FIG. 6.

Schematic representation of key events related to AA cycling at a tripartite synapse involving the presynaptic terminal, the postsynaptic spine, and an astrocyte. Release of glutamate (Glu) activates receptors (GluR) both inside and outside the synaptic cleft. The released Glu is cleared by glutamate transporter 1 (GLT1) on the adjacent astrocyte. This promotes the release of AA by heteroexchange involving GLT1 directly or activation of an intervening mechanism on the astrocyte. Events within the dashed lines indicate the presumed relationship between Glu uptake by GLT1 and AA release. It is possible that another source of AA release is a GLT1 isoform on the presynaptic terminal, but the significance of presynaptic GLT1 requires further investigation. Extracellular AA is taken up by SVCT2 on the presynaptic terminal or binds to GluR to modulate neuronal excitability. Fully oxidized AA in the form of dehydroascorbate (DHAA) is recycled back to AA in the astrocyte by glutathione (GSH), an intracellular antioxidant, which itself is oxidized to oxidized glutathione (GSSH). Glu in the astrocyte is either converted to glutamine (Gln) for conversion back to Glu in the presynaptic terminal or released by Xc⁻ in exchange for cystine, which is used to synthesize GSH. The protein(s) responsible for AA efflux is (are) unknown and could include GLT1 itself, reverse operation of SVCT2, or another protein.