Cannabidiol ameliorates cognitive decline in 5×FAD mouse model of Alzheimer’s disease through potentiating the function of extrasynaptic glycine receptors

IF 9.6 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Psychiatry Pub Date : 2024-10-12 DOI:10.1038/s41380-024-02789-x

Jin Jin, Chonglei Fu, Jing Xia, Heyi Luo, Xianglian Wang, Si Chen, Huanhuan Mao, Kai Yuan, Lin Lu, Wei Xiong, Guichang Zou

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Abstract

Emerging evidence supports the therapeutic potential of cannabinoids in Alzheimer’s disease (AD), but the underlying mechanism upon how cannabinoids impact brain cognition and AD pathology remains unclear. Here we show that chronic cannabidiol (CBD) administration significantly mitigates cognitive deficiency and hippocampal β-amyloid (Aβ) pathology in 5×FAD mouse model of AD. CBD achieves its curative effect mainly through potentiating the function of inhibitory extrasynaptic glycine receptor (GlyR) in hippocampal dentate gyrus (DG). Based on the in vitro and in vivo electrophysiological recording and calcium imaging, CBD mediated anti-AD effects via GlyR are mainly accomplished by decreasing neuronal hyperactivity of granule cells in the DG of AD mice. Furthermore, the AAV-mediated ablation of DG GlyRα1, or the GlyRα1^S296A mutation that exclusively disrupts CBD binding, significantly intercepts the anti-AD effect of CBD. These findings suggest a GlyR dependent mechanism underlying the therapeutic potential of CBD in the treatment of AD.

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大麻二酚通过增强突触外甘氨酸受体的功能改善 5×FAD 阿尔茨海默病小鼠模型的认知功能下降

越来越多的证据支持大麻素对阿尔茨海默病（AD）的治疗潜力，但大麻素如何影响大脑认知和阿尔茨海默病病理的基本机制仍不清楚。在这里，我们发现长期服用大麻二酚（CBD）可明显缓解 5×FAD 阿尔茨海默病小鼠模型的认知缺陷和海马β-淀粉样蛋白（Aβ）病理变化。CBD 主要通过增强海马齿状回（DG）抑制性突触外甘氨酸受体（GlyR）的功能来达到治疗效果。根据体外和体内电生理记录和钙成像，CBD通过GlyR介导的抗AD作用主要是通过降低AD小鼠DG中颗粒细胞的神经元过度活跃来实现的。此外，AAV 介导的 DG GlyRα1 消融或 GlyRα1S296A 突变（专门破坏 CBD 的结合）可显著阻断 CBD 的抗 AD 作用。这些研究结果表明，CBD 在治疗注意力缺失症方面的治疗潜力是一种依赖于 GlyR 的机制。

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来源期刊

Molecular Psychiatry 医学-精神病学

CiteScore

20.50

自引率

4.50%

发文量

459

审稿时长

4-8 weeks

期刊介绍： Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.