title: Transfer of glycogen-derived lactate from astrocytes to axons via specific monocarboxylate transporters supports mouse optic nerve activity.
abstract: It is hypothesized that L-lactate derived from astrocyte glycogen sustains axon excitability in mouse optic nerve (MON). This theory was tested by using a competitive antagonist of L-lactate transport and immunocytochemistry to determine whether transport proteins are appropriately distributed in adult MON. L-lactate sustained the compound action potential (CAP), indicating that exogenous L-lactate was an effective energy substrate. During 60 min of aglycemia, the CAP persisted for 30 min, surviving on a glycogen-derived substrate (probably lactate), before failing. After failing, the CAP could be partially rescued by restoring 10 mM glucose or 20 mM L-lactate. Aglycemia in the presence of 20 mM D-lactate, a metabolically inert but transportable monocarboxylate, resulted in accelerated CAP decline compared with aglycemia alone, suggesting that D-lactate blocked the axonal uptake of glycogen-derived L-lactate, speeding the onset of energy failure and loss of the CAP. The CAP was maintained for up to 2 hr when exposed to 20% of normal bath glucose (i.e., 2 mM). To test whether glycogen-derived L-lactate "supplemented" available glucose (2 mM) in supporting metabolism, L-lactate uptake into axons was reduced by the competitive inhibitor D-lactate. Indeed, in the presence of 20 mM D-lactate, the CAP was lost more rapidly in MONs bathed in 2 mM glucose artificial cerebrospinal fluid. Immunocytochemical staining demonstrated cell-specific expression of monocarboxylate transporter (MCT) subtypes, localizing MCT2 predominantly to axons and MCT1 predominantly to astrocytes, supporting the idea that L-lactate is released from astrocytes and taken up by axons as an energy source for sustaining axon excitability.
authors: Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
authors: Selva Baltan
authors: SB
authors: Tekkök
authors: Angus M
authors: AM
authors: Brown
authors: Ruth
authors: R
authors: Westenbroek
authors: Luc
authors: L
authors: Pellerin
authors: Bruce R
authors: BR
authors: Ransom
mesh_terms: D000200:Action Potentials; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001369:Axons / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009900:Optic Nerve / Q000378:metabolism*; D009924:Organ Culture Techniques; D013237:Stereoisomerism
chemical_list: D027501:Monocarboxylic Acid Transporters; D019344:Lactic Acid; D006003:Glycogen