Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
Int J Mol Sci. 2024 Jan 1;25(1):581. doi: 10.3390/ijms25010581.
Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting habitual learning. The aim of this study was to outline the role of astrocytes in regulating eCB signaling in the DLS. To this end, we employed electrophysiological slice recordings combined with metabolic, chemogenetic and pharmacological approaches in an attempt to selectively suppress astrocyte function. High-frequency stimulation induced eCB-mediated LTD (HFS-LTD) in brain slices from both male and female rats. The metabolic uncoupler fluorocitrate (FC) reduced the probability of transmitter release and depressed synaptic output in a manner that was independent on cannabinoid 1 receptor (CB1R) activation. Fluorocitrate did not affect the LTD induced by the CB1R agonist WIN55,212-2, but enhanced CB1R-dependent HFS-LTD. Reduced neurotransmission and facilitated HFS-LTD were also observed during chemogenetic manipulation using Gi-coupled DREADDs targeting glial fibrillary acidic protein (GFAP)-expressing cells, during the pharmacological inhibition of connexins using carbenoxolone disodium, or during astrocytic glutamate uptake using TFB-TBOA. While pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) failed to prevent synaptic depression induced by FC, it blocked the facilitation of HFS-LTD. While the lack of tools to disentangle astrocytes from neurons is a major limitation of this study, our data collectively support a role for astrocytes in modulating basal neurotransmission and eCB-mediated synaptic plasticity.
星形胶质细胞对于突触传递至关重要，并且可能在突触可塑性的诱导和表达中发挥作用，包括内源性大麻素介导的长时程抑制（eCB-LTD）。在背外侧纹状体（DLS）中，内源性大麻素信号在平衡兴奋和抑制以及促进习惯学习中起主要作用。本研究旨在概述星形胶质细胞在调节 DLS 中的内源性大麻素信号中的作用。为此，我们采用电生理切片记录技术，结合代谢、化学遗传学和药理学方法，试图选择性地抑制星形胶质细胞功能。高频刺激（HFS）在雄性和雌性大鼠的脑片中诱导内源性大麻素介导的 LTD（HFS-LTD）。代谢解偶联剂氟柠檬酸（FC）降低了递质释放的概率，并以不依赖于大麻素 1 型受体（CB1R）激活的方式抑制突触输出。氟柠檬酸不影响 CB1R 激动剂 WIN55,212-2 诱导的 LTD，但增强了 CB1R 依赖性 HFS-LTD。在使用靶向胶质纤维酸性蛋白（GFAP）表达细胞的 Gi 偶联 DREADD 进行化学遗传学操作、使用 carbenoxolone disodium 抑制连接蛋白或使用 TFB-TBOA 抑制星形胶质细胞谷氨酸摄取期间，也观察到神经传递减少和 HFS-LTD 易化。虽然 NMDA 受体拮抗剂 2-氨基-5-磷戊酸（APV）预处理不能防止 FC 诱导的突触抑制，但它阻断了 HFS-LTD 的易化。尽管缺乏分离神经元和星形胶质细胞的工具是本研究的一个主要局限性，但我们的数据共同支持星形胶质细胞在调节基础神经传递和内源性大麻素介导的突触可塑性中的作用。
