Participation of L-Lactate and Its Receptor HCAR1/GPR81 in Neurovisual Development

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.

Prevention of Cell Death by Activation of Hydroxycarboxylic Acid Receptor 1 (GPR81) in Retinal Explants

“…We also found an overall improvement in retinal viability in response to 3,5-DHBA agonist treatment. These findings are consistent with a previous study showing increased RGC growth in retinal explants from WT mice treated with lactate or 3,5-DHBA, which were not observed in HCA 1 R KO mice [34]. The neurogenesis effect of HCA 1 R has also been established in the cerebral ventricular and sub-ventricular zones of WT mice compared to HCA 1 R KO mice [12].…”

“…Theoretically, a decrease in cAMP would lead to reduced protein kinase A, which usually facilitates the release of glutamate through an intracellular calcium increase [56]. Protein kinase A, as well as C, have been shown to mediate axon growth in the retina, whereas these effects were absent in retinas from HCA 1 R −/− transgenic mice [34]. Moreover, the HCA 1 R ligand lactate has been shown to increase Müller glia uptake of glutamate [21].…”

“…Activation of HCA 1 R has recently also been shown to promote RGC axonal growth [33,34], suggesting that HCA 1 R may play an important role in development and preservation of the visual nervous system. However, the specific processes involved are yet to be elucidated.…”

Evolutionary View on Lactate-Dependent Mechanisms of Maintaining Cancer Cell Stemness and Reprimitivization

“…Lactate has important functions in the nervous system. The extensive investigations of GPR81’s functions in the brain and retina have revealed many new mechanisms of the action of lactate and its role as a signaling molecule in the processes of angiogenesis in the nervous system, the regulation of neuronal excitation, and neuroprotection [ 50 , 51 ].…”

Evolutionary View on Lactate-Dependent Mechanisms of Maintaining Cancer Cells Stemness and Reprimitivization 

“…Lactate has important functions in the nervous system. The recent discovery of extensive expression of GPR81 in the brain and retina has revealed many new mechanisms of action of lactate and its role as a signaling molecule in the processes of angiogenesis in the nervous system, regulation of neuronal excitation, and neuroprotection [34,35].…”