springer; 2002
41 Hermandez-Lopez S, Bargas J, Surmeier DJ. et al . D1 recpetor activation enhances evoked discharges in neotriatal medium spiny neurons by modulating an L-type Ca2+ conductace. J Neurosci. 1997; 17 3334-3342
42 Hoffman RE, Dobscha SK. Cortical pruning and the development of schizophrenia: a computer model. Schizophr Bull. 1989; 15 (3) 477-490
43 Kauer JA, Malenka RC. Synaptic plasticity and addiction. Nat Rev Neurosci. 2007; 8 844-858
44 Kitano H. Computational Systems Biology. Nature. 2002; 420 (6912) 206-210
45 Kitano H. Systems Biology: a brief overview. Science. 2002; 295 (5560) 1662-1664
46 Klingauf J, Neher E. Modeling buffered Ca2+ diffusion near the membrane: Implications for secretion in neuroendocrine celly. Biophys J. 1997; 72 674-690
47 Klipp E, Herwig R, Kowald A. et al .Systems Biology in Practice.. Weinheim: Wiley-VCH; 2005
48 Klipp E, Liebermeister W, Wierling Ch. et al .Systems Biology.. A Textbook. Weinheim: Wiley-VCH; 2009
49 Koshkina E. Extracellular dopamine concentration control: computational model of feedback control. 2006; URL: http://hdl.handle.net/1860/1160
50 LeNovere N. The long journey to a Systems Biology of neuronal function. BMC Syst Biol. 2007; 1 28
51 LeNovere N. Neurological disease: are systems approaches teh way forward?. Pharmacopsychiatry. 2008; 41 (S 01) S28-S31
52 Lewis DA, Pierri JN, Volk DW. Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia. Biol Psychiatry. 1999; 46 616-626
53 Lewis DL, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005; 6 312-324
54 Lindskog M. Modelling of DARPP32 regulation to understand intracellular signaling in pschiatric disorder. Pharmacopsychiatry. 2008; 41 (S 01) S99-S104
55 Lindskog M, Kim MS, Wikstrom MA. et al . Transient Calcium and Dopamine Increase PKA Activity and DARPP-32 Phosphorylation. PLoS Comput Biol. 2006; 2 (9) e119
56 Lisman JE, Coyle JT, Green RW. et al . Circuit-based framework fro understanding neurotransmitter and rsik gene interactions in schizophrenia. Trends Neurosci. 2008; 31 (5) 234-242
57 Markram H. Blue Brain Project. 2010; http://http:&bluebrain.epfl.ch/page18900.html
58 Markram H, Gupta A, Uziel A. et al . Information processing with frequency-dependent synptic connections. Neurobiol Learn Mem. 1998; 70 101-112
59 Marty A, Llano I. Excitatory effects of GABA in established brain networks. Trends Neurosci. 2005; 28 (6) 284-289
60 Meisenzahl EM, Scheuerecker J, Schmitt GJS. et al . Dopamine, prefrontal cortex and working memory functioning in schizophrenia. Pharmacopsychiatry. 2007; 40 (S 01) S62-S72
61 Meyer-Lindenberg A, Weinberger DR. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci. 2006; 10 818-827
62 Moghaddam B. Bringing order to the glutamate chaos in schizophrenia. Neuron. 2003; 40 881-884
63 Moore H, West AR, Grace AA. The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology. Biol Psychiatry. 1999; 46 40-55
64 Nakano T, Doi T, Yoshimoto J. et al . A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity. PLoS Comput Biol. 2010; 6 (2) e1000670
65 Neve KA, Seamans JK, Trantham-Davidson H. Dopamine Receptor. J Recept Signal Transduct Res. 2004; 24 (3) 165-205
66 Nicola SM, Surmeier J, Malenka RC. Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens. Annu Rev Neurosci. 2000; 23 185-215
67 NIH . Systems Biology. http://www.nigms.nih.gov/Initiatives/SysBio/ 2007;
68 NISB. . Netherlands Institute for Systems Biology. 2009; http://www.neurosciencecampus-amsterdam.nl/en/index.asp
69 Noble D. Multilevel modelling in Systems Biology: From Cells to Whole Organs.. In: Szallasi Z, Periwal V, Stelling J, (Ed) System, modelling in Cellular Biology. Cambridge, MA: MIT Press; 2006: 297-312
70 Noble D. The Music of Life: Biology Beyond the Genome.. New York: Oxford University Press; 2006
71 Palsson BO. Systems Biology.. Cambridge: Cambridge University Press; 2006
72 Pocklington AJ, Armstrong JD, Grant SGN. Organization of brain complexity – synapse proteome form and function. Brief Funct Genomic Proteomic. 2009; 5 (I) 66-73
73 Pocklington AJ, Cumiskey M, Armstrong JD. et al . The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour. Mol Syst Biol. 2006; 2 2006.0023
74 Qi Z, Miller G, Voit E. A mathematical model of presynaptic dopamine homeostasis: implications for schizophrenia. Pharmacopsychiatry. 2008; 41 (S 01) S89-S98
75 Reckow S, Gormanns P, Holsboer F. et al . Psychiatric disorders biomarker identification From proteins to systems biology. Pharmacopsychiatry. 2008; 41 (S 01) S70-S77
76 Scherer J, Eberle E, Tretter F. A basic mathematical model of the dopamine synapse.. In: Trappl R Hrsg. Cybernetics and Systems. Vol I. Vienna: Austrian Society for Cybernetic Studies; 2002: 335-328
77 Schmitz Y, Schmauss C, Sulzer D. Altered dopamine release and uptake kinetics in mice lacking D2 receptors. J Neurosci. 2002; 22 (18) 8002-8009
78 Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Progr Neurobiol. 2004; 74 1-58
79 Seamans JK, Durstewitz D, Christie B. et al . Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons. Proc Natl Acad Sci USA. 2001; 98 301-306
80 Shepherd G. Neurobiology.. New York: Oxford University Press; 1994
81 Shepherd G. The synaptic organization of the brain.. New York: Oxford University Press; 2004
82 Shiflet AB, Shiflet GW. Introduction to computational science.. Modeling and simulation for the sciences. Princeton, NJ: Princeton University Press; 2006
83 Sjöstrom PJ, Rancz EA, Roth A. et al . Dendritic excitability and synaptic plasticity. Physiol Rev. 2008; 88 769-840
84 Szallasi Z, Stelling J, Periwal V. (Ed) System modeling in cellular biology.. Cambridge, MA, MIT Press; 2006
85 Tarazi FI, Baldessarini RJ. Dopamine D4 receptors: significance for molecular psychiatry at the millennium. Mol Psychiatry. 1999; 4 529-538
86 Trantham-Davidson H, Neely LC, Seamans JK. Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J Neurosci. 2004; 24 (47) 10652-10659
87 Tretter F. Systemtheorie im klinischen Kontext.. Lengerich: Pabst Science Publisher; 2005
88 Tretter F, Albus M. Systems biology and psychiatry – modeling molecular and cellular networks of mental disorders. Pharmacopsychiatry. 2008; 41 (Suppl) S2-S18
89 Tretter F, Gebicke-Haerter P. Neuropsychaitry – subject, concepts, methods and computational models.. In: Tretter F, Gebicke-Haerter P, Mendoza E, Winterer G. Sysetms Biology in Psychiatric Research. Weinheim: Wiley-VCH; (in press)
90 Tretter F, Gebicke-Haerter PJ. Philosophy of neuroscience and options of systems science. Pharmacopsychiatry. 2009; 42 (S 01) S2-S10
91 Tretter F, Müller W, Carlsson A. (Eds) Systems Science, Computational Science and Neurobiology of Schizophrenia. Pharmacopsychiatry. 2006; 39 (S 01) S1-S88
92 Tretter F, Müller W. (Eds) Computational Neuropsychiatry: The Functional Architecture of Working Memory Networks in Schizophrenia – Data and Models. Pharmacopsychiatry. 2007; 40 (S 01) S1-S94
93 Tretter F, Gallinat J, Müller WE. (Eds) Systems Biology and Psychiatry: The functional architecture of molecular networks in mental disorerders – data and models. Pharmacopsychiatry. 2008; 41 (Suppl1) S1-S106
94 Tretter F, Gebicke-Haerter P, Heinz A. (Eds) Systems Biology of Addiction. Pharmacopsychiatry. 2009; 42 (S 01) S1-S152
95 Valor LM, Grant SGN. Integrating synapse proteomics with transcritpional regulation. Behav Gent. 2007; 37 18-30
96 Vernalaken I, Gründer G, Cumming P. Progress in psychopharmacotherapy through molecular imaging.. In: Tretter F, Gebicke-härter P, Mendoza E, Winterer G, (ed) Systems Biollogy in Psychiatric Research. Weinheim: Wiley-VCH; (in press)
97 Vogels TP, Abbott LF. Gating deficits in model networks: a path to schizophrenia?. Pharmacopsychiatry. 2007; 40 (S 01) S73-S77
98 Wang M, Vijayraghavan S, Goldman-Rakic PS. Selective D2 Receptor Actions on the Functional Circuitry of Working Memory. Science. 2004; 303 853-856
99 Wang XJ, Tegnér J, Constandinidis C. et al . Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory. PNAS. 2004; 101 (5) 1368-1373
100 Wang XJ. Toward a prefrontal microcircuit model for cognitive deficits in schizophrenia. Pharmacopsychiatry. 2006; 39 (S 01) S80-S87
101 Wassef A, Baker J, Kochan LD. GABA and schizophrenia: a review of basic science and clinical studies. J Clin Psychopharmacol. 2003; 23 (6) 601-640
102 Wegener N, Koch M. Neurobiology and systems physiology of the endocannabinoid system. Pharmacopsychiatry. 2009; 42 (S 01) S79-S86
103 Wightman RM, Heien ML, Wassum KM. et al . Dopamine release is heterogeneous within microenvironments of the rat nucleus accumbens. Eur J Neurosci. 2007; 26 2046-2054
104 Winterer G. Cortical microcircuits in schizophrenia – the dopamine hypothesis revisited. Pharmacopsychiatry. 2006; 39 (S 01) S68-S71
105 Winterer G. Prefrontal dopamine signaling in schizophrenia – the corticocentric model. Pharmacopsychiatry. 2007; 40 (S 01) S45-S53
106 Winterer G, Weinberger DR. Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci. 2004; 27 (11) 683-690
107 Yang ChR. Chen Targeting Prefrontal Cortical Dopamine D1 and N-methyl-D-aspartate receptor interactions in schizophrenia treatment. Neuroscientist. 2005; 11 452-470
108 Zeigler BP, Praehofer H, Kim TG. Theory of modelling and simulation.. London: Elsevier Academic Press; 2000

Correspondence

Prof. Dr. Dr. Dr. F. Tretter

Department of Addiction

Isar-Amper-Clinics

85540 Haar

Germany

Telefon: 089/4562-3708

Fax: 089/4562-3754

eMail: felix.tretter@iak-kmo.de