Tau蛋白介导抑郁症发病及氟西汀治疗的神经可塑性机制研究

Many studies have focused on the depression neuroplasticity and the effect on neuroplasticity of antidepressant in the treatment of depression. Growing evidence indicates that the cytoskeletal microtubular system which is structurally composed of Microtubules and microtubule-associated proteins could play an important role in stress-induced impairments in structural neuronal plasticity. Tau is the most important microtubule-associated proteins and has been recognized to play major roles in promoting microtubule assembly and stabilizing the microtubules and to maintain the normal morphology of the neurons. . Several studies have reported that acute and chronic stresses induce tau phosphorylation in the mouse hippocampus. Our previously study have showed that rats submitted to CUMS showed a significant reduction in locomotion and sucrose preference which accompanied by specific alterations in hippocampal phospho-tau expression and α-tubulin isoforms which indicating that microtubules were less dynamic. These studies suggest that tau may play an important role in neuronal plasticity in depression. But the role of tau in neuronal plasticity of depression and the mechanism of tau involved in the effect of antidepressant on the neuroplasticity remain unclear and need more researches. . The primary aim of the present study, therefore, is to investigate possible alteration of tau in the hippocampus of rats exposed to CUMS. We will increase and decrease the level of tau phosphorylation using Wortmanni and SB216763 in the animal and cultured hippocampal cell, respectively. Cytoskeletal microtubular system and neuroplasticity will be detected accompanied with the tau phosphorylation changes. Fluoxetine will be used to treat depressive animal and co-culture with hippocampal cell and then we will investigate the effect of fluoxetine on the tau phosphorylation and tau involved in the effect of fluoxetine on the neuroplasticity. We hope to open up a new view angle in neuronal plasticity of depression and provide helpful exploration for new antidepressant drug target.

神经可塑性在抑郁症发病机制及抗抑郁药物治疗中地位关键。细胞支架微管系统的改变是应激所致神经可塑性损伤的基础。Tau是微管系统重要组成部分，其他学者及我们的前期研究均显示急慢性应激可引起tau磷酸化水平升高，提示tau在抑郁症的神经可塑性损伤中扮演重要角色。但tau磷酸化改变对抑郁症的神经可塑性影响以及tau参与抗抑郁药物的神经可塑性机制尚未明了。本项目拟建立抑郁模型，探讨海马tau蛋白磷酸化水平的变化及该变化伴随的海马细胞支架微管系统及神经可塑性改变；进一步地，使用Wortmanni及SB216763从动物水平及细胞水平探讨升高或降低tau磷酸化水平后对上述指标的影响；同时，引入氟西汀治疗抑郁动物并与海马神经元共培养，并沉默tau，探讨tau在氟西汀治疗的神经可塑性机制中的作用；从tau及所属的细胞支架微管系统角度，探索抑郁症神经可塑性损伤的新视角，为药物的新靶点提供有益的研究基础。

神经可塑性在抑郁症发病机制及抗抑郁药物治疗中地位关键。细胞支架微管系统的改变是应激所致神经可塑性损伤的基础。Tau是微管系统重要组成部分，其他学者及我们的前期研究均显示急慢性应激可引起tau磷酸化水平升高，提示tau在抑郁症的神经可塑性损伤中扮演重要角色。但tau磷酸化改变对抑郁症的神经可塑性影响以及tau参与抗抑郁药物的神经可塑性机制尚未明了。本项目主要研究内容包含三个部分，首先建立抑郁模型，探讨海马tau蛋白磷酸化水平的变化及该变化伴随的海马细胞支架微管系统及神经可塑性改变；其次，使用Wortmanni及SB216763从动物水平及细胞水平探讨升高或降低tau磷酸化水平后对上述指标的影响；第三，引入氟西汀治疗抑郁动物并与海马神经元共培养，并沉默tau，探讨tau在氟西汀治疗的神经可塑性机制中的作用。. 在本项目的研究中，我们发现，抑郁动物模型在tau的多个磷酸化位点（Ser396、Ser199/202、Thr217、Thr231、Ser235）有病理性增高。同时，海马神经元再生及细胞支架微管蛋白均有同步的变化，细胞支架微管蛋白与tau蛋白结合率减低，由此海马神经元再生受到影响。使用药物Wortmanni及SB216763人为调高或降低tau的磷酸化后，海马神经元再生和结合率也随之相应降低和增高。氟西汀药物治疗抑郁情绪后，上述改变有所缓和。同时，在细胞水平也有类似的发现。特别是当我们沉默tau后，氟西汀药物在良性调节神经可塑性方面的作用有所受损，提示我们tau在氟西汀治疗抑郁的信号通路中扮演一定的中介作用。本研究从tau及所属的细胞支架微管系统角度，探索抑郁症神经可塑性损伤的新视角，为药物的新靶点提供有益的研究基础。