The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

• Published in: BMC psychiatry Vol. 2; no. 1; p. 8
• Main Authors: Moises, Hans W, Zoega, Tomas, Gottesman, Irving I
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.07.2002; BioMed Central; BMC
• Subjects: Adolescent; Adult; Age of Onset; Brain - growth & development; Child; Child, Preschool; Genetic Linkage; Genetic Predisposition to Disease - genetics; Genotype; Humans; Hypothesis; JC virus; Models, Genetic; Models, Theoretical; Neuregulin-1 - genetics; Neuregulin-1 - physiology; Neuroglia - physiology; Phenotype; Risk Factors; Schizophrenia - genetics; Schizophrenia - physiopathology; Seasons; Synapses - genetics; Synapses - physiology
• ISSN: 1471-244X; 1471-244X
• DOI: 10.1186/1471-244x-2-8

A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. 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. 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.