孕期使用SSRI对子代大鼠5-羟色胺能神经元环路功能影响的研究

最新调查显示，孕早期服用5-羟色胺再摄取抑制剂（SSRIs）类的抗抑郁药物可导致子代罹患自闭症增加。动物实验证明围产期大鼠给予SSRIs，如氟西汀，子代大鼠出现脑皮层环路功能障碍及社交行为异常。我们的研究显示给予孕鼠束缚应激后其子代出现焦虑及抑郁等异常行为。而产前应激大鼠的子代出生后给与氟西汀可以改善其抑郁行为及增加海马神经元的再生。由此可见，胚胎期5-羟色胺稳态是维持神经元发育的关键因素。综上，我们提出本课题的研究假设：5-羟色胺能神经元发育的关键期稳态破坏可导致子代产生自闭症。并通过以下途径探讨5-羟色胺在自闭症病因机制中的作用：①孕期使用SSRI对子代大鼠5-羟色胺能神经元环路发育的影响；②评估儿童期子代行为学的改变及应用磁共振波普检测5-羟色胺能神经元皮层环路的神经代谢；③应用蛋白组学的方法筛选与子代行为异常相关的靶蛋白及其分子通路。本研究将为新的有效治疗自闭症药物的研发提供靶点。

Antidepressant use during pregnancy can increase the prevalence of childhood autism. Perinatal SSRIs, such as, fluoxetine, exposure alters cortical network function and social behavior in rodents. We found that prenatal restraint stress cause depressive - or anxious - like behavior in their offspring. However fluxetine reverses the effects of prenatal stress on depressive - like behavior and induces hippocampal neurogenesis in adolescence. Therefore, serotonin homeostasis is required for the proper neuron development.The hypothesis of this study is that the disruption of serotonin homeostasis at its key developmental period may cause autism.Thus,the present study aims to explore the role of serotonin of the neuropathological mechanism in autism through the following ways: a. study on the effects of prenatal SSRI exposure on the development of the 5-HTergic circuitry; b. measure behavioral alterations in adolescence and measure the metabolism changes in the 5-HTergic circuitry by using MRS; screen biomarkers in prefrontal cortex in adolescence by using 2D-DIGE. Therefore, this study provides a potential new treatment in autism through finding targeted biomarkers, targeted brain regions and neurons.