Glycogen Regulation and Functional Role in Mouse White Matter

Abstract

CNS glycogen, contained predominantly in astrocytes, can be converted to a monocarboxylate and transported to axons as an energy source during aglycaemia. We analysed glycogen regulation and the role of glycogen in supporting neural activity in adult mouse optic nerve, a favourable white matter preparation. Axon function was quantified by measuring the compound action potential (CAP) area. During aglycaemia, axon function persisted for 20 min, then declined in conjunction with glycogen content. Lactate fully supported CAPs in the absence of glucose, but was unable to sustain glycogen content; thus, axon failure occurred rapidly when lactate was withdrawn. Glycogen content in the steady state was directly proportional to bath glucose concentration. Increasing [K + ] o to 10 mM caused a rapid decrease in glycogen content. Latency to onset of CAP failure during aglycaemia was directly proportional to glycogen content and varied from about 2 to 30 min. Intense neural activity reduced glycogen content in the presence of 10 mM bath glucose and CAP area gradually declined. CAP area declined more rapidly during high frequency stimulation if monocarboxylate transport was inhibited. This suggested that astrocytic glycogen was broken down to a monocarboxylate(s) that was used by rapidly discharging axons. Likewise, depleting glycogen by brief periods of high frequency axon stimulation accelerated onset of CAP decline during aglycaemia. In summary, these experiments indicated that glycogen content was under dynamic control and that glycogen was used to support the energy needs of CNS axons during both physiological as well as pathological processes.

Impairment in Long-Term Memory Formation and Learning-Dependent Synaptic Plasticity in Mice Lacking Glycogen Synthase in the Brain

“…Nevertheless, glycogenolysis also occurs in euglycemia during an increase in neuronal activity, indicating that brain glycogen also has a role in supporting neuronal function in nonpathologic condition. [1][2][3][4] In this regard, glycogen concentration seems to be more conspicuous in areas of high synaptic density. 5,6 It has been proposed that the importance of brain glycogen lies in the rapidity of its breakdown compared with the uptake of extracellular glucose.…”

Functions of optic nerve glia: axoglial signalling in physiology and pathology

“…Removal of glucose, such as that which might occur when blood supply is compromised, results in an irreversible loss of optic nerve function, but astrocyte glycogen can support axonal function in the absence of glucose. [60][61][62][63] Glycogen is the single largest energy reserve in the brain and is localised entirely in astrocytes, which break it down to lactate, for transfer to axons. [60][61][62][63] Glycogen turnover is rapid and coordinated with optic nerve activity, 63 possibly via the activitydependent increase in [K þ ] o or glutamate, which are directly related to axonal activity (Figure 3g), 55 and mediate a Ca 2 þ -dependent glycogen breakdown.…”

A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells

“…Although some papers report that lactate supports neuronal activity in the absence of glucose in CA1 (Schurr et al, 1988;Izumi et al, 1994Izumi et al, , 1997 and optic nerve (Brown et al, 2003), others find that although lactate helps to maintain ATP levels, it does not allow normal neuronal activity in CA1 (Chih et al, 2001a) and CA3 (Takata and Okada, 1995;Wada et al, 1998). Lactate is converted into pyruvate, which produces ATP via oxidative phosphorylation (Fig.…”

“…It has been suggested (but see Chih et al, 2001b) that neuronal activity-evoked glycolysis (Pellerin et al, 1998;Magistretti and Pellerin, 1999) or almost all glycolysis (Sibson et al, 1998) is in glia, which export lactate to neurons as a substrate for their mitochondria. Because neurons consume most brain energy (Attwell and Laughlin, 2001), this lactate export might explain how the main energy store of the brain (assumed to be glial glycogen) (Gruetter, 2003;Brown, 2004) could sustain the activity of the neurons during energy deprivation, but no information is available on which CNS energy stores delay the occurrence of the AD.…”