背景:产前应激(PS)可诱发后代抑郁,但是潜在的机制仍然未知。
目的:这项工作的目的是研究后代PS诱导的抑郁样行为的机制。
方法:开发了一种产前束缚应激程序,其中将GD14至GD20的怀孕大鼠每天3次,每次45分钟,首先置于通风良好的瓶子中。使用蔗糖偏好测试(SPT)和强迫游泳测试(FST)检查了雄性后代的抑郁样行为。谷氨酸水平和GluN2A的表达水平,还评估了PS易感(PS-S)后代海马中的p-CaMKII和髓磷脂碱性蛋白(MBP)。为了阐明PS导致后代抑郁的机制,我们还使用体外“神经元损伤”模型研究了皮质酮过量的影响。
结果:与对照组相比,PS-S雄性后代海马中的谷氨酸水平显着升高。GluN2A和p-CaMKII的表达水平也发生了改变。此外,MBP染色的光密度、MBPmRNA和MBP蛋白的表达水平降低,显示海马髓鞘形成受损.用GluN2A受体拮抗剂NVP-AAM077治疗PS-S后代在FST中产生抗抑郁样作用,以及MBP和p-CaMKII异常的抢救。
结论:这些发现表明GluN2A在PS诱导的抑郁症的药物治疗开发中是一个有希望的靶点。
Prenatal stress (PS) can induce depression in offspring, but the underlying mechanisms are still unknown.
The aim of this work was to investigate the mechanism that underlies PS-induced depressive-like behavior in offspring.
A prenatal restraint stress procedure was developed in which pregnant rats at GD14 to GD20 were placed head-first into a well-ventilated bottle three times each day and for 45 min each time. Depressive-like behavior in the male offspring was examined using the sucrose preference test (SPT) and the forced swim test (FST). The level of glutamate and the expression levels of GluN2A, p-CaMKII and myelin basic protein (
MBP) in the hippocampus of PS-susceptible (PS-S) offspring were also evaluated. To clarify the mechanism by which PS leads to depression in offspring, the effects of excessive corticosterone were also investigated using an in vitro \"injured neuronal\" model.
The glutamate level in the hippocampus of PS-S male offspring was significantly elevated compared to controls. The expression levels of GluN2A and p-CaMKII were also altered. In addition, the optical density of
MBP staining and the expression levels of
MBP mRNA and
MBP protein were decreased, demonstrating impaired myelinization in the hippocampus. Treatment of PS-S offspring with the GluN2A receptor antagonist NVP-AAM077 resulted in antidepressant-like effects in the FST, as well as rescue of the
MBP and p-CaMKII abnormalities.
These findings indicate that GluN2A is a promising target in the development of pharmacotherapies for PS-induced depression.