Abstract
The etiopathogenesis of many psychiatric illnesses remains unclear and a variety of
these diseases can coexist, partly mimicking each other while contributing to and
distorting symptomatic expressions. To understand the processes involved, it is necessary
to unravel signalling pathways, complex interaction networks and metabolic alterations
involving a plethora of anatomical components. When addressing such largely obscure
mechanisms, primary data mainly based on genomics and differential gene expression
patterns turns out to be of limited usefulness. Numerous direct as well as very indirect
processes modulate and dissociate gene expression from protein functions and physiological
effects. Proteomics approaches that utilise metabolic labelling and high-throughput
mass spectrometry to provide proteome dynamics data need to be utilised. However,
the data thus gathered encompasses a complex assembly of numerous types of intermixed
cells, representing biological processes that occur in both time and space across
several scalar levels. The complexities represented are such that to analytically
approach these diseases, a systems standpoint becomes necessary. This implies multiple
experimental interrogations in an iterative interplay between experimentation and
modelling. While this may be reasonably considered in the context of in vitro systems,
it can hardly be contemplated when addressing CNS tissues from heterogeneous human
origins, thereby imposing serious constraints upon the investigation of human cognitive
disorders. In this article, the authors expose a paradigm that addresses and alleviates
at least some of these major difficulties. Based on the reasoned utilisation of trait
animal models and human material, this approach has already started to deliver novel
and directly exploitable knowledge.
References
- 1
Arguello PA, Markx S, Gogos JA. et al .
Development of animal models for schizophrenia.
Dis Model Mech.
2010;
3
22-26
- 2
Beasley CL, Pennington K, Behan A. et al .
Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders:
Evidence for disease-associated changes.
Proteomics.
2006;
6
3414-3425
- 3
Ben Achour S, Pascual O.
Glia: The many ways to modulate synaptic plasticity.
Neurochem Int.
2010;
- 4
Bergemann ER, Boles RG.
Maternal inheritance in recurrent early-onset depression.
Psychiatr Genet.
2010;
20
31-34
- 5
Berretta S, Benes FM.
A rat model for neural circuitry abnormalities in schizophrenia.
Nat Protoc.
2006;
1
833-839
- 6
Bienvenu OJ, Davydow DS, Kendler KS.
Psychiatric ‘diseases’ versus behavioral disorders and degree of genetic influence.
Psychol Med.
2010;
1-8
- 7
Bosler O, Girardet C, Sage-Ciocca D. et al .
[Mechanisms of structural plasticity associated with photic synchronization of the
circadian clock within the suprachiasmatic nucleus].
J Soc Biol.
2009;
203
49-63
- 8
Bruggeman FJ.
Systems biology: from possible to plausible to actual models.
FEBS J.
2009;
276
885
- 9
Cedersund G, Roll J.
Systems biology: model based evaluation and comparison of potential explanations for
given biological data.
FEBS J.
2009;
276
903-922
- 10
Choudhuri S.
Small noncoding RNAs: biogenesis, function, and emerging significance in toxicology.
J Biochem Mol Toxicol.
2010;
24
195-216
- 11
Chvatal A, Anderova M, Kirchhoff F.
Three-dimensional confocal morphometry – a new approach for studying dynamic changes
in cell morphology in brain slices.
J Anat.
2007;
210
671-683
- 12
De Keyser J, Mostert JP, Koch MW.
Dysfunctional astrocytes as key players in the pathogenesis of central nervous system
disorders.
J Neurol Sci.
2008;
267
3-16
- 13
DeFelipe J, Alonso-Nanclares L, Arellano JI.
Microstructure of the neocortex: comparative aspects.
J Neurocytol.
2002;
31
299-316
- 14
Defelipe J, Fields RD, Hof PR. et al .
Cortical white matter: beyond the pale remarks, main conclusions and discussion.
Front Neuroanat.
2010;
4
4
- 15
Eastwood SL, Harrison PJ.
Interstitial white matter neuron density in the dorsolateral prefrontal cortex and
parahippocampal gyrus in schizophrenia.
Schizophr Res.
2005;
79
181-188
- 16
England PM.
Bridging the gaps between synapses, circuits, and behavior.
Chem Biol.
2010;
17
607-615
- 17
Enomoto T, Noda Y, Nabeshima T.
Phencyclidine and genetic animal models of schizophrenia developed in relation to
the glutamate hypothesis.
Methods Find Exp Clin Pharmacol.
2007;
29
291-301
- 18
Fellin T.
Communication between neurons and astrocytes: relevance to the modulation of synaptic
and network activity.
J Neurochem.
2009;
108
533-544
- 19
Filiou MD, Bisle B, Reckow S. et al .
Profiling of mouse synaptosome proteome and phosphoproteome by IEF.
Electrophoresis.
2010;
31
1294-1301
- 20
Fineberg NA, Saxena S, Zohar J. et al .
Obsessive-compulsive disorder: boundary issues.
CNS Spectr.
2007;
12
359-364,
367–375
- 21
Gadal F, Bozic C, Pillot-Brochet C. et al .
Integrated transcriptome analysis of the cellular mechanisms associated with Ha-ras-dependent
malignant transformation of the human breast epithelial MCF7 cell line.
Nucleic Acids Res.
2003;
31
5789-5804
- 22
Gadal F, Starzec A, Bozic C. et al .
Integrative analysis of gene expression patterns predicts specific modulations of
defined cell functions by estrogen and tamoxifen in MCF7 breast cancer cells.
J Mol Endocrinol.
2005;
34
61-75
- 23
Geier F, Timmer J, Fleck C.
Reconstructing gene-regulatory networks from time series, knock-out data, and prior
knowledge.
BMC Syst Biol.
2007;
1
11
- 24
Girardet C, Blanchard MP, Ferracci G. et al .
Daily changes in synaptic innervation of VIP neurons in the rat suprachiasmatic nucleus:
contribution of glutamatergic afferents.
Eur J Neurosci.
2010;
31
359-370
- 25
Glessner JT, Hakonarson H.
Common variants in polygenic schizophrenia.
Genome Biol.
2009;
10
236
- 26
Gourion D, Gourevitch R, Leprovost JB. et al .
[Neurodevelopmental hypothesis in schizophrenia].
Encephale.
2004;
30
109-118
- 27
Gross G, Huber G.
Schizophrenia: neurodevelopmental disorder or degenerative brain process?.
Fortschr Neurol Psychiatr.
2008;
76
(S 01)
S57-S62
- 28
Halassa MM, Fellin T, Haydon PG.
The tripartite synapse: roles for gliotransmission in health and disease.
Trends Mol Med.
2007;
13
54-63
- 29
Halassa MM, Fellin T, Haydon PG.
Tripartite synapses: roles for astrocytic purines in the control of synaptic physiology
and behavior.
Neuropharmacology.
2009;
57
343-346
- 30
Halassa MM, Fellin T, Takano H. et al .
Synaptic islands defined by the territory of a single astrocyte.
J Neurosci.
2007;
27
6473-6477
- 31
Hambsch B, Chen BG, Brenndorfer J. et al .
Methylglyoxal-mediated anxiolysis involves increased protein modification and elevated
expression of glyoxalase 1 in the brain.
J Neurochem.
2010;
113
1240-1251
- 32
Haseloff RF, Blasig IE, Bauer HC. et al .
In search of the astrocytic factor(s) modulating blood-brain barrier functions in
brain capillary endothelial cells in vitro.
Cell Mol Neurobiol.
2005;
25
25-39
- 33
Hauber W.
Dopamine release in the prefrontal cortex and striatum: temporal and behavioural aspects.
Pharmacopsychiatry.
2010;
43
(S 01)
S32-S41
- 34
Iris F, Gea M, Lampe PH. et al .
[Production and implementation of predictive biological models].
Med Sci (Paris).
2009;
25
608-616
- 35
Karl T, Chesworth R, Duffy L. et al .
Acoustic startle response and sensorimotor gating in a genetic mouse model for the
Y1 receptor.
Neuropeptides.
2010;
44
233-239
- 36
Koenig JI, Elmer GI, Shepard PD. et al .
Prenatal exposure to a repeated variable stress paradigm elicits behavioral and neuroendocrinological
changes in the adult offspring: potential relevance to schizophrenia.
Behav Brain Res.
2005;
156
251-261
- 37
Kohl P, Crampin EJ, Quinn TA. et al .
Systems biology: an approach.
Clin Pharmacol Ther.
2010;
88
25-33
- 38
Korolainen MA, Nyman TA, Aittokallio T. et al .
An update on clinical proteomics in Alzheimer's research.
J Neurochem.
2010;
112
1386-1414
- 39
Koval M.
Pathways and control of connexin oligomerization.
Trends Cell Biol.
2006;
16
159-166
- 40
Lee PR, Brady DL, Shapiro RA. et al .
Prenatal stress generates deficits in rat social behavior: Reversal by oxytocin.
Brain Res.
2007;
1156
152-167
- 41
Lee Y, Gaskins D, Anand A. et al .
Glia mechanisms in mood regulation: a novel model of mood disorders.
Psychopharmacology (Berl).
2007;
191
55-65
- 42
Lehotzky A, Lau P, Tokesi N. et al .
Tubulin polymerization-promoting protein (TPPP/p25) is critical for oligodendrocyte
differentiation.
Glia.
2010;
58
157-168
- 43
Liebal UW, Millat T, de Jong IG. et al .
How mathematical modelling elucidates signalling in B. subtilis.
Mol Microbiol.
2010;
- 44
Liljenstrom H.
Network effects of synaptic modifications.
Pharmacopsychiatry.
2010;
43
(S 01)
S67-S81
- 45
Lipska BK.
Using animal models to test a neurodevelopmental hypothesis of schizophrenia.
J Psychiatry Neurosci.
2004;
29
282-286
- 46
Maccarrone G, Turck CW, Martins-de-Souza D.
Shotgun mass spectrometry workflow combining IEF and LC-MALDI-TOF/TOF.
Protein J.
2010;
29
99-102
- 47
Martins-De-Souza D, Dias-Neto E, Schmitt A. et al .
Proteome analysis of schizophrenia brain tissue.
World J Biol Psychiatry.
2010;
11
110-120
- 48
Martins-de-Souza D, Harris LW, Guest PC. et al .
The role of proteomics in depression research.
Eur Arch Psychiatry Clin Neurosci.
2009;
- 49
Martins-de-Souza D, Maccarrone G, Wobrock T. et al .
Proteome analysis of the thalamus and cerebrospinal fluid reveals glycolysis dysfunction
and potential biomarkers candidates for schizophrenia.
J Psychiatr Res.
2010;
- 50
McNally L, Bhagwagar Z, Hannestad J.
Inflammation, glutamate, and glia in depression: a literature review.
CNS Spectr.
2008;
13
501-510
- 51
Menolascina F, Bellomo D, Maiwald T. et al .
Developing optimal input design strategies in cancer systems biology with applications
to microfluidic device engineering.
BMC Bioinformatics.
2009;
10
(S 12)
S4
- 52
Meyer U, Feldon J.
Epidemiology-driven neurodevelopmental animal models of schizophrenia.
Prog Neurobiol.
2010;
90
285-326
- 53
Meyer U, Feldon J, Fatemi SH.
In-vivo rodent models for the experimental investigation of prenatal immune activation
effects in neurodevelopmental brain disorders.
Neurosci Biobehav Rev.
2009;
33
1061-1079
- 54
Mitterauer BJ.
The syncytiopathy hypothesis of depression: downregulation of glial connexins may
protract synaptic information processing and cause memory impairment.
Med Hypotheses.
2010;
74
497-502
- 55
Moore MN, Noble D.
Editorial: computational modelling of cell & tissue processes & function.
J Mol Histol.
2004;
35
655-658
- 56
Na ES, Monteggia LM.
The role of MeCP2 in CNS development and function.
Horm Behav.
2010;
- 57
Ng MY, Levinson DF, Faraone SV. et al .
Meta-analysis of 32 genome-wide linkage studies of schizophrenia.
Mol Psychiatry.
2009;
14
774-785
- 58
Niculescu AB.
Genomic studies of mood disorders – the brain as a muscle?.
Genome Biol.
2005;
6
215
- 59
Noda Y, Mouri A, Waki Y. et al .
[Development of animal models for schizophrenia based on clinical evidence: expectation
for psychiatrists].
Nihon Shinkei Seishin Yakurigaku Zasshi.
2009;
29
47-53
- 60
Oberheim NA, Takano T, Han X. et al .
Uniquely hominid features of adult human astrocytes.
J Neurosci.
2009;
29
3276-3287
- 61
Peters BD, Blaas J, de Haan L.
Diffusion tensor imaging in the early phase of schizophrenia: What have we learned?.
J Psychiatr Res.
2010;
- 62
Pietraszek M, Michaluk J, Romanska I. et al .
1-Methyl-1,2,3,4-tetrahydroisoquinoline antagonizes a rise in brain dopamine metabolism,
glutamate release in frontal cortex and locomotor hyperactivity produced by MK-801
but not the disruptions of prepulse inhibition, and impairment of working memory in
rat.
Neurotox Res.
2009;
16
390-407
- 63
Pouillot F, Blois H, Iris F.
Genetically engineered virulent phage banks in the detection and control of emergent
pathogenic bacteria.
Biosecur Bioterror.
2010;
8
155-169
- 64
Purcell SM, Wray NR, Stone JL. et al .
Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.
Nature.
2009;
460
748-752
- 65
Radyushkin K, El-Kordi A, Boretius S. et al .
Complexin2 null mutation requires a ‘second hit’ for induction of phenotypic changes
relevant to schizophrenia.
Genes Brain Behav.
2010;
- 66
Riley AW, Valdez CR, Barrueco S. et al .
Development of a family-based program to reduce risk and promote resilience among
families affected by maternal depression: theoretical basis and program description.
Clin Child Fam Psychol Rev.
2008;
11
12-29
- 67
Schipke CG, Heuser I, Peters O.
Antidepressants act on glial cells: SSRIs and serotonin elicit astrocyte calcium signaling
in the mouse prefrontal cortex.
J Psychiatr Res.
2010;
- 68
Schroeter ML, Abdul-Khaliq H, Sacher J. et al .
Mood disorders are glial disorders: evidence from in vivo studies.
Cardiovasc Psychiatry Neurol.
2010;
2010
780645
- 69
Schulze TG.
Genetic research into bipolar disorder: the need for a research framework that integrates
sophisticated molecular biology and clinically informed phenotype characterization.
Psychiatr Clin North Am.
2010;
33
67-82
- 70
Silver RA.
Neuronal arithmetic.
Nat Rev Neurosci.
2010;
11
474-489
- 71
Suarez-Sola ML, Gonzalez-Delgado FJ, Pueyo-Morlans M. et al .
Neurons in the white matter of the adult human neocortex.
Front Neuroanat.
2009;
3
7
- 72
Sun J, Jia P, Fanous AH. et al .
Schizophrenia gene networks and pathways and their applications for novel candidate
gene selection.
PLoS One.
2010;
5
e11351
- 73
Sweet RA, Fish KN, Lewis DA.
Mapping Synaptic Pathology within Cerebral Cortical Circuits in Subjects with Schizophrenia.
Front Hum Neurosci.
2010;
4
44
- 74
Taft RJ, Pang KC, Mercer TR. et al .
Non-coding RNAs: regulators of disease.
J Pathol.
2010;
220
126-139
- 75
Verkhratsky A.
Physiology of neuronal-glial networking.
Neurochem Int.
2010;
- 76
Walter M, Henning A, Grimm S. et al .
The relationship between aberrant neuronal activation in the pregenual anterior cingulate,
altered glutamatergic metabolism, and anhedonia in major depression.
Arch Gen Psychiatry.
2009;
66
478-486
- 77
Wang L, Simpson HB, Dulawa SC.
Assessing the validity of current mouse genetic models of obsessive-compulsive disorder.
Behav Pharmacol.
2009;
20
119-133
- 78
Wang PI, Marcotte EM.
It's the machine that matters: Predicting gene function and phenotype from protein
networks.
J Proteomics.
2010;
- 79
White T, Nelson M, Lim KO.
Diffusion tensor imaging in psychiatric disorders.
Top Magn Reson Imaging.
2008;
19
97-109
- 80
Williams LE, Light GA, Braff DL. et al .
Reduced multisensory integration in patients with schizophrenia on a target detection
task.
Neuropsychologia.
2010;
- 81
Wilson C, Terry Jr AV.
Neurodevelopmental animal models of schizophrenia: role in novel drug discovery and
development.
Clin Schizophr Relat Psychoses.
2010;
4
124-137
- 82
Wray NR, Visscher PM.
Narrowing the boundaries of the genetic architecture of schizophrenia.
Schizophr Bull.
2010;
36
14-23
- 83
Young JI, Hong EP, Castle JC. et al .
Regulation of RNA splicing by the methylation-dependent transcriptional repressor
methyl-CpG binding protein 2.
Proc Natl Acad Sci USA.
2005;
102
17551-17558
Correspondence
Dr. C. W. Turck
Proteomics and Biomarkers
Max Planck Institute of
Psychiatry
Kraepelinstraße 2-10
80804 Munich
Germany
Telefon: +49/89/306 223 17
Fax: +49/89/306 226 10
eMail: turck@mpipsykl.mpg.de