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CORE Metadata, citation and similar papers at core.ac.uk Provided by Springer - Publisher Connector BMC Psychiatry BioMed Central Hypothesis2 BMC2002, Psychiatry x The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia Hans W Moises*1, Tomas Zoega2 and Irving I Gottesman3 Address: 1Molecular Genetics Laboratory, Department of Psychiatry, Kiel University Hospital, Niemannsweg 147, 24105 Kiel, Germany, 2Department of Psychiatry, National University of Iceland, Reykjavik, Iceland and 3Departments of Psychiatry and Psychology, University of Minnesota, Minneapolis, USA E-mail: Hans W Moises* - [email protected]; Tomas Zoega - [email protected]; Irving I Gottesman - [email protected] *Corresponding author Published: 3 July 2002 Received: 9 May 2002 Accepted: 3 July 2002 BMC Psychiatry 2002, 2:8 This article is available from: http://www.biomedcentral.com/1471-244X/2/8 © 2002 Moises et al; licensee BioMed Central Ltd. Verbatim copying and redistribution of this article are permitted in any medium for any purpose, provided this notice is preserved along with the article's original URL. Abstract Background: A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. Presentation of the hypothesis: Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia. Testing the hypothesis: Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations. Implications of the hypothesis: The hypothesis suggests glial cells as the locus of the genes- environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments. Background stantial evidence from clinical, epidemiological, The current understanding of the origin of schizophrenia neuropathological, and imaging studies [5,6]. Growth de- is mainly based on the multifactorial-threshold (MFT) viations found in many cases of schizophrenia support model of genetic liability and the neurodevelopmental the neurodevelopmental hypothesis, e.g., low birth model [1]. The former is supported by family, twin, adop- weight, late maturation, leptosomatic body build, large tion and modeling studies [2–4], and the latter by circum- ventricles and low brain volume [5–8]). Neuronal growth Page 1 of 14 (page number not for citation purposes) BMC Psychiatry 2002, 2 http://www.biomedcentral.com/1471-244X/2/8 1 2 3 4 5 6 Neuritin 7 8 9 10 11 12 2.2 - 9.0 GFRA2 0.1 - 7.0 NMDA TGFB FGF GDNF TNF Receptor R2 BP1 3.3 - 5.7 - 2B 1.7 - 4.5 - 6.9 7.2 NRG1 14.9 TGFA 5.5 11.7 2.8 - ErbB3 1.9 - GRM4 13.8 10.2 15.1 2.2 - 7.9 Epiregulin NRG3 2.4 - 6.0 4.1 - GRM5 IL8 Ephrin-A5 LIMK1 19.1 2.7 - 3.3 - 5.0 0.3 - 11.0 3.5 - 5.2 8.8 EGF NRG2 GAS5 0.1 - 0.4 - 12.5 1.7 - 8.7 IRS1 18.9 GRM1 IGF1 GRM6 GFRA1 Neuro- PIK3 1.6 - 6.3 - 1.8 FGF2 8.6 3.3 - 8.7 granin C2B 5.6 9.8 0.2 - 9.5 GABRB2 2.1 – 5.0 4.2 0.1 - 1.5 13 14 15 16 17 18 19 20 21 22 X Persephin 4.8 CHRA7 CHRNE INSR GFRA4 0.3 - 16.1 1.7 - 0.9 - 12.5 - 9.0 4.7 15.6 Inter- leukin-1 Receptor PICK1 Accessory p35 = 2.4 - 15.6 Protein-Like 1 CDK5R1 Grb2 0.2 - 3.7 1.0 2.0 - 13.8 Ephrin-B2 Syn- NMDA 1.0 - trophin 15.5 Receptor B2 GAS6 2C 3.4 - 13.1 3.1 - 6.9 1.4 - 5.0 Figure 1 Pooled linkage results in schizophrenia and localization of genes related to glial growth factors and synaptic strength. Data compiled from 60 published (not abstracts) linkage studies in schizophrenia (including two studies using endo- phenotypes of the disorder) [73,74,146–203]. Each dot represents evidence for linkage obtained in an independent sample. The level of significance is shown according to the criteria of Lander and Kruglyak [204]. Red indicates significant (lod score = 3.6), yellow suggestive (lod score = 2.2) evidence and white hints (p ≤ 0.05) for linkage. Only the marker showing the best evidence for linkage in the region were used from each study. Markers within a distance of 20 Megabases (Mb) are displayed at the same chromosomal position. The distance between linkage marker and gene in Mb is given below the gene. Chromosomal positions were obtained from the Unified Database for Human Genome Mapping (UDB) [205] and the UCSC Human Genome Project Working Draft [http://genome.ucsc.edu]. A susceptibility gene within a distance of 20 Mb from a genetic marker can be detected by linkage analysis. The marker-gene distances range from 0.1 to 19.1 (median 1.7) Mb. and development [9,10] is controlled by growth factors convergent functional genomics approach [16,18,19] synthesized by glial cells [11]. Glial cell loss [12], de- search for agreement between the chromosomal position creased expression levels of glia- related genes [13], and of susceptibility genes for the disease and the function of increased levels of S100B [14,15], a marker of glia cell in- the genes discovered at that position. In convergent ap- tegrity, has been observed in schizophrenia suggesting a proaches, the function of the genes is usually defined as role for glial growth factors in the pathogenesis of the dis- evidence for their involvement in the disorder, derived order. from non-linkage studies such as gene expression analyses [16,18,19] or from evidence-based hypotheses such as the Genome scans in schizophrenia have converged on sever- neurodevelopmental hypothesis of schizophrenia. Be- al chromosomal locations [16]. A convergent loci ap- cause of the essential role of the GGF neuregulin for neu- proach has been proposed in the Proceedings of the rodevelopment [20,21], we applied the CL approach to National Academy of Science USA as a technique for dis- schizophrenia linkage data and GGFs-related genes. In covering the molecular basis for a disease [17]. Conver- our view, convergent techniques do not prove the exist- gent techniques such as the convergent loci (CL) or the ence of a causal relationship. However, they are useful Page 2 of 14 (page number not for citation purposes) BMC Psychiatry 2002, 2 http://www.biomedcentral.com/1471-244X/2/8 tools for the generation and preliminary testing of causal Biochemically, NRGs are structurally related to what is hypotheses. perhaps the best studied trophic factor – epidermal growth factor (EGF) [11] and encode a large group of The GGFs deficiency hypothesis is part of the broader polypeptide growth, survival and differentiation factors working hypothesis of a decrease in the cerebral protein- [20,21] that all contain an extracellular epidermal growth synthesis rate (CPRS) developed by one of us (HWM) as factor (EGF)-like domain, which is essential for their bio- result of his attempt to find a common denominator for activity [35]. They are derived by alternative splicing from the diverse results of schizophrenia research [7]. The evo- four genes: NRG1, NRG2 also known as Don-1 and lutionary approach employed in the latter investigation NTAK, NRG3, and NRG4. NRG1-3 is expressed during suggested that neuregulin 1 (NRG1) might be one of the neurodevelopment and in the adult CNS [21], whereas susceptibility genes for schizophrenia (Figure 1 in [7]) NRG4 transcripts have not been detected in neural tissue motivating further theoretical and experimental investiga- [21]. The cytoplasmic tail of NRG interacts with the pro- tions. The hypothesis presented here provides a heuristic tein kinase LIM kinase 1 (LIMK1) [36]. explanation for the neurodevelopmental and genetic find- ings in schizophrenia. NRGs act through a network of ErbB tyrosine kinase re- ceptors consisting of ErbB1 (also termed EGF receptor or The function of glia and its growth factors HER1), ErbB2 (Neu/HER2), ErbB3 (HER3) and ErbB4 Glial cells play important roles in the developing [11] as (HER4) [11,20,21,37]. NRGs bind to ErbB2-4, EGF and well as in the adult central nervous system (CNS). In the transforming-growth factor alpha (TGFA) to ErbB1 adult CNS, glia has a supportive, a protective, a regenera- [21,37]. ErbB receptors serve as docking sites for cytoplas- tive, and an active regulatory role. Glia cells are sensors of mic signaling molecules such as Grb2-related adaptor pro- infection and produce cytokines to limit viral replication. tein 2 and phosphatidylinositol-3 kinase (PI3K) [21,37]. In adults, they induce neurogenesis in the hippocampus In addition, the ErbB receptor system integrates signaling and the subventricular zone [22], influence neuronal ac- events from other receptor classes, such as G-protein-cou- tivity and synaptic strength [23], and appear to be the pled receptors and cytokine receptors [37].