Zhou Xiaokun, Yi Wenxiang, Zhi Yiqiang, Yu Jurui, Lu Danping, Luo Zhousong, Yuan Ling, Chen Liyu, Xu Zhiheng, Xu Dan
Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, 350005, China.
College of Biological Science and Engineering, Institute of Life Sciences, Fuzhou University, Fuzhou, 350108, China.
Mol Neurobiol. 2023 May;60(5):2367-2378. doi: 10.1007/s12035-023-03209-x. Epub 2023 Jan 18.
Stress is considered as a major cause of depression. C-Jun N-terminal kinase (JNK) is a member of the stress-induced mitogen activated protein (MAP) kinase family which is often activated through phosphorylation. Clinical studies and animal experiments have found that abnormal phosphorylation/activation of JNK exists in the occurrence of various psychiatric diseases. Recently, several studies linked JNK kinase activity to depression. However, whether excessive activation of JNK activity is directly responsible for the occurrence of depression and the underlying mechanisms remain unclear. Here, we constructed a conditional transgenic mouse which is specifically expressing MKK7-JNK1 (CAJNK1) in the central nervous system. CAJNK1 mice showed activation of JNK and lead to depression-like behavior in mice. Transcriptome analysis indicates reduced expression of synaptic-associated genes in CAJNK1 mice brains. Consistently, we found abnormal dendritic spine development and PSD95 downregulation in CAJNK1 hippocampal neurons. Our studies provide compelling evidence that activation of JNK as an intrinsic factor leading to depression-like behavior in mice provides direct clues for targeting the JNK activity as a potential therapeutic strategy for depression.
应激被认为是抑郁症的主要成因。c-Jun氨基末端激酶（JNK）是应激诱导的丝裂原活化蛋白（MAP）激酶家族的成员，其通常通过磷酸化被激活。临床研究和动物实验发现，JNK的异常磷酸化/激活存在于各种精神疾病的发生过程中。最近，多项研究将JNK激酶活性与抑郁症联系起来。然而，JNK活性的过度激活是否直接导致抑郁症的发生以及潜在机制仍不清楚。在此，我们构建了一种条件转基因小鼠，其在中枢神经系统中特异性表达MKK7-JNK1（CAJNK1）。CAJNK1小鼠表现出JNK的激活，并导致小鼠出现抑郁样行为。转录组分析表明，CAJNK1小鼠大脑中与突触相关基因的表达降低。同样，我们发现CAJNK1海马神经元中树突棘发育异常和PSD95下调。我们的研究提供了令人信服的证据，即JNK的激活作为导致小鼠抑郁样行为的内在因素，为将JNK活性作为抑郁症的潜在治疗策略提供了直接线索。
