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障碍已被确立为独立的病理生理疾病，是主要的神经精神疾病。然而，最近的研究表明，精神分裂症患者的抑郁症状和阴性症状难以区分，一些报告表明，这两种疾病可能有一些重叠的症状。此外，最近开发的抗精神病药物对5-HT_<2A>受体具有高亲和力，并且具有与抗抑郁药相同的药理特性。虽然精神分裂症和抑郁症的这些症状学和药理学上的异同可能是由于细胞内信号转导机制的改变所介导的神经元可塑性改变所致，但很少有研究利用人死后的大脑来阐明疾病本身的分子基础。因此，我们研究了1)cAMP-CREB系统和死后人脑细胞质膜中gs - α的分布和更多的变化，2)出生后早期人脑神经元发育和萌芽的相关基因研究，3)神经干细胞在神经精神疾病中的作用。在死后的人类大脑额叶皮层中观察到cAMP-CREB信号的功能失衡，在抑郁症中出现紊乱，在精神分裂症中出现功能低下。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（caspases）的表达变化。此外，我们还证明了从人死后脑组织中分离和连续繁殖神经干细胞，以及cAMP信号刺激剂和神经营养因子对体外神经干细胞分化的进行性作用。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为神经精神疾病的治疗带来新的见解，而开发与这些观察结果相关的外周组织生物标志物是很重要的。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