Roles of neuronal cellular signaling and plasticity disturbances in the pathophysiology of affective disorders and schizophrenia

精神分裂症和情感性精神障碍作为主要的神经精神障碍已被确立为独立的病理生理疾病。然而，近年来的研究表明，精神分裂症患者的抑郁症状和阴性症状很难区分，有些报道指出，这两种疾病可以有一些重叠的症状。此外，最近发现的抗抑郁药对5-HT_2受体有很高的亲和力<2A>，并具有与抗抑郁药相同的药理作用。虽然精神分裂症和抑郁症的这些病理学和药理学上的相似性和差异性可能是由细胞内信号转导机制的交替介导的神经元可塑性变化引起的，但很少有研究利用死后人脑来阐明疾病本身的分子基础。因此，我们研究了：1）cAMP-CREB系统及其分布， 关于我们 本文综述了死后人脑细胞质膜Gsα的变化、生后早期人脑神经元发育和出芽相关基因的研究以及神经干细胞在神经精神疾病中的作用，发现死后人脑额叶皮层cAMP-CREB信号功能失调，抑郁症患者cAMP-CREB信号紊乱，精神分裂症患者cAMP-CREB信号功能低下。在发育早期的人额叶皮层中发现了cAMP相关基因（CBP）、营养因子相关基因（人胰岛素样生长因子结合蛋白5）和凋亡相关基因（caspase）的表达变化。此外，我们证明了神经干细胞从人死后脑组织中的分离和连续繁殖，以及cAMP信号刺激剂和神经营养因子对神经干细胞体外分化的促进作用。总之，调节cAMP-CREB系统的新药开发和神经干细胞治疗的进展可能会导致治疗神经精神疾病的新见解，并且重要的是开发与其观察相关的外周组织中的生物标志物。少

The schizophrenia and the affective disorders have been established independent pathophysiological diseases as major neuropsychiatric disorders. However, recent studies demonstrate the difficulty of discrimination of the depressive symptoms and negative symptoms in the schizophrenic patients, and some reports indicate that these illnesses can have some overlapped symptoms each other. In addition, it is also suggested that recently depveloped anthipsychotics showed high affinity for the 5-HT_<2A> receptors and had pharmachological properties in common with antidepressants. Although, these symptomatological and pharmachological similarities and differences of schizophrenia and depression may be resulted from the neuronal plasticity changes mediated by the alternation of intracellular signal transduction mechanisms, there are few studies to clarify the molecular basis of the illness itself using postmortem human brains. Therefore we investigated that 1) cAMP-CREB system and the distributi … More onal changes of Gsα in the cytoplasmic membranes in the postmortem human brains, 2) genes researches related to the neuronal development and sprouting in the early postnatal stages of human brains, and 3) roles of neural stem cells on the neuropsychiatric disorders.The functional imbalances of cAMP-CREB signalling were observed in the frontal cortex from postmortem human brains, with disturbance in depression, while hypofunction in schizophrenia. The cAMP related gene (CBP), trophic factor related gene (human insulin-like growth factor binding protein 5) and apoptosis related gene (caspases) expression changes were recognized in the early developing human frontal cortex. Moreover, we demonstrated the isolation and successive propagation of neural stem cells from human post mortem brain tissues and progressive effects of cAMP signaling stimulating agents and neurotrophic factos on neural stem cell differentiation in vitro. Altogether, progress of novel drugs development that modulates cAMP-CREB systems and neural stem cell therapy may lead to new insights treating neuropsychiatric disorders, and it is important to develop the biological markers in peripheral tissues related to their observations. Less