Ambient but not local lactate underlies neuronal tolerance to prolonged glucose deprivation.

Courtney Sobieski,Hong-Jin Shu,Steven Mennerick,Natasha Warikoo

doi:10.1371/journal.pone.0195520

Courtney Sobieski, Hong-Jin Shu + Show 2 more

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https://doi.org/10.1371/journal.pone.0195520

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Journal: PloS one	Publication Date: Apr 4, 2018
Citations: 10	License type: CC BY 4.0

Affiliation: Washington University in St. Louis

Abstract

Neurons require a nearly constant supply of ATP. Glucose is the predominant source of brain ATP, but the direct effects of prolonged glucose deprivation on neuronal viability and function remain unclear. In sparse rat hippocampal microcultures, neurons were surprisingly resilient to 16 h glucose removal in the absence of secondary excitotoxicity. Neuronal survival and synaptic transmission were unaffected by prolonged removal of exogenous glucose. Inhibition of lactate transport decreased microculture neuronal survival during concurrent glucose deprivation, suggesting that endogenously released lactate is important for tolerance to glucose deprivation. Tandem depolarization and glucose deprivation also reduced neuronal survival, and trace glucose concentrations afforded neuroprotection. Mass cultures, in contrast to microcultures, were insensitive to depolarizing glucose deprivation, a difference attributable to increased extracellular lactate levels. Removal of local astrocyte support did not reduce survival in response to glucose deprivation or alter evoked excitatory transmission, suggesting that on-demand, local lactate shuttling is not necessary for neuronal tolerance to prolonged glucose removal. Taken together, these data suggest that endogenously produced lactate available globally in the extracellular milieu sustains neurons in the absence of glucose. A better understanding of resilience mechanisms in reduced preparations could lead to therapeutic strategies aimed to bolster these mechanisms in vulnerable neuronal populations.

Highlights

The human brain represents only 2% of total body mass, yet it accounts for a disproportionately large amount of total energy consumption
Fig 3A) produced no deficit in basal transmission (Fig 3B) but compromised the ability of evoked excitatory postsynaptic currents (EPSCs) to recover following K+-induced depolarization and vesicle depletion, as described earlier (Fig 3C). These results suggest that neurons utilize monocarboxylate transport to supply oxidative phosphorylation (OXPHOS) needed for neuronal survival and synaptic transmission following prolonged glucose deprivation
In this study we investigated the effects of prolonged glucose deprivation on neuronal survival and synaptic physiology in a reduced, controlled environment

Summary

Introduction

The human brain represents only 2% of total body mass, yet it accounts for a disproportionately large amount of total energy consumption. The energy requirements of the mammalian brain are largely met by the metabolism of glucose. Neurons are tasked with the upkeep of many energetically expensive functions such as maintaining ion gradients, generating and propagating action potentials, and fueling synaptic transmission, all of which require a significant amount of ATP [1]. Synaptic transmission is considered the most metabolically expensive neuronal function [2] and is especially sensitive to disruptions in glucose availability and subsequent ATP production. Neurons canonically do not possess glycogen[10] (though see[11,12]) and have limited phosphocreatine reserves to supply ATP. They rely heavily on the availability of extracellular metabolic substrates[13]

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