Hypothesis

The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

Hans W Moises¹ , Tomas Zoega² and Irving I Gottesman³

¹  Molecular Genetics Laboratory, Department of Psychiatry, Kiel University Hospital, Niemannsweg 147, 24105 Kiel, Germany

²  Department of Psychiatry, National University of Iceland, Reykjavik, Iceland

³  Departments of Psychiatry and Psychology, University of Minnesota, Minneapolis, USA

author email corresponding author email

BMC Psychiatry 2002, 2:8doi:10.1186/1471-244X-2-8

Published:	3 July 2002

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.