Glial Na(+) -dependent ion transporters in pathophysiological conditions

Abstract

Sodium dynamics are essential for regulating functional processes in glial cells. Indeed, glial Na(+) signaling influences and regulates important glial activities, and plays a role in neuron-glia interaction under physiological conditions or in response to injury of the central nervous system (CNS). Emerging studies indicate that Na(+) pumps and Na(+) -dependent ion transporters in astrocytes, microglia, and oligodendrocytes regulate Na(+) homeostasis and play a fundamental role in modulating glial activities in neurological diseases. In this review, we first briefly introduced the emerging roles of each glial cell type in the pathophysiology of cerebral ischemia, Alzheimer's disease, epilepsy, Parkinson's disease, Amyotrophic Lateral Sclerosis, and myelin diseases. Then, we discussed the current knowledge on the main roles played by the different glial Na(+) -dependent ion transporters, including Na(+) /K(+) ATPase, Na(+) /Ca(2+) exchangers, Na(+) /H(+) exchangers, Na(+) -K(+) -Cl(-) cotransporters, and Na(+) - HCO3- cotransporter in the pathophysiology of the diverse CNS diseases. We highlighted their contributions in cell survival, synaptic pathology, gliotransmission, pH homeostasis, and their role in glial activation, migration, gliosis, inflammation, and tissue repair processes. Therefore, this review summarizes the foundation work for targeting Na(+) -dependent ion transporters in glia as a novel strategy to control important glial activities associated with Na(+) dynamics in different neurological disorders. GLIA 2016;64:1677-1697.

Keywords: Na+-HCO3- cotransporter; Na+-K+-Cl- cotransporter; Na+/Ca2+ exchanger; Na+/H+ exchanger; Na+/K+ ATPase; astrocytes; microglia; oligodendrocytes.

FIGURE 1

Schematic representation of the Na⁺-dependent transporters involved in Na⁺ dynamics during the hypoxic-ischemic insult in astrocytes, microglia, and oligodendrocytes.

FIGURE 2

Schematic representation of the emerging roles of the glial Na⁺-dependent transporters in different neurological disorders. According to the different CNS diseases the diagram summarizes the major alterations in expression level and activity for each Na⁺ dependent transporter in astrocytes, microglia and oligodendrocytes. Similarly, the contribution of each Na⁺ dependent transporter to cell survival/death, and diverse glial activities is also indicated. The symbol (−) indicates “not directly tested.”

FIGURE 3

Impaired oligodendrocyte lineage response in the spinal cord of EAE mice lacking ncx3 gene. A, Confocal double immunofluorescence images displaying at a lower (a, c) and higher (b, d) magnification NG2 (red) and CNPase (green) distribution in the white matter of ncx3^+/+ (a–b) and ncx3^−/− (c–d) mice in the chronic stage of EAE disease. NG2/CNPase double-labeled cells are frequently observed in the white matter of ncx3^+/+ mice (arrows in b), but not in ncx3^−/− mice. Scale bars: 50 μm in a and c; 20 μm in b and d. B, Western blotting and densitometric analysis of NG2 (left panel) and PDGFα receptor (right panel) protein levels in spinal cord lysates from control and MOG^35–55-immunized mice in the chronic stage of EAE. Data were normalized on the basis of α-tubulin and expressed as percentage of controls. The protein levels of both NG2 and PDGFα receptor, two proteins that are characteristically co-expressed by OPCs, are significantly downregulated in the spinal cord homogenates from ncx3^−/− mice when compared with ncx3^+/+ mice. The values represent the means±S.E.M. (n=3–4). *P < 0.05 versus controls. This figure was modified by Casamassa et al., 2016, Glia, 64:1124–1137.