创伤后应激障碍（PTSD）是一种严重的压力依赖性精神障碍，其特征是恐惧记忆消退受损；然而，确定 PTSD 患者恐惧记忆消退受损的生物标志物仍不清楚。在由单一长期应激 (SPS) 引起的 PTSD 样行为的雄性小鼠中，与对照组相比，在海马体中发现了 19 种差异表达的蛋白质。其中，一种名为deleted的生物大分子蛋白在结直肠癌（DCC）中高度上调。海马区 DCC 的特异性过度表达会引起与 SPS 小鼠中观察到的类似的长时程增强 (LTP) 损伤和恐惧记忆消退。通过使用中和抗体抑制海马 DCC 功能，可以改善 SPS 小鼠的恐惧记忆消退损伤。机制研究表明，敲低或抑制海马神经元中的 μ-calpain 会增加 DCC 表达并诱导恐惧记忆消退受损。此外，SPS 引发的海马 LTP 损伤和恐惧记忆消退可以通过激活 Rac1-Pak1 信号通路来挽救。我们的研究提供了证据，表明钙蛋白酶介导的 DCC 调节可控制 SPS 小鼠的海马 LTP 和恐惧记忆消退，这可能是通过激活 Rac1-Pak1 信号通路实现的。© 2024 作者。

Post-traumatic stress disorder (PTSD) is a severe stress-dependent psychiatric disorder characterized by impairment of fear memory extinction; however, biological markers to determine impaired fear memory extinction in PTSD remain unclear. In male mice with PTSD-like behaviors elicited by single prolonged stress (SPS), 19 differentially expressed proteins in the hippocampus were identified compared with controls. Among them, a biological macromolecular protein named deleted in colorectal cancer (DCC) was highly upregulated. Specific overexpression of DCC in the hippocampus induced similar impairment of long-term potentiation (LTP) and fear memory extinction as observed in SPS mice. The impairment of fear memory extinction in SPS mice was improved by inhibiting the function of hippocampal DCC using a neutralizing antibody. Mechanistic studies have shown that knocking down or inhibiting μ-calpain in hippocampal neurons increased DCC expression and induced impairment of fear memory extinction. Additionally, SPS-triggered impairment of hippocampal LTP and fear memory extinction could be rescued through activation of the Rac1-Pak1 signaling pathway. Our study provides evidence that calpain-mediated regulation of DCC controls hippocampal LTP and fear memory extinction in SPS mice, which likely through activation of the Rac1-Pak1 signaling pathway.© 2024 The Authors.