Neuronal vs glial glutamate uptake: Resolving the conundrum

• A review of expression of glutamate transporters in neurons.
• EAAT2 accounts for 95% of Glu uptake activity and 1% of forebrain protein.
• Most of EAAT2 is in glia, but a small proportion is present in terminals.
• EAAT3 in neuronal cell bodies and dendrites, and EAAT2 in axon-terminals.
• Synaptosome preparations measure mostly neuronal EAAT2.

Neither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that both astrocytes and neurons express glutamate transporters. However the relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) a hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox.