p53调控星形胶质细胞自噬及其与抑郁症的相关性

Major depressive disorder (MDD) has been associated with astroglial dysfunction, but the underlying mechanisms have remained elusive. Many antidepressants were reported to treat depression by inducing autophagy in astrocytes, and we found that the expression of p53 was decreased in hippocampal of depressed mice and corticosterone-treated astrocytes. Thus, we suppose that p53 could regulate astrocytes autophagy in MDD. Here, using p53 transgenic overexpression mice and p53 downregulation mice, we will establish chronic mild stress (CMS)-induced anhedonia model of depression to clarify the relationship of p53 mediated autophagy in astrocytes with MDD. Moreover, primary astrocyte and the CRISPR/Cas9 genome editing technology will be used to verify the effects of p53 mediated autophagy on astrocyte function. The expected results not only further deepen the understanding of astrocytes in the pathogenesis of depression, but also provide the academic foundation for the development of new antidepressant drugs targeting p53 to regulate astrocyte function.

星形胶质细胞病理改变在抑郁症发生发展中不容忽视，多种抗抑郁药物能够诱导星形胶质细胞自噬从而对其产生保护作用。申请者实验室前期研究发现抑郁症模型小鼠海马及体外星形胶质细胞皮质酮模型p53表达下调，推测p53调控星形胶质细胞自噬与抑郁症密切相关。为验证该假设，本项目拟应用p53过表达小鼠和海马星形胶质细胞p53低表达小鼠建立慢性温和应激抑郁症动物模型，整体验证p53调控星形胶质细胞自噬与抑郁症的相关性。并通过原代星形胶质细胞培养、CRISPR/Cas9基因编辑等技术体外验证p53调控自噬对星形胶质细胞功能的影响。预期研究结果不仅进一步深化对星形胶质细胞参与抑郁症发病机理的认识，同时为研发靶向p53调控星形胶质细胞功能的新型抗抑郁药物积累重要的学术基础。

星形胶质细胞病理改变在抑郁症发生发展中不容忽视，多种抗抑郁药物能够诱导星形胶质细胞自噬从而对其产生保护作用。本项目前期研究发现抑郁症模型小鼠海马及体外星形胶质细胞皮质酮模型p53表达下调，推测p53与抑郁症密切相关。为验证该假设，本项目使用p53敲除小鼠建立CMS模型，通过多种行为学指标评价了野生型小鼠及p53敲除小鼠抑郁样行为的差异，初步确定p53与抑郁症的相关性。同时，本项目使用体内及体外实验表明抑郁状态下细胞自噬无明显变化，氟西汀可以显著改善CMS模型小鼠海马星形胶质细胞线粒体的损伤，并促进自噬小体的形成。本项目的研究结果不仅进一步深化对星形胶质细胞参与抑郁症发病机理的认识，同时为研发靶向p53的新型抗抑郁药物积累重要的学术基础。