Fig. 1.

This schematic depicts an excitatory synapse that is ensheathed by astrocytic processes in an asymmetrical manner, resulting in a greater distance between glial processes and neurons on the presynaptic aspect of the synapse. Glu release in response to synaptic activation quickly reaches a concentration in the synaptic cleft capable of stimulating low-affinity AMPA receptors (A) that are located proximal to the release sites, as well as laterally distributed high-affinity receptors including NMDA (N) and mGlu receptors (M). Diffusion and clearance by excitatory amino acid transporters (E) are thought to rapidly lower the levels of extracellular glutamate in the synaptic cleft. Glutamine (Glt) is released by astrocytes and is considered to be a critical substrate needed to replenish neuronal glutamate stores. In addition to glutamine, astrocytes are also capable of releasing glutamate. The illustration depicts system x_c⁻ (X), which exchanges cystine (C-C) and glutamate on a 1:1 stoichiometry, the direction of the exchange being determined by relative substrate concentration gradients. Glutamate release from system x_c⁻, which is also described as a cystine-glutamate exchanger or antiporter, has been shown to regulate synaptic neurotransmitter release by stimulating extrasynaptic glutamate receptors.