Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, People's Republic of China.
The Second Clinical Medical School, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, People's Republic of China.
Int Immunopharmacol. 2023 Nov;124(Pt B):111023. doi: 10.1016/j.intimp.2023.111023. Epub 2023 Oct 12.
Depression is a common mental disease, accompanied by anxiety and persistent depression. Endophilin A1 (EPA1) is a brain-specific protein enriched in synaptic terminals that is primarily expressed in the central nervous system. It has been reported that EPA1 is involved in neurotransmitter release, which indicates that the protein may be involved in depression. However, it is unclear whether EPA1 is implicated in the development of depression.
The mice depression model was established by chronic unpredicted mild stress (CUMS). Depression-like behaviors were detected by sucrose preference test (SPT), forced swim test (FST), tail-suspension test (TST) and open-field test (OFT). Neuronal histopathology was applied by hematoxylin and eosin stain (H&E), and Nissl stain. EPA1, NLRP1 inflammatory complexes, NADPH oxidase2 (NOX2), synaptic-related protein expression of the mice were tested by western blot. Immunofluorescence was applied to detect the expression of EPA1 and ROS in mice hippocampus. EPA1 knockdown was performed by an adeno-associated virus (AAV) vector containing EPA1-shRNA-EGFP infusion.
CUMS exposure induced depressive-like behaviors and increased the expression of EPA1 in the hippocampus. Knockdown hippocampal EPA1 ameliorated CUMS-induced depressive-like behaviors, decreased calcium (Ca) overload, decreased ROS generation and NOX2 expression, inhibited NLRP1 inflammasome-driven neuroinflammation, and restored the levels of BDNF, PSD95, GAP-43, SYN, and MAP-2 in the hippocampus.
EPA1 contributes to CUMS induced depressive-like behaviors and the mechanism may be related to NLRP1 inflammasome-driven inflammatory response, regulating calcium ion homeostasis and ROS generation, and alleviating synaptic function damage. This indicated that EPA1 may participate in the occurrence and development of depression.
抑郁症是一种常见的精神疾病，伴有焦虑和持续抑郁。内啡肽 A1（EPA1）是一种在突触末梢中丰富表达的脑特异性蛋白，主要在中枢神经系统中表达。有报道称，EPA1 参与神经递质的释放，这表明该蛋白可能与抑郁症有关。然而，EPA1 是否参与抑郁症的发生尚不清楚。
采用慢性不可预测轻度应激（CUMS）建立小鼠抑郁模型。通过蔗糖偏好测试（SPT）、强迫游泳测试（FST）、悬尾测试（TST）和旷场测试（OFT）检测抑郁样行为。通过苏木精和伊红染色（H&E）和尼氏染色检测神经元组织病理学。通过 Western blot 检测小鼠 EPA1、NLRP1 炎症复合物、NADPH 氧化酶 2（NOX2）和突触相关蛋白的表达。免疫荧光法检测小鼠海马 EPA1 和 ROS 的表达。通过含有 EPA1-shRNA-EGFP 的腺相关病毒（AAV）载体进行 EPA1 敲低。
CUMS 暴露诱导抑郁样行为，并增加海马 EPA1 的表达。敲低海马 EPA1 可改善 CUMS 诱导的抑郁样行为，减少钙（Ca）超载，减少 ROS 生成和 NOX2 表达，抑制 NLRP1 炎性小体驱动的神经炎症，并恢复海马 BDNF、PSD95、GAP-43、SYN 和 MAP-2 的水平。
EPA1 参与 CUMS 诱导的抑郁样行为，其机制可能与 NLRP1 炎性小体驱动的炎症反应有关，调节钙离子稳态和 ROS 生成，并缓解突触功能损伤。这表明 EPA1 可能参与抑郁症的发生和发展。
