What is the role of astrocyte calcium in neurophysiology?

Abstract

Astrocytes comprise approximately half of the volume of the adult mammalian brain and are the primary neuronal structural and trophic supportive elements. Astrocytes are organized into distinct nonoverlapping domains and extend elaborate and dense fine processes that interact intimately with synapses and cerebrovasculature. The recognition in the mid 1990s that astrocytes undergo elevations in intracellular calcium concentration following activation of G protein-coupled receptors by synaptically released neurotransmitters demonstrated not only that astrocytes display a form of excitability but also that astrocytes may be active participants in brain information processing. The roles that astrocytic calcium elevations play in neurophysiology and especially in modulation of neuronal activity have been intensely researched in recent years. This review will summarize the current understanding of the function of astrocytic calcium signaling in neurophysiological processes and discuss areas where the role of astrocytes remains controversial and will therefore benefit from further study.

Figure 1. View of the Organization of Astrocytes in Nonoverlapping Anatomical Territories and Their Close Association to Neuronal Dendrites

(A) View of two neighboring astrocytes in the CA1 area of hippocampus labeled with different colored fluorescent dyes (Alexa 488, green; Alexa 568, red). The elaborate and dense processes of each astrocyte do not overlap, and peripheral fine terminal processes interdigitate with one another (yellow). Pyramidal CA1 neurons appear in blue. (B) View of an astrocyte (green) extending its highly ramified processes in close proximity to a CA1 neuronal dendrite (red). These processes can cover most synapses in the astrocyte domain. Panel (A), courtesy of M.H. Ellisman; panel (B), modified from Fiacco and McCarthy (2004).

Figure 2. Schematic Depicting the Tripartite Synapse

The presynaptic and postsynaptic compartments together with the enveloping astrocytic process form the tripartite synapse. Neurotransmitters released from presynaptic terminals act on postsynaptic receptors and astrocytic G_q GPCRs following spillover from the synaptic cleft. Astrocytic G_q GPCR-mediated Ca²⁺ elevations may trigger the release of gliotransmitters through unresolved pathways. Astrocyte-released gliotransmitters may then signal back to neurons by activating presynaptic or postsynaptic (extrasynaptic) neuronal receptors to modulate synaptic transmission.

Figure 3. Tools for Evoking Astrocytic Ca²⁺ Elevations in Brain Slices In Situ

Schematic depicting the main approaches used to increase astrocytic Ca²⁺ in situ. Abbreviations: α, G_q α subunit; βγ, G_q βγ subunits; G_q GPCR, G_q-protein coupled receptor; ER, endoplasmic reticulum; IP₃, inositol 1,4,5-trisphosphate; PIP₂, phosphatidylinositol 4,5-bisphosphate; IP₃R, IP₃ receptor; PLC, phospholipase C.

Figure 4. Schematic Showing the Current Understanding of Astrocytic Ca²⁺ Signaling Involvement at the Synapse

(Left panel) Both in situ and in vivo studies strongly support the conclusion that synaptic release of neurotransmitters, under basal and heightened levels of stimulation, elicits Ca²⁺ increases in astrocytes mostly via the activation of G_q GPCRs. These astrocytic Ca²⁺ elevations can remain localized within small territories (microdomains) within the cell or propagate as intracellular waves into more distant compartments, depending on the level of neuronal activity. (Right panel) Whether or not astrocytic Ca²⁺ increases evoke the release of gliotransmitters to modulate pre- or postsynaptic metabotropic or ionotropic neuronal receptors is still under debate. To date, there are no in vivo data available, and data in situ argue both for and against the concept of gliotransmission. The potential significance of gliotransmission in neurophysiology and neuropathophysiology remains an open issue.