Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue.
Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue.
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DOI：
10.1177/0271678x221080324
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发表时间：
2022-09
影响因子：
6.3
通讯作者：
Chatton, Jean-Yves
中科院分区：
文献类型：
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作者：
Briquet, Marc;Rocher, Anne-Berengere;Alessandri, Maxime;Rosenberg, Nadia;Abrantes, Haissa de Castro;Wellbourne-Wood, Joel;Schmuziger, Celine;Ginet, Vanessa;Puyal, Julien;Pralong, Etienne;Daniel, Roy Thomas;Offermanns, Stefan;Chatton, Jean-Yves
乳酸可以被神经元用作能量底物来支持其活动。有证据表明，乳酸还作用于一种称为 HCAR1 的代谢受体，这种受体首先在脂肪组织中被描述。 HCAR1 是否也调节神经元回路仍不清楚。在这项研究中，我们使用 qRT-PCR 证明 HCAR1 存在于接受切除手术的癫痫患者的人脑中。在这些患者的脑切片中，使用非代谢激动剂药理 HCAR1 激活降低了自发神经元 Ca2+ 尖峰和兴奋性突触后电流 (sEPSC) 的频率。在小鼠大脑中，我们使用荧光报告小鼠系和原位杂交发现 HCAR1 在不同区域表达。在齿状回中，HCAR1 主要存在于苔藓细胞中，苔藓细胞是海马兴奋性回路的关键参与者，已知与颞叶癫痫有关。通过使用小鼠和大鼠切片中的全细胞膜片钳记录，我们发现 HCAR1 激活导致颗粒细胞（苔藓细胞的主要输出）的兴奋性、sEPSC 和微型 EPSC 频率降低。总的来说，我们认为乳酸可以被认为是一种神经调节剂，可以减少人类和啮齿动物大脑中的突触活动，这使得 HCAR1 成为癫痫治疗的一个有吸引力的靶点。
Lactate can be used by neurons as an energy substrate to support their activity. Evidence suggests that lactate also acts on a metabotropic receptor called HCAR1, first described in the adipose tissue. Whether HCAR1 also modulates neuronal circuits remains unclear. In this study, using qRT-PCR, we show that HCAR1 is present in the human brain of epileptic patients who underwent resective surgery. In brain slices from these patients, pharmacological HCAR1 activation using a non-metabolized agonist decreased the frequency of both spontaneous neuronal Ca2+ spiking and excitatory post-synaptic currents (sEPSCs). In mouse brains, we found HCAR1 expression in different regions using a fluorescent reporter mouse line and in situ hybridization. In the dentate gyrus, HCAR1 is mainly present in mossy cells, key players in the hippocampal excitatory circuitry and known to be involved in temporal lobe epilepsy. By using whole-cell patch clamp recordings in mouse and rat slices, we found that HCAR1 activation causes a decrease in excitability, sEPSCs, and miniature EPSCs frequency of granule cells, the main output of mossy cells. Overall, we propose that lactate can be considered a neuromodulator decreasing synaptic activity in human and rodent brains, which makes HCAR1 an attractive target for the treatment of epilepsy.