Abstract
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 gpr81−/− transgenic mice. Living gpr81−/− 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.
Highlights
The physiological significance of lactic acid and its conjugate base lactate have been a major source of controversy since their discovery in biological tissues
GPR81 protein immunoreactivity was consistently detected in the Outer Nuclear Layer (ONL), Inner Nuclear Layer (INL), Inner Plexiform Layer (IPL), retinal ganglion cells (RGCs), and the RGC fiber layer of hamsters (Figure 1A–C)
The colocalization of GPR81 with the specific RGC marker Brn-3a showed that GPR81 is predominantly expressed in RGCs and
Summary
The physiological significance of lactic acid and its conjugate base lactate have been a major source of controversy since their discovery in biological tissues. Occurring as the L-enantiomer in physiological conditions, lactate is known to have multiple effects on cell homeostasis, serving as a metabolic fuel and buffering agent, while acting as a signaling molecule, known as “Lactormone”. This signaling action is obtained via the hydroxycarboxylic acid receptor 1 (HCAR1) [1,2]. Known as GPR81, this is a G-protein-coupled receptor activated by L-lactate and the exogenous agonist 3,5dihydroxybenzoic acid (3,5-DHBA) [3]. GPR81 is expressed in diverse organs, including adipose tissues, skeletal muscle, liver, kidney, brain, and retina [4,5]
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