Differential effects of energy deprivation on intracellular sodium homeostasis in neurons and astrocytes

Abstract

1-ATPase (NKA) is critical for brain function. In both neurons and glial cells, NKA activity is required to counteract changes in the sodium gradient due to opening of voltage-and ligand-gated channels and/or activation of sodium-dependent secondary active transporters. Because NKA consumes about 50% of cellular ATP, sodium homeostasis is strictly dependent on an intact cellular energy metabolism. Despite the high energetic costs of electrical signaling, neurons do not contain significant energy stores themselves, but rely on a close metabolic interaction with surrounding astrocytes. A disruption of energy supply as observed during focal ischemia causes a rapid drop in ATP in both neurons and astrocytes. There is accumulating evidence that dysregulation of intracellular sodium is an inherent consequence of a reduction in cellular ATP, triggering secondary failure of extra-and intracellular homeostasis of other ions -in particular potassium, calcium, and protons-and thereby promoting excitotoxicity. The characteristics, cellular mechanisms and direct consequences of harmful sodium influx, however, differ between neurons and astrocytes. Moreover, recent work has shown that an intact astrocyte metabolism and sodium homeostasis are critical to maintain the sodium homeostasis of surrounding neurons as well as their capacity to recover from imposed sodium influx. Understanding the mechanisms of sodium increases upon metabolic failure and the differential responses of neurons and glial cells as well as their metabolic interactions will be critical to fully unravel the events causing cellular malfunction, failure and cell death following energy depletion. V C 2017 Wiley Periodicals, Inc.

Relation between activity‐induced intracellular sodium transients and ATP dynamics in mouse hippocampal neurons

“…However, for periods of energy restriction, such as during ischaemia or hypoxia, insufficient ATP availability has been shown to slow down NKA, resulting in a failure of Na + extrusion and a rise in [Na + ] i that aggravates damage by, for example, secondary loading of neurons with protons or Ca 2+ (Dagani & Erecinska, ; Somjen, ; Gerkau et al . ).…”

“…; Gerkau et al . ). In addition to ATP‐dependent ion transporters, many neurons express K ATP channels that couple their metabolic state to their excitability and which are activated by a more moderate decline in cellular [ATP] (Proks & Ashcroft, ; Tanner et al .…”

FRET‐based imaging of intracellular ATP in organotypic brain slices

“…Recent work has indeed established diverse metabolic interactions between neurons and astrocytes (Allaman, Belanger, & Magistretti, ; Bolanos, ; Gerkau, Rakers, Petzold, & Rose, ; Rose & Chatton, ). For example, it has been demonstrated that increased neuronal activity results in increased uptake and breakdown of glucose by astrocytes (Pellerin & Magistretti, ).…”

A method for multiparametric statistical quantification of the heterogeneity of free Na+ concentration by 19F MR spectroscopy: Proof of principle in silico and in vitro

“…However, these methods have not taken into consideration [Na + ] i heterogeneity within a measured volume or voxel. For instance, baseline Na + i levels have been shown by fluorescence microscopy to vary significantly in cultured astrocytes as a function of glycolytic activity (by up to several tens of mM), but not in neurons . In the brain, neurons are located in the immediate vicinity of astrocytes as both interact closely (distances in the μm range).…”

“…For instance, baseline Na + i levels have been shown by fluorescence microscopy to vary significantly in cultured astrocytes as a function of glycolytic activity (by up to several tens of mM), but not in neurons. 9 In the brain, neurons are located in the immediate vicinity of astrocytes as both interact closely (distances in the μm range). Therefore, energy deprivation will result in brain microenvironments (containing both astrocytes and neurons) with differing Na + i levels; in addition, even neurons located within the same microenvironment will not have uniform [Na + ] i values in the presence of a significant gradient in glycolytic activity.…”