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 STATEMENTThe 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.

Expression of a linear current–voltage (I–V) relationship (passive) K⁺ membrane conductance is a hallmark of mature hippocampal astrocytes. However, the molecular identifications of the K⁺ channels underlying this passive conductance remain unknown. We provide the following evidence supporting significant contribution of the two-pore domain K⁺ channel (K_2P) isoforms, TWIK-1 and TREK-1, to this conductance. First, both passive astrocytes and the cloned rat TWIK-1 and TREK-1 channels expressed in CHO cells conduct significant amounts of Cs⁺ currents, but vary in their relative P_Cs/P_K permeability, 0.43, 0.10, and 0.05, respectively. Second, quinine, which potently inhibited TWIK-1 (IC₅₀ = 85 μm) and TREK-1 (IC₅₀ = 41 μm) currents, also inhibited astrocytic passive conductance by 58% at a concentration of 200 μm. Third, a moderate sensitivity of passive conductance to low extracellular pH (6.0) supports a combined expression of acid-insensitive TREK-1, and to a lesser extent, acid-sensitive TWIK-1. Fourth, the astrocyte passive conductance showed low sensitivity to extracellular Ba²⁺, and extracellular Ba²⁺ blocked TWIK-1 channels at an IC₅₀ of 960 μm and had no effect on TREK-1 channels. Finally, an immunocytochemical study showed colocalization of TWIK-1 and TREK-1 proteins with the astrocytic markers GLAST and GFAP in rat hippocampal stratum radiatum. In contrast, another K_2P isoform TASK-1 was mainly colocalized with the neuronal marker NeuN in hippocampal pyramidal neurons and was expressed at a much lower level in astrocytes. These results support TWIK-1 and TREK-1 as being the major components of the long-sought K⁺ channels underlying the passive conductance of mature hippocampal astrocytes.

Glia show marked heterogeneity in terms of electrophysiology in the developing brain, and two major types can be identified based on GFAP or NG2 expression. However, it remains to be determined if such an electrophysiological diversity holds for the adult brain and how GFAP and NG2 lineage glia are associated with different electrophysiological phenotypes during the course of development. To address these fundamental questions, we performed in situ whole cell recording from morphologically identified glia from the rat hippocampal CA1 region from postnatal (P) days 1–106 and double-stained postrecorded cells with GLAST and NG2 antibodies. We found glia express mostly voltage-gated outward K⁺ currents and also have inward Na⁺ currents in the newborn (P1–P3), but these are no longer present after P22. They consist equally of GLAST(+) and NG2(+) cells in the newborn, but are mainly NG2(+) in juvenile animals (P4–P21). Glia showing voltage-gated outward and inward K⁺ currents are also present at P1, peak at P5 and decline to a stationary level of ∼10% in the adult. They are GLAST(+) astrocytes from newborn to juvenile but NG2(+) glia in the adult. Electrophysiologically passive glia first appear at P4 and increase to 91% in adults, of which 85% are GLAST(+). These results indicate that glial electrophysiological diversity occurs predominantly in the developing brain. While most glia in the NG2 lineage preserve a certain amount of voltage-gated ion conductances, mature GLAST(+) astrocytes are electrophysiologically passive.

We have shown previously that process-bearing GFAP+ astrocytes freshly isolated from rat hippocampus CA1 and CA3 regions are heterogeneous in ion channel expression and K⁺uptake capabilities, such that two distinct populations of astrocytes can be described (Zhou and Kimelberg, 2000). In the present study, we report that glutamate transporter (GT) currents can only be measured from one type of these freshly isolated hippocampal CA1 astrocytes [variably rectifying astrocytes (VRAs)] but were not detectable in the second type of astrocyte [outwardly rectifying astrocytes (ORAs)]. The GT currents showed a strict Na⁺dependency and high affinity for glutamate (EC₅₀ of 4 ± 1.1 μm). The astrocytes lacking GT currents (ORAs) showed an AMPA receptor current density (55 pA/pF) that was 42-fold higher than VRAs (1.3 pA/pF). In contrast, the GABA_A currents were of comparable current density in both types. The specificity of these differences makes it unlikely that they are attributable to preparative damage. Therefore, these findings strongly indicate that, within a single region of the hippocampus, GFAP+ astrocytes comprise a functionally diverse population that are qualitatively different in their functional glutamate transporter and quantitatively different in their functional AMPA receptor expression. This heterogeneity implies that GFAP+ astrocytes may participate in or modulate glutamate synaptic transmission differently.