Glial Glutamate and Metabolic Transporters as a Target for Neurodegenerative Therapy and Biomarkers

Abstract

Glial cells play a significant functional role in neuronal function and synaptic transmission and glial dysfunction contributes greatly to the development and progression of a large number of chronic and acute neurodegenerative disorders. Here, we report the importance of two glial plasma membrane transporter proteins, the astroglial glutamate/excitatory amino acid transporters (EAATs) and the oligodendroglial lactate/monocarboxylate transporters (MCTs), both of which have been shown to be dysregulated in disease. As action potentials invade presynaptic neuronal terminals, glutamate gets released into the synaptic cleft, where it binds and opens postsynaptic onotropic glutamate receptors. To limit excessive postsynaptic stimulation, glutamate is taken up by astrocytes through EAATs, a process coupled to Na⁺ uptake and increased Na⁺/K⁺ pump activity leading to an increased metabolic demand, i.e. the production of ATP. To enhance ATP generation, glucose is taken up from blood vessels into the astrocytes through glucose transporters. The astrocytes convert glucose to pyruvate and lactate , generating ATP through glycolysis. Lactate, the end product of glycolysis could diffuse through gap junctions to oligodendrocytes. Alternatively, oligodendrocytes might generate lactate through glycolysis after glucose uptake from the blood stream. Oligodendrocytes export lactate through MCT1 transporters upon which neurons can import lactate through lactate transporters and use as a metabolic substrate. Any imbalance of the glutamate and/or lactate homeostasis can lead to neuronal degeneration, as shown in a number of neurodegenerative disorders .