Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China; Henan Key Lab of Biological Psychiatry of Xinxiang Medical University, Xinxiang, China.
Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
Behav Brain Res. 2024 May 8;465:114962. doi: 10.1016/j.bbr.2024.114962. Epub 2024 Mar 16.
Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in the hippocampus of patients with depression, while pharmacological inhibition of hippocampal MKP1 can mitigate depression-like behaviors in rodents. In addition, MAPK signaling regulates autophagy, and antidepressants were recently shown to target autophagic signaling pathways. We speculated that MKP1 contributes to depression by enhancing hippocampal autophagy through dephosphorylation of the MAPK isoform ERK1/2.
We established a rat depression model by exposure to chronic unpredictable mild stress (CUMS), and then examined depression-like behaviors in the sucrose preference test (SPT) and forced swimming test (FST) as well as expression changes in hippocampal MKP1, ERK1/2, phosphorylated ERK1/2, and autophagy-related proteins LC3II by Western blotting and immunostaining. These same measurements were repeated in rats exposed to CUMS following hippocampal infusion of a MKP1-targeted shRNA. Finally, the effects of MKP1 expression level on autophagy we examined in rat GMI-R1 microglia.
CUMS-exposed rats demonstrated anhedonia in the SPT and helplessness in the FST, two core depression-like behaviors. Expression levels of MKP1 and LC3II were upregulated in the hippocampus of CUMS rats, suggesting enhanced autophagy, while pERK/ERK was downregulated. Knockdown of hippocampal MKP1 mitigated depression-like behaviors, downregulated hippocampal LC3II expression, and upregulated hippocampal pERK/ERK. Similarly, MKP1 knockdown in GMI-R1 cells upregulated pERK/ERK and reduced the number of LC3II autophagosomes, while MKP1 overexpression had the opposite effects.
Enhanced hippocampal autophagy via MKP1-mediated ERK dephosphorylation may contribute to the development of depression.
促分裂原活化蛋白激酶（MAPK）磷酸酶-1（MKP1）在抑郁症患者的海马体中上调，而海马体中 MKP1 的药理学抑制可以减轻啮齿动物的抑郁样行为。此外，MAPK 信号通路调节自噬，最近发现抗抑郁药靶向自噬信号通路。我们推测，MKP1 通过去磷酸化 MAPK 同工型 ERK1/2 来增强海马体自噬，从而导致抑郁。
我们通过慢性不可预测轻度应激（CUMS）建立大鼠抑郁模型，然后通过蔗糖偏好测试（SPT）和强迫游泳测试（FST）检查抑郁样行为，以及通过 Western blot 和免疫染色检查海马体中 MKP1、ERK1/2、磷酸化 ERK1/2 和自噬相关蛋白 LC3II 的表达变化。在海马体输注靶向 MKP1 的 shRNA 后，在 CUMS 暴露的大鼠中重复进行了相同的测量。最后，我们在大鼠 GMI-R1 小胶质细胞中检查了 MKP1 表达水平对自噬的影响。
CUMS 暴露的大鼠在 SPT 中表现出快感缺失，在 FST 中表现出无助，这是两种核心的抑郁样行为。CUMS 大鼠海马体中 MKP1 和 LC3II 的表达水平上调，表明自噬增强，而 pERK/ERK 下调。海马体中 MKP1 的敲低减轻了抑郁样行为，下调了海马体 LC3II 的表达，上调了海马体 pERK/ERK。同样，GMI-R1 细胞中 MKP1 的敲低上调了 pERK/ERK，减少了 LC3II 自噬体的数量，而 MKP1 的过表达则产生了相反的效果。
通过 MKP1 介导的 ERK 去磷酸化增强海马体自噬可能导致抑郁的发生。
