转位蛋白18kDa通过调控外侧缰核中GABA能抑制性传递在产后抑郁中的作用及机制研究

Postpartum depression (PPD) is a severe mental disorder and threat to maternal and neonatal health, however, the mechanisms involved in the development of PPD are still unclear and there are no specific targets for the treatment. Therefore, it is very important to explore the new strategies for prevention and therapy of PPD, as well as targets for clinical treatment. Evidence showed that activation of translocator protein 18KDa (TSPO) exhibited antidepressant effects by enhancing GABAergic transmission. Our previous data showed that that activation of TSPO significantly alleviated the PPD mice depression- and anxiety-like behaviors. Electrophysiological recordings revealed that activation of TSPO promoted the excitability of the GABAergic neurons in the lateral Habenula nucleus (LHb), but not affected the novel object recognition ability of mice. This implicates the potential antidepressant effects of activation of TSPO is through enhancing the inhibitory neural transmission. This project firstly proposes that activation of TSPO exerts antidepressant effects by enhancing GABAergic transmission in the LHb. We will combine mutiple methods, including behavioral tests, electrophysiological recordings, and molecular biology, to investigate the roles of TSPO in PPD and the underlying mechanisms. The research will help to elucidate the pathological mechanisms of PPD and provide new potential targets for PPD.

产后抑郁（PPD）严重威胁产妇与新生儿健康，发病机制未明且尚无有效的治疗方法，探究其防治新策略和药物新靶点是临床热点。研究证实，激活转位蛋白18KDa（TSPO）可显著增强GABA传导功能，表现出抗抑郁效应。我们前期研究发现，应用TSPO激动剂可以显著缓解PPD小鼠抑郁样行为，兼有神经保护、抗焦虑、改善脑缺血再灌注损伤的作用；电生理记录发现TSPO激动剂显著增强PPD小鼠外侧僵核（LHb）GABAA受体介导的抑制性传递，并且不影响小鼠新物体识别的学习记忆能力。提示TSPO可作为PPD的潜在药物治疗靶点。据此本项目首次提出，激活TSPO调控LHb中GABA能抑制性传递具有抗PPD的作用。本项目拟采用多种研究技术，探讨PPD发病时LHb中TSPO介导抑制性神经传递紊乱的作用及其机制。为揭示PPD发病的新机制，发现治疗PPD药物作用新靶点，研发新型PPD防治药提供新的思路。

产后抑郁（PPD）严重威胁产妇与新生儿健康，发病机制未明且尚无有效的治疗方法，探究其防治新策略和药物新靶点是临床热点。我们前期研究发现ZBD-2提高TSPO表达水平可减轻PPD动物模型的焦虑抑郁样行为，兼有神经保护、改善脑缺血再灌注损伤的作用。然而其作用机制尚未见报道。本项目以PPD小鼠及其子鼠为研究模型，利用电生理、免疫组织化学、药理学和行为学等手段，探索ZBD-2对PPD的治疗作用，为抗PPD提供了新的靶点。研究发现，ZBD-2治疗PPD的作用机制可能与调节下丘脑-垂体-肾上腺（HPA）轴，增强5-HT表达，并维持兴奋性和抑制性突触蛋白表达至正常水平有关。电生理记录发现ZBD-2通过激动TSPO显著增强PPD小鼠BLA中GABAA受体介导的抑制性传递。提示ZBD-2通过调节TSPO调控BLA中GABA能抑制性传递发挥抗PPD的作用, TSPO可作为PPD的潜在药物治疗靶点。同时课题组关注ZBD-2在PPD子代小鼠学习记忆、突触发育与可塑性中的作用。研究发现，ZBD-2对PPD子鼠生长发育（体重、睁眼时间、存活率）都有显著提高；对PPD子鼠焦虑、抑郁情绪障碍有改善作用；对PPD子鼠神经元发育产生显著影响，使PPD子鼠海马区突触和棘突数量增多；PPD子代小鼠CA1锥体神经元自发放电的频率降低，LTP诱导障碍, 导致学习记忆障碍，ZBD-2可显著改善PPD子代小鼠突触可塑性中长时程（LTP）诱导障碍，显著改善PPD子鼠学习记忆能力。这是关于ZBD-2参与TSPO介导PPD发病时BLA中抑制性神经传递紊乱及对PPD子代神经发育影响的首次报道。对于进一步认识PPD的病理机制具有重要意义，并为发掘潜在的药物治疗新靶点，为临床治疗提供新的思路和理论依据。