A novel relationship between creatine transport at the blood-brain and blood-retinal barriers, creatine biosynthesis, and its use for brain and retinal energy homeostasis.

Evidence is increasing that the creatine/phosphocreatine shuttle system plays an essential role in energy homeostasis in the brain and retina to ensure proper development and function. Thus, our understanding of the mechanism of creatine supply and creatine usage in the brain and retina and of creatine supplementation in patients with creatine deficiency syndromes is an important step towards improved therapeutic strategies for brain and retinal disorders. Our recent research provides novel molecular-anatomical evidence that (i) at the blood-brain barrier and the inner blood-retinal barrier, the creatine transporter (CRT/SLC6AS) functions as a major pathway for supplying creatine to the brain and retina, and that (ii) local creatine is preferentially synthesized in the glial cells, e.g., oligodendrocytes, astrocytes, and Müller cells, in the brain and retina. Thus, the blood-brain barrier and inner blood-retinal barrier play important roles not only in supplying energy sources (glucose and lactate), but also in supplying an energy 'buffer' (creatine). These findings lead to the novel insight that the creatine/phosphocreatine shuttle system is based on an intricate relationship between the blood-brain barrier, inner blood-retinal barrier, glia, and neurons (photoreceptor cells) to maintain and ensure energy homeostasis in the brain and retina.