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.
Highlights
The maintenance of ion gradients between the cytoplasm and the extracellular space (ECS) is one of the most important functions in living cells ensuring cell survival and the execution of physiological processes
We found an association between peri-infarct depolarizations (PID) and propagating Na+ elevations in neurons and astrocytes in vivo, as well as in tissue slices that underwent brief chemical ischemia (Figure 4)
As discussed above for the Familial hemiplegic migraine 2 (FHM2) model, the reduced capacity to remove glutamate out of the synaptic cleft after neuronal activity will lead to excitotoxicity, which will lead to further disruptions in NKA activity, thereby initiating a vicious circle
Summary
The maintenance of ion gradients between the cytoplasm and the extracellular space (ECS) is one of the most important functions in living cells ensuring cell survival and the execution of physiological processes. Most studies addressed the possible consequences of changes in astrocytic Na+ in the context of altered driving force for Na+ dependent transporters The latter couple Na+ homeostasis to the regulation of other ions, neurotransmitters, and diverse substrates processes highly relevant for astrocytic function and for their communication with neurons (Kirischuk et al, 2012; Rose and Karus, 2013; Verkhratsky et al, 2019). Na+-triggered, NCX-mediated Ca2+-signaling has been implemented in the mobility of mitochondria, coupling neuronal activity to astrocyte metabolism (Jackson and Robinson, 2018) Since both GLAST and GLT-1 activity are mainly energized by the Na+ gradient, increases in [Na+]i reduce their driving force and may exert a negative feedback on extracellular glutamate clearance (Barbour et al, 1991; Bergles et al, 2002; Kelly et al, 2009; Unichenko et al, 2012). As discussed above for the FHM2 model, the reduced capacity to remove glutamate out of the synaptic cleft after neuronal activity will lead to excitotoxicity, which will lead to further disruptions in NKA activity, thereby initiating a vicious circle
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