Transfer of glycogen-derived lactate from astrocytes to axons via specific monocarboxylate transporters supports mouse optic nerve activity.
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.
Tekkök
Selva Baltan
SB
Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
Brown
Angus M
AM
Westenbroek
Ruth
R
Pellerin
Luc
L
Ransom
Bruce R
BR
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
D027501:Monocarboxylic Acid Transporters; D019344:Lactic Acid; D006003:Glycogen