The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia.
BACKGROUND
A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors.


OBJECTIVE
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.


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


CONCLUSIONS
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.
Moises
Hans W
HW
Molecular Genetics Laboratory, Department of Psychiatry, Kiel University Hospital, Niemannsweg 147, 24105 Kiel, Germany. moises@psychiatry.uni-kiel.de
Zoega
Tomas
T
Gottesman
Irving I
II
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001921:Brain / Q000254:growth & development; D002648:Child; D002675:Child, Preschool; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D008962:Models, Theoretical; D020890:Neuregulin-1 / Q000235:genetics / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology; D010641:Phenotype; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology*; D012621:Seasons; D013569:Synapses / Q000235:genetics / Q000502:physiology*
D020890:Neuregulin-1