Propagating calcium waves as a substrate of glial excitability

In physiological conditions, glia are stimulated by relatively brief and local exposures to neurotransmitters. This local stimulation produces similarly localized events of Ca2+ release through InsP3R; yet these highly localized events (which in essence are a summation of several puffs) may give rise to a propagating signal that will swamp the whole cell. Importantly in glial cells, particularly in astro-cytes, propagation of these Ca2+ waves is not limited by cellular borders; instead they cross the intercellular boundaries and spread over a relatively long distance through the astrocytic syncytium.

Intracellular propagation of Ca2+ signals is determined by a special property of the ER membrane, which, similar to the plasmalemma of excitable cells, is able to convert a local supra-threshold response into a propagating wave of excitation. The Ca2+ sensitivity of the RyRs and InsP3Rs is what makes the ER membrane an excitable medium. A focal Ca2+ release induced by a localized elevation of InsP3 recruits neighbouring channels, which not only amplifies the initial Ca2+ release event, but also creates a propagating wave of Ca2+ release along the ER membrane. This simple mechanism underlies the propagation of Ca2+ signals in almost any type of nonexcitable cell. It is important to remember that the Ca2+ wave is not a propagating wave of Ca2+ ions, because the movement of Ca2+ ions is severely restricted by cytoplasmic Ca2+ buffering. Instead, the Ca2+wave results from a propagating wave of elementary Ca2+ release events through the endomembrane.

Intercellular propagation of Ca2+ signals is primarily a function of astro-cytes, and involves several mechanisms, including: (1) direct intercellular diffusion of InsP3 via gap junctions; (2) regenerative release of a diffusible extracellular messenger (e.g. ATP) triggering metabotropic receptor-mediated Ca2+ release in neighbouring cells; (3) diffusion of an extracellular messenger after release from a single cell (which may be important in microglia as well as astrocytes); and (4) any combination of the above (see schemes on Figure 5.13). Astroglial networks in different areas of the brain can have distinct mechanisms of intercellular Ca2+ wave propagation. For example, genetic deletion of Cx43, which forms gap junctions between brain astrocytes (see Chapter 5.4), results in the complete disappearance of astroglial Ca2+ waves in the neocortex, but not in the corpus callosum or hippocampus, where Ca2+ wave propagation relies primarily on ATP release. Furthermore, intercellular Ca2+ waves can be propagated outside

Brain Diffusion Astrocytes

Figure 5.13 Mechanisms of generation of propagating intercellular Ca2+ waves. Propagation of inter-glial Ca2+ waves can be supported by several distinct mechanisms, which can operate separately or in combination:

A. Ca2+ waves can be maintained by diffusion of InsP3 through the gap junction and secondary initiation of InsP3-induced Ca2+ release;

B. Ca2+ waves can be maintained by regenerative Ca2+-dependent release of 'gliotransmitters' (see Figure 5.14) acting on neighbouring cells through extracellular diffusion;

C. Ca2+ waves can result from a focal release of 'gliotransmitter', which then diffuses over a long distance.

Figure 5.13 Mechanisms of generation of propagating intercellular Ca2+ waves. Propagation of inter-glial Ca2+ waves can be supported by several distinct mechanisms, which can operate separately or in combination:

A. Ca2+ waves can be maintained by diffusion of InsP3 through the gap junction and secondary initiation of InsP3-induced Ca2+ release;

B. Ca2+ waves can be maintained by regenerative Ca2+-dependent release of 'gliotransmitters' (see Figure 5.14) acting on neighbouring cells through extracellular diffusion;

C. Ca2+ waves can result from a focal release of 'gliotransmitter', which then diffuses over a long distance.

of the astroglial syncytium by the release of extracellular messengers to act on neighbouring neurones, oligodendrocytes and microglia.

Intercellular Ca2+ waves may travel for 300-400 ^m at a velocity of ~15-20 ^m/s, and provide astrocytes with the means for long-distance communication. Thus, astrocytes are 'excitable', but signal propagation is fundamentally different from that in neurones. In neurones, the substrate for excitability is the plasma membrane, which generates a rapidly (milliseconds) propagating wave of openings/closures of Na+/K+ channels (propagating action potential). In contrast, the substrate for excitability in astrocytes is the intracellular ER membrane, which generates a much slower (seconds to minutes) propagating wave of openings/closures of Ca2+ channels.

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