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

The origin and evolution of the Gran Desierto Sand Sea, Sonora, Mexico

The Gran Desierto Sand Sea of Sonora, Mexico is located on the northeastern shore of the Gulf of California, east of the Colorado River Delta. The modern sand sea covers an area of 5700 km² and is the largest active dunefield in North America. The Gran Desierto is well-suited for investigation into the timing and nature of aeolian activity and regional climate change as it contains multiple dune geomorphic elements that compose the complex pattern observed today. Individual generations of dune geomorphic features are identified and "backstripped" through the utilization of several techniques. Methods include remote sensing and statistical analysis of physical parameters of the dune geomorphic forms, as well as absolute age determination of individual generations through optically stimulated luminescence (OSL) age dating techniques. Individual generations of dune geomorphic features are digitized from a Landsat 7 multispectral composite. Crestline lengths, spacings and orientations are statistically analyzed in order to identify distinct trends among individual groups of dunes. These groups are then compared with dune geomorphic features visible on a satellite image overlain on a vertically exaggerated digital elevation model. OSL ages are utilized to determine individual generations within each dune group. These generations are then correlated with global climatic events, and associated variability in predominant wind regimes. Aeolian units sit on top of alluvium that is sourced from distal alluvial fans of Tertiary granitic outcrops, and from fluvial sediments deposited as the ancient Colorado River avulsed westward across the region throughout the Pleistocene. Alluvium is dated from ~87 ka to ~26 ka. Six generations of dune geomorphic features ranging in age from 26,000 years to modern are identified. Based on gross bedform normal transport, wind regimes are reconstructed since LGM. From ~26 ka to ~12 ka, winds shifted from N and NNW to NW and S. From ~12 ka to ~ 10 ka, winds shifted to SE dominant with a subordinate NW component. From ~10 ka to ~6 ka, NW winds became dominant over the south winds and more northerly. Modern conditions were reached by (at latest) ~6 ka, with the exception of enhanced ENSO cycles ~2.4-2.8 ka.Geological Science

Development of spatially diverse and complex dune-field patterns: Gran Desierto Dune Field, Sonora, Mexico

The pattern of dunes within the Gran Desierto of Sonora, Mexico, is both spatially diverse and complex. Identification of the pattern components from remote-sensing images, combined with statistical analysis of their measured parameters demonstrate that the composite pattern consists of separate populations of simple dune patterns. Age-bracketing by optically stimulated luminescence (OSL) indicates that the simple patterns represent relatively short-lived aeolian constructional events since ~25 ka. The simple dune patterns consist of: (i) late Pleistocene relict linear dunes; (ii) degraded crescentic dunes formed at ~12 ka; (iii) early Holocene western crescentic dunes; (iv) eastern crescentic dunes emplaced at ~7 ka; and (v) star dunes formed during the last 3 ka. Recognition of the simple patterns and their ages allows for the geomorphic backstripping of the composite pattern. Palaeowind reconstructions, based upon the rule of gross bedform-normal transport, are largely in agreement with regional proxy data. The sediment state over time for the Gran Desierto is one in which the sediment supply for aeolian constructional events is derived from previously stored sediment (Ancestral Colorado River sediment), and contemporaneous influx from the lower Colorado River valley and coastal influx from the Bahia del Adair inlet. Aeolian constructional events are triggered by climatic shifts to greater aridity, changes in the wind regime, and the development of a sediment supply. The rate of geomorphic change within the Gran Desierto is significantly greater than the rate of subsidence and burial of the accumulation surface upon which it rests

Associations between DNA methylation and schizophrenia-related intermediate phenotypes:A gene set enrichment analysis

Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data 01 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identity markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (ERIIA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia. (C) 2015 Elsevier Inc. All rights reserved