Figure 1.

Roles of ascorbic acid during synaptic activity and astrocyte-mediated recycling. (1) During synaptic activity glutamate released into the synaptic space is taken up by astrocytes, where it stimulates ascorbic acid release from these cells through different hypothesized mechanisms (after astrocyte swelling by VSOAC induced via GLAST glutamate-aspartate transporter; Connexin-hemichannels; or through exocytosis of secretion vesicles); (2) Astrocyte-released ascorbic acid is taken up by neurons through SVCT2; (3) It participates as a neuromodulator (glutamatergic and GABA-ergic neurotransmission); (4) Regulates neuronal metabolic substrate preference via specific GLUT3 inhibition (metabolic switch). Reactive oxidant species (ROS) produced during synaptic activity (5) and neuronal metabolism (6) oxidize ascorbic acid to DHAsc; (7) DHAsc is released from neurons and is taken up by astrocytes through glucose transporters (GLUTs); (8) Astrocytes can reduce oxidized ascorbic acid via direct reaction with glutathione o via glutathione-dependent reductases such as glutaredoxin and protein disulfide isomerase. AMPAR, (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptor; Asc, ascorbic acid; DHA, dehydroascorbic acid, oxidized ascorbic acid; EAAT, excitatory amino acid transporter; GABA (γ amino butyric acid); GLAST, (glutamate transporter in astrocytes); GLUT3, glucose transporter isoform 3; GSH, reduced gluthatione; GSSG, oxidized gluthatione; MCT, monocarboxylate transporter; ROS, reactive oxygen species; SVCT2, sodium-vitamin C transporter isoform 2; VSOAC, Volume-sensitive organic osmolyte-anion channel.