The Role of Brain Glycogen in Supporting Physiological Function

Abstract

Glycogen is present in the mammalian brain but occurs at concentrations so low it is unlikely to act as a conventional energy reserve. Glycogen has the intriguing feature of being located exclusively in astrocytes, but its presence benefits neurones, suggesting that glycogen is metabolized to a conduit that is transported between the glia and neural elements. In the rodent optic nerve model glycogen supports axon conduction in the form of lactate to supplement axonal metabolism during aglycemia, hypoglycemia and during periods of increased energy demand under normoglycemic conditions. In the hippocampus glycogen plays a vital role in supplying the neurones with lactate during memory formation. The physiological processes that glycogen supports, such as learning and memory, imply an inclusive and vital role in supporting physiological brain functions.

Keywords: glucose; glycogen; lactate; memory; optic nerve.

FIGURE 1

Morphological and metabolic compartmentalization in the honeybee retina. The glial components take up glucose, which is ultimately converted to alanine. The alanine is then shuttled to the photoreceptors where it is oxidatively metabolized. Such a scheme serves as a template for the lactate shuttling present in the mammalian CNS.

FIGURE 2

The astrocyte-neuron lactate shuttle hypothesis (ANLSH). In this scheme glutamate released at the synapse is taken up by Na⁺ coupled glutamate transporters (1). The glutamate is converted by glutaminase to glutamine, an ATP requiring reaction (3), with the glutamine transported to the presynaptic terminal as an inert compound that will not cause excitotoxicity. The Na⁺ that is transported with the glutamate is pumped out of the astrocyte by the energy requiring Na⁺ pump (2). The uptake of glutamate triggers glucose uptake into the astrocyte, which is glycolytically converted to lactate, producing two molecules of ATP. These ATP fuel the re-equilibration after glutamate uptake and the lactate is shuttled to the neurones for oxidative metabolism.

FIGURE 3

Glycogen content dictates latency to CAP failure in the MON model. (A) In MONs pre-incubated in 10 mM glucose (straight line), the CAP starts to fail at about 20 min after introducing 0 mM glucose aCSF, i.e., simulated aglycaemia, and falls rapidly to zero in the continued presence of aglycemia. In nerves pre-incubated for 2 h in increasing concentrations of glucose (circle – 15 mM, triangle – 20 mM, square – 30 mM), the latency to CAP failure increased in line with the glucose concentration. (B) There is a linear relationship between glycogen content (pmole μg protein^–1) at the onset of aglycemia and latency to CAP failure.

FIGURE 4

The ability of the MON to conduct CAPs is determined by the balance between tissue and energy demand and supply of substrate to the nerve. In MONs supplied with 10 mM glucose the imposition of 100 Hz stimulus causes the CAP area to fall. However replacing 10 mM glucose with 30 mM glucose in the aCSF restores the CAP to its full area. The horizontal bars indicate the glucose concentration present in the aCSF.

FIGURE 5

The combination of recording the stimulus evoked CAP (triangle) with real time recordings of lactate (black line) allow for a fuller picture of the cellular interactions to emerge. (A) At the onset of aglycemia the lactate falls almost immediately followed by the CAP. (B) Glucose is taken up by astrocytes and either stored as glycogen or directly processed glycolytically to lactate. The lactate is then transported to the axons for oxidative metabolism. Removing glucose from the aCSF or inhibiting glycogen metabolism with DAB or isofagomine causes the lactate to rapidly fall to zero followed by the CAP.

FIGURE 6

Glycogen metabolism underlies memory consolidation. Glycogen, located in astrocytes in the hippocampus, is metabolized to lactate, which is transported to the pre and postsynaptic terminals, where it fulfils separate roles, being converted to glutamate in the presynaptic terminal, and aiding consolidation in the postsynaptic terminal.