Chen Si, Lin Zhengdong, Tan Kai-Leng, Chen Risheng, Su Wenfang, Zhao Haishan, Tan Qiwen, Tan Wen
Department of Human Anatomy and Histology & Embryology, Zunyi Medical University, Zhuhai Campus, Zhuhai, China.
Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China.
Front Psychiatry. 2020 Sep 11;11:564843. doi: 10.3389/fpsyt.2020.564843. eCollection 2020.
Butyrylcholinesterase (BChE) efficiently hydrolyzes acetylcholine (ACh) at high concentrations when acetylcholinesterase (AChE) is substrate-inhibited. Recent studies have shown that BChE also has a function that is independent of ACh, but it has not been fully explored. Low BChE expression is accompanied with higher stress-induced aggression and ghrelin levels in stress models, and BChE knockout mice exhibit cognitive and memory impairments. However, the role of BChE in posttraumatic stress disorder (PTSD) remains unclear. In the present study, we investigated the role of BChE in contextual fear memory and its regulatory effect on the expression of factors related to the glutamate (Glu)-glutamine (Gln) cycle knockdown studies. We used AAVs and lentiviruses to knockdown BChE expression in the mouse hippocampal CA1 region and C8D1A astrocytes. Our behavioral data from those mice injected with AAV-shBChE in the hippocampal CA1 region showed strengthened fear memory and increased dendritic spine density. Elevated Glu levels and glutamine synthetase (GS) enzyme activity were detected in contextual fear conditioned-BChE knockdown animals and astrocytes. We observed that an AAV-shBChE induced lowering of BChE expression in the hippocampus CA1 region enhanced contextual fear memory expression and promoted the astrocytic Glu-Gln cycle but did not elevate ACh-hydrolyzing activity. This study provides new insight into the regulatory role of BChE in cognition and suggests potential target for stress-related psychiatric disorder such as PTSD where patients experience fear after exposure to severe life-threatening traumatic events.
当乙酰胆碱酯酶（AChE）受到底物抑制时，丁酰胆碱酯酶（BChE）能在高浓度下有效水解乙酰胆碱（ACh）。最近的研究表明，BChE还具有独立于ACh的功能，但尚未得到充分探索。在应激模型中，低BChE表达伴随着较高的应激诱导攻击性和胃饥饿素水平，并且BChE基因敲除小鼠表现出认知和记忆障碍。然而，BChE在创伤后应激障碍（PTSD）中的作用仍不清楚。在本研究中，我们通过基因敲低研究，探究了BChE在情境恐惧记忆中的作用及其对谷氨酸（Glu）-谷氨酰胺（Gln）循环相关因子表达的调节作用。我们使用腺相关病毒（AAV）和慢病毒在小鼠海马CA1区和C8D1A星形胶质细胞中敲低BChE表达。我们对在海马CA1区注射AAV-shBChE的小鼠进行行为学检测，数据显示其恐惧记忆增强，树突棘密度增加。在情境恐惧条件下的BChE基因敲除动物和星形胶质细胞中，检测到Glu水平升高和谷氨酰胺合成酶（GS）酶活性增强。我们观察到，在海马CA1区，AAV-shBChE诱导的BChE表达降低增强了情境恐惧记忆表达，并促进了星形胶质细胞的Glu-Gln循环，但未提高ACh水解活性。本研究为BChE在认知中的调节作用提供了新的见解，并为创伤后应激障碍等与应激相关的精神疾病提出了潜在靶点，此类疾病患者在经历严重危及生命的创伤事件后会出现恐惧情绪。
