Does shuttling of glycogen‐derived lactate from astrocytes to neurons take place during neurotransmission and memory consolidation?

Abstract

Glycogen levels in resting brain and its utilization rates during brain activation are high, but the functions fulfilled by glycogenolysis in living brain are poorly understood. Studies in cultured astrocytes have identified glycogen as the preferred fuel to provide ATP for Na+,K+‐ATPase for the uptake of extracellular K+ and for Ca2+‐ATPase to pump Ca2+ into the endoplasmic reticulum. Studies in astrocyte–neuron co‐cultures led to the suggestion that glycogen‐derived lactate is shuttled to neurons as oxidative fuel to support glutamatergic neurotransmission. Furthermore, both knockout of brain glycogen synthase and inhibition of glycogenolysis prior to a memory‐evoking event impair memory consolidation, and shuttling of glycogen‐derived lactate as neuronal fuel was postulated to be required for memory. However, lactate shuttling has not been measured in any of these studies, and procedures to inhibit glycogenolysis and neuronal lactate uptake are not specific. Testable alternative mechanisms to explain the observed findings are proposed: (i) disruption of K+ and Ca2+ homeostasis, (ii) release of gliotransmitters, (iii) imposition of an energy crisis on astrocytes and neurons by inhibition of mitochondrial pyruvate transport by compounds used to block neuronal monocarboxylic acid transporters, and (iv) inhibition of astrocytic filopodial movements that secondarily interfere with glutamate and K+ uptake from the synaptic cleft. Evidence that most pyruvate/lactate derived from glycogen is not oxidized and does not accumulate suggests predominant glycolytic metabolism of glycogen to support astrocytic energy demands. Sparing of blood‐borne glucose for use by neurons is a reasonable explanation for the requirement for glycogenolysis in neurotransmission and memory processing.

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

“…Astroglial lactate production, especially that derived from glycogen (i.e., glycogenolysis), has been implicated in the formation of long‐term memory . The exact mechanism by which lactate consolidates memories has not been elucidated and remains somewhat controversial . Several experiments support the idea that lactate produced in astroglia may serve as an energy source for neuronal synapse remodeling and gene expression, but not for the TCA cycle .…”

Aspects of astrocytic cAMP signaling with an emphasis on the putative power of compartmentalized signals in health and disease

“…As noted above, the two β receptors evoke clearly compartmentalized cAMP signals in cardiac myocytes (Nikolaev et al, ). On a final note, it should be pointed out that lactate transfer might not be the explanation for astrocytic support of synaptic plasticity but rather that the breakdown of glycogen in astrocytes spares extracellular/blood‐borne glucose for neuronal use, as suggested recently by Dienel ().…”

The “protected” glucose transport through the astrocytic endoplasmic reticulum is too slow to serve as a quantitatively‐important highway for nutrient delivery

“…The notion of lactate shuttling has many serious shortcomings that invalidate its importance in brain energetics in vivo (reviewed by [Ashrafi & Ryan, ; Dienel, , , ; Yellen, ]). For example, activated neurons in brain slices and in vivo consume more glucose, not extracellular lactate derived from either glucose or glycogen (Diaz‐Garcia et al, ; Diaz‐Garcia & Yellen, ).…”

“…Thus, increased neuronal utilization of glucose is important for neuronal functions, presumably because in neurons glycolytic ATP preferentially supports specific processes enhanced by activation, for example, Na + , K + ‐ATPase activity (DiNuzzo, Giove, Maraviglia, & Mangia, ), loading neurotransmitter glutamate into synaptic vesicles (Ueda, ), and synaptic vesicle recycling (Ashrafi et al, ; Rangaraju, Calloway, & Ryan, ), and glucose provides neurons with Glc‐6‐P for their pentose phosphate shunt pathway to manage oxidative stress. The importance of neuronal and astrocytic glycolysis compared with oxidation in all cells during activation in vivo is underscored by the disproportionate upregulation of glucose and glycogen metabolism compared with oxygen consumption by all cells (CMR O2 ) (reviewed in [Dienel, , , ]). If lactate produced by astrocytic non‐oxidative metabolism of glucose were a major neuronal fuel, the rise in CMR O2 would stoichiometrically match that of CMR glc .…”

“…The notion of lactate shuttling has many serious shortcomings that invalidate its importance in brain energetics in vivo (reviewed by Dienel, 2017Dienel, , 2019aDienel, , 2019bYellen, 2018]).…”