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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: 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.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.

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: 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.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.

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