The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

Hans W Moises 2 Tomas Zoega 1 Irving I Gottesman 0 0 Departments of Psychiatry and Psychology, University of Minnesota , Minneapolis , USA 1 Department of Psychiatry, National University of Iceland , Reykjavik , Iceland 2 Molecular Genetics Laboratory, Department of Psychiatry, Kiel University Hospital , Niemannsweg 147, 24105 Kiel , Germany 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 genesenvironment 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. - Background The current understanding of the origin of schizophrenia is mainly based on the multifactorial-threshold (MFT) model of genetic liability and the neurodevelopmental model [1]. The former is supported by family, twin, adoption and modeling studies [24], and the latter by circumstantial evidence from clinical, epidemiological, neuropathological, and imaging studies [5,6]. Growth deviations found in many cases of schizophrenia support the neurodevelopmental hypothesis, e.g., low birth weight, late maturation, leptosomatic body build, large ventricles and low brain volume [58]). Neuronal growth 6 Neuritin 7 Persephin 4.8 INSR 0.9 4.7 and development [9,10] is controlled by growth factors synthesized by glial cells [11]. Glial cell loss [12], decreased expression levels of glia- related genes [13], and increased levels of S100B [14,15], a marker of glia cell integrity, has been observed in schizophrenia suggesting a role for glial growth factors in the pathogenesis of the disorder. Genome scans in schizophrenia have converged on several chromosomal locations [16]. A convergent loci approach has been proposed in the Proceedings of the National Academy of Science USA as a technique for discovering the molecular basis for a disease [17]. Convergent techniques such as the convergent loci (CL) or the convergent functional genomics approach [16,18,19] search for agreement between the chromosomal position of susceptibility genes for the disease and the function of the genes discovered at that position. In convergent approaches, the function of the genes is usually defined as evidence for their involvement in the disorder, derived from non-linkage studies such as gene expression analyses [16,18,19] or from evidence-based hypotheses such as the neurodevelopmental hypothesis of schizophrenia. Because of the essential role of the GGF neuregulin for neurodevelopment [20,21], we applied the CL approach to schizophrenia linkage data and GGFs-related genes. In our view, convergent techniques do not prove the existence of a causal relationship. However, they are useful The GGFs deficiency hypothesis is part of the broader working hypothesis of a decrease in the cerebral proteinsynthesis rate (CPRS) developed by one of us (HWM) as result of his attempt to find a common denominator for the diverse results of schizophrenia research [7]. The evolutionary approach employed in the latter investigation suggested that neuregulin 1 (NRG1) might be one of the susceptibility genes for schizophrenia (Figure 1 in [7]) motivating further theoretical and experimental investigations. The hypothesis presented here provides a heuristic explanation for the neurodevelopmental and genetic findings in schizophrenia. The function of glia and its growth factors Glial cells play important roles in the developing [11] as well as in the adult central nervous system (CNS). In the adult CNS, glia has a supportive, a protective, a regenerative, and an active regulatory role. Glia cells are sensors of infection and produce cytokines to limit viral replication. In adults, they induce neurogenesis in the hippocampus and the subventricular zone [22], influence neuronal activity and synaptic strength [23], and appear to be the third partner in synaptic transmission (tripartite synapse) [24]. Synaptic strength and cellular growth depend on the synaptic and the general protein-synthesis rate [25,26] which is influenced by growth factors such as neurotrophins and neuregulins [27,28]. Glial cells are part of a positive feedback loop between presynaptic neurons and their postsynaptic targets [29] involving neurotrophins and neuregulins (NRGs). NRGs are synthesized by neurons [11] and promote the differentiation, survival and repair of the neuronal targets such as glial cells [11], acetylcholine receptors [21], and postsynaptic densities (PSD) in hippocampal neurons [30]. Neuregulin-1 (NRG1) is concentrated at synaptic sites suggesting a role in synapse-specific gene expression [28]. Furthermore, NRGs influence the growth of neural precursor cells, the radial migration of newborn neurons during neocortex genesis, the rate of migration in a dosedependent manner [31], the interaction between pre- and postsynaptic neurons during synaptogenesis including neuromuscular synapse, activity-dependent maintenance of synaptic connections, synaptic plasticity, long-term potentiation, and the expression of ligand and voltage-gated channels in central neurons [9,11,20,21,3234]. NRGs are also known as glial growth factor (GGF), Neu differentiation factor (NDF), heregulin, sensory and motor neuron derived factor (SMDF), and acetylcholine receptor inducing activity (ARIA) [21]. Biochemically, NRGs are structurally related to what is perhaps the best studied trophic factor epidermal growth factor (EGF) [11] and encode a large group of polypeptide growth, survival a (...truncated)