Phasuk Sarayut, Pairojana Tanita, Suresh Pavithra, Yang Chee-Hing, Roytrakul Sittiruk, Huang Shun-Ping, Chen Chien-Chang, Pakaprot Narawut, Chompoopong Supin, Nudmamud-Thanoi Sutisa, Liu Ingrid Y
Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.
Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Mol Brain. 2021 Feb 25;14(1):42. doi: 10.1186/s13041-021-00754-1.
Fear dysregulation is one of the symptoms found in post-traumatic stress disorder (PTSD) patients. The functional abnormality of the hippocampus is known to be implicated in the development of such pathology. Peroxiredoxin 6 (PRDX6) belongs to the peroxiredoxin family. This antioxidant enzyme is expressed throughout the brain, including the hippocampus. Recent evidence reveals that PRDX6 plays an important role in redox regulation and the modulation of several signaling molecules involved in fear regulation. Thus, we hypothesized that PRDX6 plays a role in the regulation of fear memory. We subjected a systemic Prdx6 knockout (Prdx6) mice to trace fear conditioning and observed enhanced fear response after training. Intraventricular injection of lentivirus-carried mouse Prdx6 into the 3rd ventricle reduced the enhanced fear response in these knockout mice. Proteomic analysis followed by validation of western blot analysis revealed that several proteins in the MAPK pathway, such as NTRK2, AKT, and phospho-ERK1/2, cPLA2 were significantly upregulated in the hippocampus of Prdx6 mice during the retrieval stage of contextual fear memory. The distribution of PRDX6 found in the astrocytes was also observed throughout the hippocampus. This study identifies PRDX6 as a participant in the regulation of fear response. It suggests that PRDX6 and related molecules may have important implications for understanding fear-dysregulation associated disorders like PTSD.
恐惧调节异常是创伤后应激障碍（PTSD）患者的症状之一。已知海马体的功能异常与这种病理状态的发展有关。过氧化物酶6（PRDX6）属于过氧化物酶家族。这种抗氧化酶在包括海马体在内的整个大脑中都有表达。最近的证据表明，PRDX6在氧化还原调节以及参与恐惧调节的几种信号分子的调节中发挥重要作用。因此，我们假设PRDX6在恐惧记忆的调节中起作用。我们对系统性Prdx6基因敲除（Prdx6）小鼠进行了痕迹恐惧条件反射实验，并观察到训练后恐惧反应增强。将携带小鼠Prdx6的慢病毒脑室内注射到第三脑室可降低这些基因敲除小鼠增强的恐惧反应。蛋白质组学分析并经蛋白质印迹分析验证后发现，在情境恐惧记忆的检索阶段，Prdx6小鼠海马体中丝裂原活化蛋白激酶（MAPK）途径中的几种蛋白质，如神经营养酪氨酸激酶2（NTRK2）、蛋白激酶B（AKT）、磷酸化细胞外信号调节激酶1/2（phospho-ERK1/2）、胞质磷脂酶A2（cPLA2）显著上调。还观察到PRDX6在整个海马体的星形胶质细胞中的分布。本研究确定PRDX6是恐惧反应调节的参与者。这表明PRDX6及相关分子可能对理解与恐惧调节异常相关的疾病如PTSD具有重要意义。
