Neuropharmacology Laboratory, School of Optometry, Université de Montréal, Montreal, QC H3T 1P1, Canada.
Department of Pediatrics, Research Center-CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada.
Cells. 2021 Jun 30;10(7):1640. doi: 10.3390/cells10071640.
During the development of the retina and the nervous system, high levels of energy are required by the axons of retinal ganglion cells (RGCs) to grow towards their brain targets. This energy demand leads to an increase of glycolysis and L-lactate concentrations in the retina. L-lactate is known to be the endogenous ligand of the GPR81 receptor. However, the role of L-lactate and its receptor in the development of the nervous system has not been studied in depth. In the present study, we used immunohistochemistry to show that GPR81 is localized in different retinal layers during development, but is predominantly expressed in the RGC of the adult rodent. Treatment of retinal explants with L-lactate or the exogenous GPR81 agonist 3,5-DHBA altered RGC growth cone (GC) morphology (increasing in size and number of filopodia) and promoted RGC axon growth. These GPR81-mediated modifications of GC morphology and axon growth were mediated by protein kinases A and C, but were absent in explants from transgenic mice. Living mice showed a decrease in ipsilateral projections of RGCs to the dorsal lateral geniculate nucleus (dLGN). In conclusion, present results suggest that L-lactate and its receptor GPR81 play an important role in the development of the visual nervous system.
在视网膜和神经系统的发育过程中，视网膜神经节细胞（RGCs）的轴突需要大量的能量来向大脑目标生长。这种能量需求导致视网膜中的糖酵解和 L-乳酸浓度增加。已知 L-乳酸是 GPR81 受体的内源性配体。然而，L-乳酸及其受体在神经系统发育中的作用尚未得到深入研究。在本研究中，我们使用免疫组织化学方法显示，GPR81 在发育过程中定位于不同的视网膜层，但在成年啮齿动物的 RGC 中主要表达。用 L-乳酸或外源性 GPR81 激动剂 3,5-DHBA 处理视网膜外植体改变了 RGC 生长锥（GC）的形态（大小增加，丝状伪足增多），并促进了 RGC 轴突生长。这些 GPR81 介导的 GC 形态和轴突生长的改变是通过蛋白激酶 A 和 C 介导的，但在转基因小鼠的外植体中不存在。活体小鼠显示同侧 RGC 向背外侧膝状体核（dLGN）的投射减少。总之，目前的结果表明，L-乳酸及其受体 GPR81 在视觉神经系统的发育中发挥重要作用。
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