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Review
. 2020 Aug 12:11:871.
doi: 10.3389/fphys.2020.00871. eCollection 2020.

Sodium Fluctuations in Astroglia and Their Potential Impact on Astrocyte Function

Lisa Felix  1 , Andrea Delekate  2 , Gabor C Petzold  2   3 , Christine R Rose  1
Affiliations
Review

Sodium Fluctuations in Astroglia and Their Potential Impact on Astrocyte Function

Lisa Felix et al. Front Physiol. .

Abstract

Astrocytes are the main cell type responsible for the regulation of brain homeostasis, including the maintenance of ion gradients and neurotransmitter clearance. These processes are tightly coupled to changes in the intracellular sodium (Na+) concentration. While activation of the sodium-potassium-ATPase (NKA) in response to an elevation of extracellular K+ may decrease intracellular Na+, the cotransport of transmitters, such as glutamate, together with Na+ results in an increase in astrocytic Na+. This increase in intracellular Na+ can modulate, for instance, metabolic downstream pathways. Thereby, astrocytes are capable to react on a fast time scale to surrounding neuronal activity via intracellular Na+ fluctuations and adjust energy production to the demand of their environment. Beside the well-documented conventional roles of Na+ signaling mainly mediated through changes in its electrochemical gradient, several recent studies have identified more atypical roles for Na+, including protein interactions leading to changes in their biochemical activity or Na+-dependent regulation of gene expression. In this review, we will address both the conventional as well as the atypical functions of astrocytic Na+ signaling, presenting the role of transporters and channels involved and their implications for physiological processes in the central nervous system (CNS). We will also discuss how these important functions are affected under pathological conditions, including stroke and migraine. We postulate that Na+ is an essential player not only in the maintenance of homeostatic processes but also as a messenger for the fast communication between neurons and astrocytes, adjusting the functional properties of various cellular interaction partners to the needs of the surrounding network.

Keywords: astrocyte; brain; gamma-aminobutyric acid; glutamate; ischemia; sodium imaging; sodium signaling; sodium/potassium-ATPase.

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Figures

Figure 1
Figure 1
Main efflux and influx pathways for Na+ in astrocytes. Note that the Na+/K+-ATPase (NKA) is the major mechanism for Na+ export. Other transporters may function in the inward or outward mode, thereby generating influx or efflux of Na+. Most other carriers and all ion channels mediate Na+ influx into astrocytes. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ASCT2, alanine, serine, cysteine transporter 2; CNT, concentrative nucleoside transporter; EAAT, excitatory amino acid transporter; GAT, gamma-aminobutyric acid transporter; GlyT, glycine transporter; NBC, Na+-HCO3− cotransporter; NCX, Na+/Ca2+ exchanger; NCLX, mitochondrial Na+/Ca2+/Li+ exchanger; NHE, Na+/H+ exchanger; NKA, Na+/K+-ATPase; NKCC1, Na+-K+-2 Cl− co-transporter 1; NMDA, N-methyl-d-aspartate receptor; SNAT3/5, sodium-coupled neutral amino acid transporter; and SVCT2, sodium-dependent vitamin C transporter 2.
Figure 2
Figure 2
Different forms of Na+ signaling in astrocytes. (A) Spontaneous Na+ fluctuations as recently reported from neonate hippocampus and cortex (Felix et al., 2020). (B) More rapid, global Na+ oscillations, which are synchronized between cells and accompany recurrent network activity in mouse hippocampus (Karus et al., 2015, 2017). (C) Local Na+ transients induced in different types of astrocytes and brain regions upon afferent synaptic stimulation of glutamatergic fibers (e.g., Kirischuk et al., 2007; Langer and Rose, 2009). (D) Gap junction mediated rapid spread of Na+ signals in the astrocytic syncytium to neighboring cells, which then depict slower kinetics and reduced amplitudes (Langer et al., 2012, 2017).
Figure 3
Figure 3
Conventional and more “atypical” consequences of Na+ and Na+ signaling. Left: conventional roles, largely established and accepted to be relevant for astrocytes. Right: atypical roles, partly hypothetic and based on insights from other systems.
Figure 4
Figure 4
Na+ signaling in the experimental middle cerebral artery occlusion (MCAO) stroke model. Induction of an ischemic stroke by insertion of a filament into the internal carotid artery until the MCA is blocked (upper panel). In the ischemic core, dying cells initiate peri-infarct depolarizations (PIDs), which travel through the penumbra and lead to excess glutamate release and higher energy consumption (bottom left panel). Glutamate uptake by astrocytes is accompanied by Na+ cotransport through glutamate transporters, which results in detectable intracellular Na+ elevations in response to PIDs (right panel; Na+ traces adapted with permission from Gerkau et al. 2018; images created with BioRender.com).
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