Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter.
We tested the hypothesis that astrocytic glycogen sustains axon function during and enhances axon survival after 60 min of glucose deprivation. Axon function in the rat optic nerve (RON), a CNS white matter tract, was monitored by measuring the area of the stimulus-evoked compound action potential (CAP). Switching to glucose-free artificial CSF (aCSF) had no effect on the CAP area for approximately 30 min, after which the CAP rapidly failed. Exposure to glucose-free aCSF for 60 min caused irreversible injury, which was measured as incomplete recovery of the CAP. Glycogen content of the RON fell to a low stable level 30 min after glucose withdrawal, compatible with rapid use in the absence of glucose. An increase of glycogen content induced by high-glucose pretreatment increased the latency to CAP failure and improved CAP recovery. Conversely, a decrease of glycogen content induced by norepinephrine pretreatment decreased the latency to CAP failure and reduced CAP recovery. To determine whether lactate represented the fuel derived from glycogen and shuttled to axons, we used the lactate transport blockers quercetin, alpha-cyano-4-hydroxycinnamic acid (4-CIN), and p-chloromercuribenzene sulfonic acid (pCMBS). All transport blockers, when applied during glucose withdrawal, decreased latency to CAP failure and decreased CAP recovery. The inhibitors 4-CIN and pCMBS, but not quercetin, blocked lactate uptake by axons. These results indicated that, in the absence of glucose, astrocytic glycogen was broken down to lactate, which was transferred to axons for fuel.
Wender
R
R
Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Brown
A M
AM
Fern
R
R
Swanson
R A
RA
Farrell
K
K
Ransom
B R
BR
D002731:4-Chloromercuribenzenesulfonate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D001692:Biological Transport / Q000187:drug effects; D002470:Cell Survival; D003373:Coumaric Acids / Q000494:pharmacology; D003470:Culture Media / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006003:Glycogen / Q000378:metabolism*; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D009900:Optic Nerve / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D011930:Reaction Time / Q000187:drug effects
D003373:Coumaric Acids; D003470:Culture Media; D004791:Enzyme Inhibitors; C007175:alpha-cyano-4-hydroxycinnamate; D019344:Lactic Acid; D002731:4-Chloromercuribenzenesulfonate; D006003:Glycogen; D011794:Quercetin; D005947:Glucose