Bidirectional astrocytic GLUT1 activation by elevated extracellular K⁺

Abstract

The acute rise in interstitial K+ that accompanies neural activity couples the energy demand of neurons to the metabolism of astrocytes. The effects of elevated K+ on astrocytes include activation of aerobic glycolysis, inhibition of mitochondrial respiration and the release of lactate. Using a genetically encoded FRET glucose sensor and a novel protocol based on 3‐O‐methylglucose trans‐acceleration and numerical simulation of glucose dynamics, we report that extracellular K+ is also a potent and reversible modulator of the astrocytic glucose transporter GLUT1. In cultured mouse astrocytes, the stimulatory effect developed within seconds, engaged both the influx and efflux modes of the transporter, and was detected even at 1 mM incremental K+. The modulation of GLUT1 explains how astrocytes are able to maintain their glucose pool in the face of strong glycolysis stimulation. We propose that the stimulation of GLUT1 by K+ supports the production of lactate by astrocytes and the timely delivery of glucose to active neurons.

A perspective on astrocyte regulation of neural circuit function and animal behavior

“…• Transporter expression (e.g., GLAST) • Ion channel expression (e.g., Kir4.1) • Gap junctional coupling (e.g., Cx43) • Ca 2+ signaling (e.g., hippocampus vs. striatum) • Metabolism • Structural properties (e.g., GFAP expression, spine coverage) Chai et al, 2017;Fernández-Moncada et al, 2021;Herde et al, 2020;Hirrlinger et al, 2008;Kelley et al, 2018;Köhler et al, 2021;Köhler et al, 2018;Kronschläger et al, 2021;Miller et al, 2019;Oheim et al, 2018;Olsen et al, 2007 used to study primate-specific interlaminar astrocytes in mice (Padmashri et al, 2021). Strikingly, grafting human astrocytes into the mouse forebrain enhanced synaptic plasticity and learning (Han et al, 2013).…”

“…Chai et al, 2017; Fernández‐Moncada et al, 2021; Herde et al, 2020; Hirrlinger et al, 2008; Kelley et al, 2018; Köhler et al, 2021; Köhler et al, 2018; Kronschläger et al, 2021; Miller et al, 2019; Oheim et al, 2018; Olsen et al, 2007; Theis & Giaume, 2012…”

How expensive is the astrocyte?

“…77 The role of K þ buffering and associated energy demand in neuroprotection is complex. Reactive astrocytes are predicted to spend less energy and glucose during neural activity, 78,79 contributing to the well-being of neurons, which use glucose for antioxidation; 52 but they would also fail to remove extracellular K þ and reduce their own oxygen consumption on demand, 70,73 to the detriment of neurons. Supporting the latter, in a mouse model of Huntington's disease Kir4.1 was found to be diminished in astrocytes, leading to K þ accumulation and neuronal hyperexcitability.…”

Micromotion derived fluid shear stress mediates peri-electrode gliosis through mechanosensitive ion channels

“…Together, these data indicate that PIEZO1 activation impacts mitochondrial functions and cellular metabolism, which are crucial for the homeostasis of neural tissues [213,214] and play an important role in controlling both neuron and astrocyte functions [51]. Mechanistically, it can be hypothesised that shear stress-induced PIEZO1 activation, promotes a sustained augmentation of intracellular calcium transportation processes which leads to the release of fatty acids and to the impairment of mitochondrial functions, drastically reducing ATP production and promoting neuronal death and astrocyte reactivity (Figure 9).…”