Lang Undine E, Puls Imke, Muller Daniel J, Strutz-Seebohm Nathalie, Gallinat Jurgen
Department of Psychiatry, Charité University Medicine Berlin, Campus Mitte, Berlin (Germany).
Cell Physiol Biochem. 2007;20(6):687-702. doi: 10.1159/000110430.
Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.
精神分裂症是一种复杂的疾病，家族、双胞胎和收养研究表明该疾病具有高度遗传性，且这种疾病并非简单地由几个主要基因决定，而是由特定基因簇的累加或增强演变而来，随后决定个体的遗传易感性。连锁和关联研究表明，遗传易感性并非必然导致疾病，因为已确定了触发因素和环境影响，如出生并发症、药物滥用、城市背景或出生时间。这导致人们认为精神分裂症不仅是一种由基因定义的静态疾病，而是一个导致多种途径失调的动态过程。基于该疾病的多个方面存在几种不同的假说，其中一些是由于治疗药物的机制相对为人所知。精神分裂症最广泛被考虑的神经发育假说整合了环境影响和致病基因。精神分裂症的多巴胺假说基于这样一个事实，即所有常见治疗都涉及抗多巴胺能机制，并且诸如DRD2、DRD3、DARPP - 32、BDNF或COMT等基因与多巴胺能系统功能密切相关。精神分裂症的谷氨酸能假说最近促成了第一种成功的mGlu2/3受体激动剂药物的出现，并且有在调节谷氨酸能系统的基因（SLC1A6、SLC1A2、GRIN1、GRIN2A、GRIA1、NRG1、ErbB4、DTNBP1、DAAO、G72/30、GRM3）中的重要发现作为支撑。相应地，有人提出γ-氨基丁酸（GABA）可调节该疾病的病理生理学，这表现为GABRA1、GABRP、GABRA6和Reelin等基因的参与。此外，据报道，一些涉及免疫、信号传导和网络缺陷的基因与该疾病有关，如DISC1、RGS4、PRODH、DGCR6、ZDHHC8、DGCR2、Akt、CREB、IL - 1B、IL - 1RN、IL - 10、IL - 1B。然而，分子研究结果表明，受体、激酶、蛋白质和激素之间的复杂相互作用与精神分裂症有关。在一个统一的假说中，不同的级联相互融合，最终导致符合精神分裂症障碍的症状出现。
