The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia.
The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia.
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DOI：
10.1186/1471-244x-2-8
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发表时间：
2002-07-03
期刊：
影响因子：
4.4
通讯作者：
Gottesman II
中科院分区：
文献类型：
--
作者：
Moises HW;Zoega T;Gottesman II
一个系统的方法来理解精神分裂症的病因需要一个能够整合遗传和神经发育因素的理论。基于基因座共定位的方法和大量的间接证据，我们提出，神经胶质生长因子和神经胶质细胞产生的生长因子的功能缺陷是导致精神分裂症发展的基因-表型链的远端原因之一。这些因子包括神经调节蛋白、胰岛素样生长因子I、胰岛素、表皮生长因子、神经营养生长因子、erbB受体、磷脂酰肌醇-3激酶、生长停滞特异性基因、神经素、肿瘤坏死因子α、谷氨酸、NMDA和胆碱能受体。基因和表观遗传学决定的胶质生长因子信号和突触强度的低基线预计会增加进一步减少的易感性(例如，感染神经胶质细胞的HHV-6和JC病毒)。这应该会导致突触前神经元和其靶点之间的正反馈回路减弱，并低于某个阈值，从而导致突触不稳定和精神分裂症。在知情的猜想和经验事实的支持下，这一假说为大量进一步研究提供了一个有吸引力的案例。这一假说认为，神经胶质细胞是精神分裂症基因-环境相互作用的中心，神经胶质衰弱是精神分裂症遗传易感性的重要因素，催乳素和/或胰岛素增加是传统和非典型抗精神病药物治疗的可能作用机制。
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.
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影响因子：
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