Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Neuropsychopharmacology. 2022 Jul;47(8):1493-1502. doi: 10.1038/s41386-021-01232-x. Epub 2021 Nov 22.
Astrocytes provide structural and metabolic support of neuronal tissue, but may also be involved in shaping synaptic output. To further define the role of striatal astrocytes in modulating neurotransmission we performed in vivo microdialysis and ex vivo slice electrophysiology combined with metabolic, chemogenetic, and pharmacological approaches. Microdialysis recordings revealed that intrastriatal perfusion of the metabolic uncoupler fluorocitrate (FC) produced a robust increase in extracellular glutamate levels, with a parallel and progressive decline in glutamine. In addition, FC significantly increased the microdialysate concentrations of dopamine and taurine, but did not modulate the extracellular levels of glycine or serine. Despite the increase in glutamate levels, ex vivo electrophysiology demonstrated a reduced excitability of striatal neurons in response to FC. The decrease in evoked potentials was accompanied by an increased paired pulse ratio, and a reduced frequency of spontaneous excitatory postsynaptic currents, suggesting that FC depresses striatal output by reducing the probability of transmitter release. The effect by FC was mimicked by chemogenetic inhibition of astrocytes using G-coupled designer receptors exclusively activated by designer drugs (DREADDs) targeting GFAP, and by the glial glutamate transporter inhibitor TFB-TBOA. Both FC- and TFB-TBOA-mediated synaptic depression were inhibited in brain slices pre-treated with the dopamine D2 receptor antagonist sulpiride, but insensitive to agents acting on presynaptic glutamatergic autoreceptors, NMDA receptors, gap junction coupling, cannabinoid 1 receptors, µ-opioid receptors, P2 receptors or GABA receptors. In conclusion, our data collectively support a role for astrocytes in modulating striatal neurotransmission and suggest that reduced transmission after astrocytic inhibition involves dopamine.
星形胶质细胞为神经元组织提供结构和代谢支持，但也可能参与调节突触输出。为了进一步确定纹状体星形胶质细胞在调节神经递质传递中的作用，我们进行了体内微透析和离体脑片电生理学结合代谢、化学遗传学和药理学方法的研究。微透析记录显示，纹状体内灌注代谢解偶联剂氟柠檬酸（FC）可显著增加细胞外谷氨酸水平，并伴有谷氨酰胺的平行和渐进性下降。此外，FC 还显著增加了微透析液中多巴胺和牛磺酸的浓度，但没有调节细胞外甘氨酸或丝氨酸的水平。尽管谷氨酸水平升高，但离体电生理学显示 FC 引起的纹状体神经元兴奋性降低。诱发电位的下降伴随着成对脉冲比的增加和自发性兴奋性突触后电流频率的降低，表明 FC 通过降低递质释放的概率来抑制纹状体的输出。星形胶质细胞的化学遗传学抑制使用靶向 GFAP 的 G 蛋白偶联受体设计药物（DREADD）模拟了 FC 的作用，并且谷氨酸转运体抑制剂 TFB-TBOA 也模拟了 FC 的作用。在预先用多巴胺 D2 受体拮抗剂舒必利处理的脑片中，FC 和 TFB-TBOA 介导的突触抑制均可被抑制，但对作用于突触前谷氨酸能自身受体、NMDA 受体、缝隙连接偶联、大麻素 1 受体、µ-阿片受体、P2 受体或 GABA 受体的药物不敏感。总之，我们的数据共同支持星形胶质细胞在调节纹状体神经传递中的作用，并表明星形胶质细胞抑制后传递减少涉及多巴胺。
