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The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia.

Moises HW, Zoega T, Gottesman II - BMC Psychiatry (2002)

Bottom Line: 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).Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Genetics Laboratory, Department of Psychiatry, Kiel University Hospital, Niemannsweg 147, 24105 Kiel, Germany. moises@psychiatry.uni-kiel.de

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.

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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 endophenotypes 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 . 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.
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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 endophenotypes 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 . 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.

Mentions: A search for convergent loci revealed 41 genes (see Fig. 1) with related functions localized within significant or potential linkage regions of schizophrenia (chromosomal localization in parenthesis): neuregulin-1 (NRG1) (8), neuregulin-2 (NRG2) (5), neuregulin-3 (NRG3) (10), epidermal growth factor (EGF) (4), and neuregulin receptor ErbB3 (12), transforming-growth factor alpha (TGFA) (2), transforming-growth factor beta receptor II (TGFBR2) (3), LIMK1 (7), Grb2-related adaptor protein 2 (22), phosphoinositide-3 kinase class 2 beta polypeptide (PIK3C2B) (1), GABA receptor beta 2 (GABRB2) (5), acetylcholine receptor alpha 7 (CHRA7) (15) and epsilon (CHRNE) (17), growth factors such as glial cell line derived neurotrophic factor (GDNF) (5), GDNF receptor alpha 1 (GFRA1) (10), GFRA2 (8), GFRA4 (20), GDNF family related persephin (19), glutamate and its receptors (GRM1, metabotropic glutamate receptor 1) (6), GRM4 (6) GRM5 (11) and GRM6 (5), insulin-like growth factor I (IGF1) (12), insulin receptor (INSR) (19), insulin receptor substrate 1 (IRS1) (2), GAS6 (13) and GAS5 (1), neuritin (6), syntrophin B2 (16), protein kinase C interacting protein (PICK1) (22), NMDA receptor 2B (12) and 2 C (17), p35 (CDK5R1) (17). Furthermore, epiregulin (4) is a potent pan-ErbB ligand [60]. Ephrins such as ephrin-B2 (13) and ephrin-A5 (5) are involved in neurodevelopment, and in the adult CNS in LTP, synaptic strength [61], and cell proliferation of the adult subventricular zone [62]. Fibroblast growth factors such as FGF2 (4) and indirectly the FGF binding protein 1 (FGFBP1) (4) have a similar effect on development, adult neurogenesis, cell survival and synaptic transmission [63,64]. Cytokines are neurotoxic or neurotrophic [65]. For example, interleukin-8 (IL8) (4) exerts neurotrophic effects on glial cells [65] and the latter constitutively release tumor necrosis factor alpha (TNF) (6), another cytokine, which markedly influences synaptic strength [66] and leads to impaired insulin signaling via ErbB2 and ErbB3 [67]. Moreover, interleukin-1 receptor accessory protein-like 1 (X), a member of the IL1 receptor family, is highly expressed in the adult hippocampus suggesting a role in learning, memory, and synaptic strength [68]. Neurogranin (11) is concentrated in the post-synaptic terminals of the hippocampus and involved in learning, LTP, and synaptic plasticity [69].


The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia.

Moises HW, Zoega T, Gottesman II - BMC Psychiatry (2002)

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 endophenotypes 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 . 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.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC117774&req=5

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 endophenotypes 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 . 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.
Mentions: A search for convergent loci revealed 41 genes (see Fig. 1) with related functions localized within significant or potential linkage regions of schizophrenia (chromosomal localization in parenthesis): neuregulin-1 (NRG1) (8), neuregulin-2 (NRG2) (5), neuregulin-3 (NRG3) (10), epidermal growth factor (EGF) (4), and neuregulin receptor ErbB3 (12), transforming-growth factor alpha (TGFA) (2), transforming-growth factor beta receptor II (TGFBR2) (3), LIMK1 (7), Grb2-related adaptor protein 2 (22), phosphoinositide-3 kinase class 2 beta polypeptide (PIK3C2B) (1), GABA receptor beta 2 (GABRB2) (5), acetylcholine receptor alpha 7 (CHRA7) (15) and epsilon (CHRNE) (17), growth factors such as glial cell line derived neurotrophic factor (GDNF) (5), GDNF receptor alpha 1 (GFRA1) (10), GFRA2 (8), GFRA4 (20), GDNF family related persephin (19), glutamate and its receptors (GRM1, metabotropic glutamate receptor 1) (6), GRM4 (6) GRM5 (11) and GRM6 (5), insulin-like growth factor I (IGF1) (12), insulin receptor (INSR) (19), insulin receptor substrate 1 (IRS1) (2), GAS6 (13) and GAS5 (1), neuritin (6), syntrophin B2 (16), protein kinase C interacting protein (PICK1) (22), NMDA receptor 2B (12) and 2 C (17), p35 (CDK5R1) (17). Furthermore, epiregulin (4) is a potent pan-ErbB ligand [60]. Ephrins such as ephrin-B2 (13) and ephrin-A5 (5) are involved in neurodevelopment, and in the adult CNS in LTP, synaptic strength [61], and cell proliferation of the adult subventricular zone [62]. Fibroblast growth factors such as FGF2 (4) and indirectly the FGF binding protein 1 (FGFBP1) (4) have a similar effect on development, adult neurogenesis, cell survival and synaptic transmission [63,64]. Cytokines are neurotoxic or neurotrophic [65]. For example, interleukin-8 (IL8) (4) exerts neurotrophic effects on glial cells [65] and the latter constitutively release tumor necrosis factor alpha (TNF) (6), another cytokine, which markedly influences synaptic strength [66] and leads to impaired insulin signaling via ErbB2 and ErbB3 [67]. Moreover, interleukin-1 receptor accessory protein-like 1 (X), a member of the IL1 receptor family, is highly expressed in the adult hippocampus suggesting a role in learning, memory, and synaptic strength [68]. Neurogranin (11) is concentrated in the post-synaptic terminals of the hippocampus and involved in learning, LTP, and synaptic plasticity [69].

Bottom Line: 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).Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Genetics Laboratory, Department of Psychiatry, Kiel University Hospital, Niemannsweg 147, 24105 Kiel, Germany. moises@psychiatry.uni-kiel.de

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.

Show MeSH
Related in: MedlinePlus