Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu, Shizuoka 431-3192, Japan.
Med Hypotheses. 2012 Sep;79(3):304-7. doi: 10.1016/j.mehy.2012.05.015. Epub 2012 Jun 7.
Schizophrenia is a complex psychiatric disorder clinically categorized into three main symptom domains: positive, negative and cognitive deficits. Many reports have shown that great reduction in spine number was observed in schizophrenia patients. In addition, genetic studies have identified mutations in numerous genes that encode synaptic proteins in schizophrenia patients. Furthermore, it is well known that antipsychotic drugs change the number of spines, indicating that disturbance in spine homeostasis is deeply involved in the pathogenesis of schizophrenia. On the other hand, it is commonly accepted that alteration in dopaminergic systems is also involved in the pathogenesis of schizophrenia. However, the relationships between the changes of spine homeostasis and those of the dopaminergic system are largely unknown. Recently, spine homeostasis is reported to be tightly regulated by dopamine D1 receptors. Thus, I will set a new notion that disturbed spine homeostasis results in compensatory up-regulation in the dopaminergic system to keep normal cognitive functions. The hypothesis is as follows. Disturbance in spine homeostasis based on genetic vulnerabilities is the main cause of schizophrenia, and this disturbance results in network deficiency, negative symptoms and cognitive deficits. Since spine homeostasis is deeply regulated by dopamine D1 receptors, disturbed spine homeostasis leads to compensatory hyperactivity in the dopamine system to keep normal cognitive functions. This dopaminergic hyperactivity stimulates dopamine D2 receptors, leading to positive symptoms. All current antipsychotic medications have antagonist actions at dopamine D2 receptors. However, these drugs are not so effective to negative symptoms, consistent with the hypothesis, where dopamine D2 receptor over-activation is secondary. Thus, this hypothesis can integrally explain three main symptom domains: positive, negative and cognitive deficits.
精神分裂症是一种复杂的精神疾病，临床上分为阳性、阴性和认知缺陷三个主要症状领域。许多报道表明，精神分裂症患者的棘突数量明显减少。此外，遗传研究已经确定了许多编码突触蛋白的基因突变存在于精神分裂症患者中。此外，众所周知，抗精神病药物会改变棘突的数量，这表明棘突的动态平衡紊乱与精神分裂症的发病机制密切相关。另一方面，多巴胺能系统的改变也被普遍认为与精神分裂症的发病机制有关。然而，棘突动态平衡的变化与多巴胺能系统的变化之间的关系在很大程度上尚不清楚。最近，有研究报道称，棘突的动态平衡受到多巴胺 D1 受体的紧密调控。因此，我将提出一个新的概念，即棘突动态平衡的紊乱会导致多巴胺能系统的代偿性上调，以维持正常的认知功能。该假说如下。基于遗传易感性的棘突动态平衡紊乱是精神分裂症的主要病因，这种紊乱会导致网络缺陷、阴性症状和认知缺陷。由于棘突的动态平衡受到多巴胺 D1 受体的深度调控，因此，棘突动态平衡的紊乱会导致多巴胺能系统的代偿性过度活跃，以维持正常的认知功能。这种多巴胺能的过度活跃会刺激多巴胺 D2 受体，导致阳性症状。目前所有的抗精神病药物都对多巴胺 D2 受体具有拮抗作用。然而，这些药物对阴性症状的疗效并不显著，这与假设一致，即多巴胺 D2 受体的过度激活是次要的。因此，该假说可以全面解释阳性、阴性和认知缺陷这三个主要症状领域。
