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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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Brain growth and the age at onset of schizophrenia. The end of head and brain growth, presumably associated with a decline in growth factors, marks the beginning of the age of onset in schizophrenia. Data from [2,207]. The growth curve is supported by results from developmental studies of brain metabolism and of brain volume [10,208]. In addition, several studies have reported smaller head size at birth in individuals who later developed schizophrenia compared to controls (for review [8]).
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Figure 3: Brain growth and the age at onset of schizophrenia. The end of head and brain growth, presumably associated with a decline in growth factors, marks the beginning of the age of onset in schizophrenia. Data from [2,207]. The growth curve is supported by results from developmental studies of brain metabolism and of brain volume [10,208]. In addition, several studies have reported smaller head size at birth in individuals who later developed schizophrenia compared to controls (for review [8]).

Mentions: (8) Age of onset: Brain growth might be used as an indirect indicator of the activity of GGFs. Fig. 3 shows that a decrease in head and brain growth is accompanied by a sharp increase in the risk for developing schizophrenia.


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

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

Brain growth and the age at onset of schizophrenia. The end of head and brain growth, presumably associated with a decline in growth factors, marks the beginning of the age of onset in schizophrenia. Data from [2,207]. The growth curve is supported by results from developmental studies of brain metabolism and of brain volume [10,208]. In addition, several studies have reported smaller head size at birth in individuals who later developed schizophrenia compared to controls (for review [8]).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Brain growth and the age at onset of schizophrenia. The end of head and brain growth, presumably associated with a decline in growth factors, marks the beginning of the age of onset in schizophrenia. Data from [2,207]. The growth curve is supported by results from developmental studies of brain metabolism and of brain volume [10,208]. In addition, several studies have reported smaller head size at birth in individuals who later developed schizophrenia compared to controls (for review [8]).
Mentions: (8) Age of onset: Brain growth might be used as an indirect indicator of the activity of GGFs. Fig. 3 shows that a decrease in head and brain growth is accompanied by a sharp increase in the risk for developing schizophrenia.

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