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对背侧海马CA1区星形胶质细胞活化的抑制改善脂多糖诱导的小鼠认知损伤

井思琪¹, 章颖², 史威国², 仝坤³, 孔贯祥^2,*

¹徐州医科大学基础医学院，徐州 221000；²沭阳县中医院麻醉科，沭阳 223600；³ 徐州医科大学附属医院麻醉科，徐州 221000

摘要

本文旨在探讨对背侧海马CA1 (dorsal hippocampal CA1, dCA1)区星形胶质细胞活化的抑制是否可以改善脂多糖(lipopolysaccharide, LPS)诱导的小鼠认知损伤。小鼠腹腔注射LPS 建立认知损伤模型，并接受腹腔注射雷帕霉素或dCA1 区星形胶质细胞的化学遗传学抑制，用行为学实验检测小鼠活动度和认知能力，用免疫荧光染色法观察小鼠dCA1 区胶质纤维酸性蛋白(glial fibrillary acidic protein, GFAP)、神经元即刻早期基因编码的蛋白c-Fos 及γ-氨基丁酸(γ-aminobutyric acid,GABA)的表达。结果显示，与对照组相比，LPS组小鼠活动度无明显改变，恐惧记忆能力显著下降，dCA1 区GFAP表达上调，而c-Fos 与GABA共表达神经元数量显著下降；雷帕霉素显著缓解LPS 处理小鼠恐惧记忆损伤，下调dCA1 区GFAP表达，提高c-Fos 与GABA共表达神经元数目；用化学遗传学抑制dCA1 区星形胶质细胞可显著缓解LPS处理小鼠恐惧记忆损伤。上述结果提示，LPS可诱导dCA1 区星形胶质细胞活化，使GABA能神经元活性下降，损伤小鼠认知能力，而雷帕霉素或化学遗传学可通过抑制dCA1区星形胶质细胞活化改善神经炎症诱导的认知损伤。

关键词： 雷帕霉素; 海马星形胶质细胞; GABA能神经元; 认知损伤

Inhibition of activation of astrocytes in dorsal hippocampal CA1 relieves lipopolysaccharide-induced cognitive impairment

JING Si-Qi¹, ZHANG Ying², SHI Wei-Guo², TONG Kun³, KONG Guan-Xiang^2,*

¹School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou 221000, China；²Department of Anesthesiology, Shuyang Hospital of Traditional Chinese Medicine, Shuyang 223600, China；³Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China

Abstract

This study aimed to investigate whether inhibiting the activation of astrocytes in the dorsal hippocampal CA1 (dCA1) region could ameliorate lipopolysaccharide (LPS)-induced cognitive impairment in mice. Mice were intraperitoneally injected with LPS to establish a cognitive impairment model, and received intraperitoneal injection of rapamycin or chemogenetic inhibition of astrocytes in the dCA1 region. Behavioral experiments were used to detect activity and cognitive ability of mice. Immunofluorescence staining was employed to detect the expression of glial fibrillary acidic protein (GFAP), neuronal immediate early gene protein c-Fos, and γ-aminobutyric acid (GABA) in the dCA1 region of mice. The results showed that, compared with the control group, the LPS group exhibited no significant change in locomotor activity but a marked decrease in fear memory. Meanwhile, GFAP expression in the dCA1 was up-regulated, while the number of neurons co-expressing c-Fos and GABA was significantly reduced. Rapamycin significantly alleviated LPS-induced fear memory impairment, down-regulated GFAP expression in the dCA1 region, and increased the number of c-Fos/GABA co-expressing neurons. Additionally, chemogenetic inhibition of astrocytes in the dCA1 remarkably mitigated fear memory impairment in LPS-treated mice. These findings suggest that LPS can induce astrocyte activation in the dCA1 region, reduce the activity of GABAergic neurons, and impair cognitive function in mice. Intraperitoneal injection of rapamycin or chemogenetics can improve neuroinflammation-induced cognitive impairment by inhibiting the activation of dCA1 astrocytes.

Key words: Rapamycin; hippocampal astrocytes; GABAergic neurons; cognitive impairment

收稿日期：　　录用日期：

通讯作者：孔贯祥　　E-mail:

DOI: 10.13294/j.aps.2025.0096

引用本文：

井思琪, 章颖, 史威国, 仝坤, 孔贯祥. 对背侧海马CA1区星形胶质细胞活化的抑制改善脂多糖诱导的小鼠认知损伤[J]. 生理学报 2025; 77 (6): 1148-1156.

JING Si-Qi, ZHANG Ying, SHI Wei-Guo, TONG Kun, KONG Guan-Xiang. Inhibition of activation of astrocytes in dorsal hippocampal CA1 relieves lipopolysaccharide-induced cognitive impairment. Acta Physiol Sin 2025; 77 (6): 1148-1156 (in Chinese with English abstract).