Study for the molecular basis of affective disorders caused by the dysregulated homeostasis of endocrine system

我们发现，脑发育过程中依赖糖皮质激素(GC)的短暂性发育迟缓是由于依赖GC受体(GR)上调钙调蛋白表达导致神经元迁移障碍所致。在这种短暂的发育迟缓之后，MRI显示青春期大脑中神经元网络的形成不足。这些发现为行为异常和情感障碍风险增加提供了新的见解。我们进一步建立了GC缺失的神经元细胞培养体系，在该体系中神经元可以形成突触。使用这种培养系统，GC被证明是不利的突触形成，通过下调钙调蛋白表达介导的肌动蛋白细丝的不稳定。我们还发现，抑制SRF共调控因子MRTF-B可以下调钙调蛋白的表达。因此，本研究为理解GC相关内分泌系统失调引起的情感性精神障碍的发病提供了分子基础。

We found that glucocorticoid(GC)-dependent transient retardation during cerebral development was caused by the disturbance of neuronal migration via the GC receptor (GR)-dependent upregulation of caldesmon expression. After this transient retardation, insufficient neuronal network formation was found in the adolescent brain as revealed by MRI. These findings provide a novel insight regarding behavioral abnormalities and increased risks of affective disorders. We further established a GC-deficit neuronal cell culture system in which neurons can form synapses. Using this culture system, GCs were demonstrated to be detrimental for synaptic formation via the destabilization of actin filaments mediated by the downregulation of caldesmon expression. We also showed that the expression of caldesmon was downregulated by suppression of SRF co-regulator MRTF-B. Thus this study presents the molecular basis for understanding the onset of affective disorders caused by the dysregulation of GC-linked endocrine system.