Role of Brain Glycogen During Ischemia, Aging and Cell-to-Cell Interactions

Abstract

The astrocyte-neuron lactate transfer shuttle (ANLS) is one of the important metabolic systems that provides a physiological infrastructure for glia-neuronal interactions where specialized architectural organization supports the function. Perivascular astrocyte end-feet take up glucose via glucose transporter 1 to actively regulate glycogen stores, such that high ambient glucose upregulates glycogen and low levels of glucose deplete glycogen stores. A rapid breakdown of glycogen into lactate during increased neuronal activity or low glucose conditions becomes essential for maintaining axon function. However, it fails to benefit axon function during an ischemic episode in white matter (WM). Aging causes a remarkable change in astrocyte architecture characterized by thicker, larger processes oriented parallel to axons, as opposed to vertically-transposing processes. Subsequently, aging axons become more vulnerable to depleted glycogen, although aging axons can use lactate as efficiently as young axons. Lactate equally supports function during aglycemia in corpus callosum (CC), which consists of a mixture of myelinated and unmyelinated axons. Moreover, axon function in CC shows greater resilience to a lack of glucose compared to optic nerve, although both WM tracts show identical recovery after aglycemic injury. Interestingly, emerging evidence implies that a lactate transport system is not exclusive to astrocytes, as oligodendrocytes support the axons they myelinate, suggesting another metabolic coupling pathway in WM. Future studies are expected to unravel the details of oligodendrocyte-axon lactate metabolic coupling to establish that all WM components metabolically cooperate and that lactate may be the universal metabolite to sustain central nervous system function.

Keywords: Ageing; Axon; Corpus callosum; D-lactate; End-feet; Ischemia; White matter.

Fig. 1

Schematic diagram of structural and functional components of the astrocyte-neuron lactate shuttle transport (ANLST) in WM. Astrocytes (purple) enwrap capillaries (red) with their end-feet to take up glucose via glucose transporter 1 (GLUT) to store it as glycogen and convert it to lactate via monocarboxylate transporter 1 (MCT1) when ambient glucose levels are low. Axons (blue) take up lactate via MCT2 to derive energy using their mitochondria

Fig. 2

Electrophysiological recording configuration of axon function. (a) Evoked compound action potentials (CAPs) in mouse optic nerve using suction electrodes display a typical three-peaked CAPs at 37 °C. Peaks denote most myelinated and faster-conducting (P1) to lightly myelinated, slow-conducting axons in order (P3). (b) Evoked CAPs in corpus callosum show two peaks using extracellular recording configuration at 34 °C. The first peak (P1) represents myelinated, while the second peak (P2) represent the unmyelinated axon response. Recording chambers were oxygenated with 95% O₂ + 5% CO₂

Fig. 3

Lactate cannot be used as a substrate during ischemia. (a) Time course of compound action potential (CAPs) area shows that following oxygen glucose deprivation (OGD), axon function recorded in MONs incubated in high (30 mM, purple) glucose declines faster than in MONs incubated in normal (10 mM, green) glucose, but both groups recover to similar levels following 60 min of OGD. (b) Histograms show that CAP area recovery is similar between the two groups and is independent of lactate availibility during OGD (60 min). Figure reproduced from Baltan 2015, Met. Brain Dis

Fig. 4

CC axons are more resilient to removal of glucose than MONs. (a) Exposing MONs (light green) and CC (dark green) to aglycemia (0 mM glucose for 60 min) shows a more rapid (green arrows) loss of axon function in MONs compared to CC (b), although axon function recovers to similar extent after aglycemia. (a, c) Interestingly, greater number of axons remain functional during aglycemia in CC (dark green histogram in c and asteriks in (a)). ∗∗p < 0.01

Fig. 5

Aging causes increase in astrocyte size and increased vulnerability to aglycemia in axon function. (a) GFAP (+) astrocytes (green) increase in size and display a horizontal orientation with age, while their nuclei remain the same size (Sytox (+) blue). Note the magnified images for compasion between young and aging astrocytes. (b, c) Aging axons (red line and red histogram) become more vulnerble to removal of glucose compared to young axons (green line and green histograms). ∗∗∗p < 0.001

Fig. 6

Aging axons use lactate as an alternative energy substrate as efficiently as young axons. (a, b) Replacing glucose (10 mM) with lactate (20 mM, carbon equivalent) fully sustains young axon function during aglycemia (blue line and blue histogram) compared to aglycemia (green line, green histogram). (c, d) Aging axons use lactate (yellow line, yellow histogram) when glucose is not available to fully maintain their function as opposed to aglucose (red line and red histogram). ∗∗p < 0.01, ∗∗∗p < 0.001