New Insights on Astrocyte Ion Channels: Critical for Homeostasis and Neuron-Glia Signaling

Abstract

Initial biophysical studies on glial cells nearly 50 years ago identified these cells as being electrically silent. These first studies also demonstrated a large K(+) conductance, which led to the notion that glia may regulate extracellular K(+) levels homeostatically. This view has now gained critical support from the study of multiple disease models discussed herein. Dysfunction of a major astrocyte K(+) channel, Kir4.1, appears as an early pathological event underlying neuronal phenotypes in several neurodevelopmental and neurodegenerative diseases. An expanding list of other astrocyte ion channels, including the calcium-activated ion channel BEST-1, hemichannels, and two-pore domain K(+) channels, all contribute to astrocyte biology and CNS function and underpin new forms of crosstalk between neurons and glia. Once considered merely the glue that holds the brain together, it is now increasingly recognized that astrocytes contribute in several fundamental ways to neuronal function. Emerging new insights and future perspectives of this active research area are highlighted within.

Significance statement: The critical role of astrocyte potassium channels in CNS homeostasis has been reemphasized by recent studies conducted in animal disease models. Emerging evidence also supports the signaling role mediated by astrocyte ion channels such as BEST1, hemichannels, and two-pore channels, which enable astrocytes to interact with neurons and regulate synaptic transmission and plasticity. This minisymposium highlights recent developments and future perspectives of these research areas.

Figure 1.

KCNJ10 expression is upregulated during late fetal and early postnatal development. In human cortex, KCNJ10 expression begins to show significant increase during late middle to late fetal development and continues to increase through early childhood. Expression stabilizes between early (<6 years of age) and middle to late childhood (12 years of age). Similar temporal patterns of expression were observed in amygdala, hippocampus, striatum, and medial dorsal nucleus of the thalamus (data not shown). Figure reprinted with permission (Kang et al., 2011).

Figure 2.

Location of KCNJ10 mutations in patients with SeSAME syndrome. A schematic view of the protein is shown, with intracellular N and C termini, two transmembrane helices (plasma membrane shown in shaded gray), and one pore. This structure is characteristic of the inward rectifier family. Locations of mutations that were nonconducting are indicated by red circles and reduced conductions are indicated by green circles. L166Q is a human single nucleotide polymorphism identified by PolyPhen analysis as being “probably damaging” (purple circle). Homozygous expression of this channel resulted in reduced K⁺ currents and K⁺ uptake. The respective amino acid change for each mutation is noted. Figure adapted with permission (Scholl et al., 2009).

Figure 3.

Role of astrocyte K⁺ and signaling channels. Shown is a confocal image of a hippocampal astrocyte in situ revealed by intracellular loading of Alexa Fluor-488 (courtesy of Jonathan Zapata). Scale bar, 20 μm. A, Kir 4.1 functions as a major K⁺ channel establishing hyperpolarized astrocyte membrane potential and spatially redistributing the K⁺ concentration. B, Cx43 hemichannels modulate basal glutamatergic synaptic activity through ATP signaling. In basal conditions, Cx43 hemichannels boost hippocampal excitatory postsynaptic activity through ATP signaling. A possible scenario is that Cx43 hemichannels release ATP, which activates P2 receptors on CA1 pyramidal cells that increase glutamatergic postsynaptic activity. C, Astrocytic GABA is produced via putrescine degradation pathway with a key biosynthetic enzyme, MAOB. GABA release from Best1 contributes significantly to the tonic GABA release under physiological and various pathologic conditions. D, Activation of mGluR3 translocates TWIK-1 from recycling endosome to membrane that enhances NH₄⁺ uptake, which may facilitate glutamine-glutamate cycle for replenishment of neurotransmitters in neurons.