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. 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

Estimation of the Effective Permeability of Heterogeneous Porous Media by Using Percolation Concepts

In this paper we present new methods to estimate the effective permeability (k_eff) of heterogeneous porous media with a wide distribution of permeabilities and various underlying structures, using percolation concepts. We first set a threshold permeability (k_th) on the permeability density function (pdf) and use standard algorithms from percolation theory to check whether the high permeable grid blocks (i.e. those with permeability higher than k_th) with occupied fraction of “p” first forms a cluster connecting two opposite sides of the system in the direction of the flow (high permeability flow pathway). Then we estimate the effective permeability of the heterogeneous porous media in different ways: a power law (k_eff=k_th p^m), a weighted power average (k_eff=[p.k_th^m+(1-p).k_g^m ]^(1/m) with k_g the geometric average of the permeability distribution) and a characteristic shape factor multiplied by the permeability threshold value. We found that the characteristic parameters (i.e. the exponent “m”) can be inferred either from the statistics and properties of percolation sub-networks at the threshold point (i.e. high and low permeable regions corresponding to those permeabilities above and below the threshold permeability value) or by comparing the system properties with an uncorrelated random field having the same permeability distribution. These physically based approaches do not need fitting to the experimental data of effective permeability measurements to estimate the model parameter (i.e. exponent m) as is usually necessary in empirical methods. We examine the order of accuracy of these methods on different layers of 10th SPE model and found very good estimates as compared to the values determined from the commercial flow simulators