Physiology of Astroglial Excitability

Abstract

Classic physiology divides all neural cells into excitable neurons and nonexcitable neuroglia. Neuroglial cells, chiefly responsible for homeostasis and defense of the nervous tissue, coordinate their complex homeostatic responses with neuronal activity. This coordination reflects a specific form of glial excitability mediated by complex changes in intracellular concentration of ions and second messengers organized in both space and time. Astrocytes are equipped with multiple molecular cascades, which are central for regulating homeostasis of neurotransmitters, ionostasis, synaptic connectivity, and metabolic support of the central nervous system. Astrocytes are further provisioned with multiple receptors for neurotransmitters and neurohormones, which upon activation trigger intracellular signals mediated by Ca²⁺, Na⁺, and cyclic AMP. Calcium signals have distinct organization and underlying mechanisms in different astrocytic compartments thus allowing complex spatiotemporal signaling. Signals mediated by fluctuations in cytosolic Na⁺ are instrumental for coordination of Na⁺ dependent astrocytic transporters with tissue state and homeostatic demands. Astroglial ionic excitability may also involve K⁺, H^+, and Cl^-. The cyclic AMP signalling system is, in comparison to ions, much slower in targeting astroglial effector mechanisms. This evidence review summarizes the concept of astroglial intracellular excitability.

Keywords: astrocyte; astrocytic processes; astroglial excitability; calcium signaling; ionic signaling; sodium signaling.

Figure 1.

Morphofunctional Organization of Ca²⁺ Signaling Compartments in Protoplasmic Astrocyte. Morphological compartments of protoplasmic astrocyte^, are represented by (1) soma; (2) main processes also known as branches; (3) secondary to tertiary processes designated as branchlets; (4) peripheral parenchymal and perisynaptic processes known as leaflets; and (5) perivascular processes, which terminate with end feet plastering blood vessels; these latter are not shown on the figure. Calcium signaling in soma, branches, and branchlets are mainly associated with Ca²⁺ release from the ER with subsequent SOCE. This Ca²⁺ release is mediated by InsP₃ receptors (InsP₃R); InsP₃ is synthesized by phospholipase C (PLC) linked to G-protein metabotropic receptors. Calcium signaling in the leaflets is associated with Ca²⁺ entry through ionotropic receptors (NMDA glutamate receptors or P2X purinoceptors) or Ca²⁺-permeable channels (such as, for example, TRPA1 channels). Plasmalemmal Ca²⁺ influx can also be mediated by the NCX operating in the reverse mode.

Figure 2.

Formation of Ca²⁺ Microdomain in the Perisynaptic Appendages of Cerebellar Bergmann Glial Cells. Reconstruction of an appendage is based on electron microscopic data. (A) Fluorescence light micrograph of a dye-injected Bergmann glial cell is shown; the red square corresponds to the portion that was reconstructed from consecutive ultrathin sections. (B) One of the lateral appendages (marked in blue), arising directly from main process. (C) The same appendage is shown in isolation and at higher magnification. (D) Calcium signaling in the appendages of Bergmann glial cells is mediated solely through metabotropic receptors (mGluR5 or P2Y purinoceptors), which stimulate induced synthesis of InsP₃ with subsequent InsP₃-induced Ca²⁺ release from the ER and secondary SOCE. Modified from Ref. Grosche et al.

Figure 3.

Membrane Molecular Pathways of Na⁺ Signaling in Astrocytes. Influx of Na⁺ occurs though (1) Na⁺-permeable channels, which include ionotropic receptors (AMPAR, NMDAR, P2XR - AMPA, NMDA glutamate receptors and ionotropic purinoceptors); channels of the TRP family (TRPC1/4/5 channels that operate as a part of store-operated Ca²⁺ entry and hence generate Na⁺ influx in response to the depletion of ER Ca²⁺ stores; as well as TRPA and TRPV channels); voltage-dependent Na_v channels and [Na⁺]_o-activated Na_x channels; (2) through Na⁺-dependent SLC transporters that include excitatory amino acid transporters EAAT1,2, GABA transporters GAT 1,3, glycine transporters GlyT, NA transporters NET or concentrative adenosine transporters CNT2/3. The main pathway for Na⁺ exit is provided by Na⁺-K⁺ pump, NKA. The Na⁺-Ca²⁺ exchanger NCX fluctuates between forward and reverse mode and couples Na⁺ and Ca²⁺ signaling. Modified from Verkhratsky et al.

Figure 4.

Distinct Temporal Dynamics of cAMP and Ca²⁺-Excitability in Astrocytes. Activation of astrocytic metabotropic receptors coupled to Gq proteins leads to phasic oscillations in intracellular Ca²⁺ levels (left), while the activation of metabotropic receptors coupled to Gs proteins leads to tonic long-lasting increase in cAMP-dependent PKA activity without oscillations (right). Cyclic AMP is produced by AC from ATP. PLC, phospholipase C; InsP₃R, receptor. Modified from Horvat et al.