Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter

We tested the hypothesis that astrocytic glycogen sustains axon function du ring and enhances axon survival after 60 min of glucose deprivation. Axon f unction in the rat optic nerve (RON), a CNS white matter tract, was monitor ed 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 similar to 30 min, after which the CAP rapidly failed. Exposur e to glucose-free aCSF for 60 min caused irreversible injury, which was mea sured as incomplete recovery of the CAP. Glycogen content of the RON fell t o 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 norepi nephrine pretreatment decreased the latency to CAP failure and reduced CAP recovery. To determine whether lactate represented the fuel derived from gl ycogen and shuttled to axons, we used the lactate transport blockers querce tin, 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. T he 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 fu el.