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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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The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. The hypothesis is depicted in form of the multifactorial-threshold model for schizophrenia developed by Gottesman and Shields [206] and postulates that several genes (e.g., NRG1, TNF, GAS6, INF1 etc.) and environmental factors influence the positive feedback loop between the presynaptic neuron and its target cells. The hypothesis assumes that the baseline strength of synaptic connections is normally distributed in the general population, such that those whose synaptic strength falls below a certain threshold develop synaptic destabilization and schizophrenic symptoms. The strength of the growth signaling correlates with the efficacy and stability of the synaptic connection. Environmental and genetic factors increase or decrease growth signaling and in consequence synaptic strength. Viruses may cause synaptic destabilization by triggering the release of neurotoxic cytokines from glial cells or by decreasing the synthesis of GGFs via a reduction of the protein-synthesis rate in viral infected glial cells.
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Figure 2: The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. The hypothesis is depicted in form of the multifactorial-threshold model for schizophrenia developed by Gottesman and Shields [206] and postulates that several genes (e.g., NRG1, TNF, GAS6, INF1 etc.) and environmental factors influence the positive feedback loop between the presynaptic neuron and its target cells. The hypothesis assumes that the baseline strength of synaptic connections is normally distributed in the general population, such that those whose synaptic strength falls below a certain threshold develop synaptic destabilization and schizophrenic symptoms. The strength of the growth signaling correlates with the efficacy and stability of the synaptic connection. Environmental and genetic factors increase or decrease growth signaling and in consequence synaptic strength. Viruses may cause synaptic destabilization by triggering the release of neurotoxic cytokines from glial cells or by decreasing the synthesis of GGFs via a reduction of the protein-synthesis rate in viral infected glial cells.

Mentions: The growth factors deficiency and synaptic destabilization hypothesis of schizophrenia (GGF/SD) states that a functional deficiency of glial growth factors and of growth factors produced by glial cells such as neurotrophins and glutamate (termed here GGFs) leading to a weakening of the synaptic strength may be implicated as one of the important causes of schizophrenia (see Fig. 2).


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

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

The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. The hypothesis is depicted in form of the multifactorial-threshold model for schizophrenia developed by Gottesman and Shields [206] and postulates that several genes (e.g., NRG1, TNF, GAS6, INF1 etc.) and environmental factors influence the positive feedback loop between the presynaptic neuron and its target cells. The hypothesis assumes that the baseline strength of synaptic connections is normally distributed in the general population, such that those whose synaptic strength falls below a certain threshold develop synaptic destabilization and schizophrenic symptoms. The strength of the growth signaling correlates with the efficacy and stability of the synaptic connection. Environmental and genetic factors increase or decrease growth signaling and in consequence synaptic strength. Viruses may cause synaptic destabilization by triggering the release of neurotoxic cytokines from glial cells or by decreasing the synthesis of GGFs via a reduction of the protein-synthesis rate in viral infected glial cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC117774&req=5

Figure 2: The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. The hypothesis is depicted in form of the multifactorial-threshold model for schizophrenia developed by Gottesman and Shields [206] and postulates that several genes (e.g., NRG1, TNF, GAS6, INF1 etc.) and environmental factors influence the positive feedback loop between the presynaptic neuron and its target cells. The hypothesis assumes that the baseline strength of synaptic connections is normally distributed in the general population, such that those whose synaptic strength falls below a certain threshold develop synaptic destabilization and schizophrenic symptoms. The strength of the growth signaling correlates with the efficacy and stability of the synaptic connection. Environmental and genetic factors increase or decrease growth signaling and in consequence synaptic strength. Viruses may cause synaptic destabilization by triggering the release of neurotoxic cytokines from glial cells or by decreasing the synthesis of GGFs via a reduction of the protein-synthesis rate in viral infected glial cells.
Mentions: The growth factors deficiency and synaptic destabilization hypothesis of schizophrenia (GGF/SD) states that a functional deficiency of glial growth factors and of growth factors produced by glial cells such as neurotrophins and glutamate (termed here GGFs) leading to a weakening of the synaptic strength may be implicated as one of the important causes of schizophrenia (see Fig. 2).

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