原肌球蛋白受体激酶B
PI3K/AKT/mTOR通路
脑源性神经营养因子
海马结构
蛋白激酶B
海马体
神经营养因子
突触后电位
细胞生物学
化学
信号转导
神经科学
内科学
内分泌学
医学
生物
受体
作者
Xin Shi,Xiaozhong Zhou,Gang Chen,Weifeng Luo,Caddie Zhou,Tong Chuan He,Mandar T. Naik,Qin Jiang,John Marshall,Cong Cao
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2024-04-30
卷期号:17 (834)
标识
DOI:10.1126/scisignal.adn4556
摘要
Signaling mediated by brain-derived neurotrophic factor (BDNF), which is supported by the postsynaptic scaffolding protein PSD-95, has antidepressant effects. Conversely, clinical depression is associated with reduced BDNF signaling. We found that peptidomimetic compounds that bind to PSD-95 promoted signaling by the BDNF receptor TrkB in the hippocampus and reduced depression-like behaviors in mice. The compounds CN2097 and Syn3 both bind to the PDZ3 domain of PSD-95, and Syn3 also binds to an α-helical region of the protein. Syn3 reduced depression-like behaviors in two mouse models of stress-induced depression; CN2097 had similar but less potent effects. In hippocampal neurons, application of Syn3 enhanced the formation of TrkB–Gα i1/3 –PSD-95 complexes and potentiated downstream PI3K-Akt-mTOR signaling. In mice subjected to chronic mild stress (CMS), systemic administration of Syn3 reversed the CMS-induced, depression-associated changes in PI3K-Akt-mTOR signaling, dendrite complexity, spine density, and autophagy in the hippocampus and reduced depression-like behaviors. Knocking out Gα i1/3 in hippocampal neurons prevented the therapeutic effects of Syn3, indicating dependence of these effects on the TrkB pathway. The findings suggest that compounds that induce the formation of PSD-95–TrkB complexes have therapeutic potential to alleviate depression.
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