Emerging Roles for Glycogen in the CNS

Abstract

The ability of glycogen, the depot into which excess glucose is stored in mammals, to act as a source of rapidly available energy substrate, has been exploited by several organs for both general and local advantage. The liver, expressing the highest concentration of glycogen maintains systemic normoglycemia ensuring the brain receives a supply of glucose in excess of demand. However the brain also contains glycogen, although its role is more specialized. Brain glycogen is located exclusively in astrocytes in the adult, with the exception of pathological conditions, thus in order to benefit neurons, and energy conduit (lactate) is trafficked inter-cellularly. Such a complex scheme requires cell type specific expression of a variety of metabolic enzymes and transporters. Glycogen supports neural elements during withdrawal of glucose, but once the limited buffer of glycogen is exhausted neural function fails and irreversible injury ensues. Under physiological conditions glycogen acts to provide supplemental substrates when ambient glucose is unable to support function during increased energy demand. Glycogen also supports learning and memory where it provides lactate to neurons during the conditioning phase of in vitro long-term potentiation (LTP), an experimental correlate of learning. Inhibiting the breakdown of glycogen or intercellular transport of lactate in in vivo rat models inhibits the retention of memory. Our current understanding of the importance of brain glycogen is expanding to encompass roles that are fundamental to higher brain function.

Control of brain energy supply by astrocytes

“…To ensure that the fluctuating activity-dependent energy requirements of neurons are met, the brain has evolved 'neurovascular coupling' mechanisms to regulate energy supply, which increase the blood flow to regions where neurons are active -a response termed 'functional hyperaemia' [4]. Once delivered to an active area, glucose must then be successfully transferred from the blood to brain cells, where it is used to generate ATP, converted to other forms of energy substrate (such as lactate or glutamate) or converted to the storable energy reserve glycogen [5,6].…”

Astrocyte glycogen and lactate: New insights into learning and memory mechanisms

“…Reed, Ransom, & Brown, 2017), and, under conditions of high energy demand such as glucose deprivation or intense neural activity, can be catabolized to rapidly deliver metabolic substrates (i.e., pyruvate and lactate) (Brown & Ransom, 2015). Although neurons possess the enzymatic machinery to store and break down glycogen, under physiological conditions they suppress glycogen storage through a series of mechanisms.…”

Developmental maturation of activity‐induced K+ and pH transients and the associated extracellular space dynamics in the rat hippocampus

“…The nature of the pH transients led us to identify pH-regulating transporters, mainly the electrogenic Na + /bicarbonate cotransporter 1 (NBCe1) and the monocarboxylate transporters (MCTs), acting as mechanisms underlying a portion of the activity-evoked ECS shrinkage in rat hippocampal slices . The NBCe1 is activated by the K + -mediated cellular depolarization and the alkaline pH transient (Theparambil et al 2014;, whereas MCT is predicted to be activated by the K + -mediated increase in metabolism (Wender et al 2000;Choi et al 2012;Brown & Ransom, 2015;Waitt et al 2017). These findings suggest that K + clearance, pH changes and ECS shrinkage are linked but not directly coupled.…”

“…2012; Brown & Ransom, ; Waitt et al . ). These findings suggest that K + clearance, pH changes and ECS shrinkage are linked but not directly coupled.…”