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Astrocyte Ca²⁺-evoked ATP release regulates myelinated axon excitability and conduction speed.

ABSTRACT: In the brain’s gray matter, astrocytes regulate synapse properties, but their role is unclear for the white matter, where myelinated axons rapidly transmit information between gray matter areas. We found that in rodents, neuronal activity raised the intracellular calcium concentration ([Ca²⁺]_i) in astrocyte processes located near action potential–generating sites in the axon initial segment (AIS) and nodes of Ranvier of myelinated axons. This released adenosine triphosphate, which was converted extracellularly to adenosine and thus, through A_2a receptors, activated HCN2-containing cation channels that regulate two aspects of myelinated axon function: excitability of the AIS and speed of action potential propagation. Variations in astrocyte-derived adenosine level between wake and sleep states or during energy deprivation could thus control white matter information flow and neural circuit function.

SUBMITTER: Lezmy J

PROVIDER: S-EPMC7611967 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Astrocyte Ca2+-evoked ATP release regulates myelinated axon excitability and conduction speed.

Lezmy Jonathan J Arancibia-Cárcamo I Lorena IL Quintela-López Tania T Sherman Diane L DL Brophy Peter J PJ Attwell David D

Science (New York, N.Y.) 20211015 6565

In the brain’s gray matter, astrocytes regulate synapse properties, but their role is unclear for the white matter, where myelinated axons rapidly transmit information between gray matter areas. We found that in rodents, neuronal activity raised the intracellular calcium concentration ([Ca2+]i) in astrocyte processes located near action potential–generating sites in the axon initial segment (AIS) and nodes of Ranvier of myelinated axons. This released adenosine triphosphate ...[more]

PMID: 34648330

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Project description:BackgroundIntracellular Ca2+ modulates several microglial activities, such as proliferation, migration, phagocytosis, and inflammatory mediator secretion. Extracellular ATP, the levels of which significantly change during epileptic seizures, activates specific receptors leading to an increase of intracellular free Ca2+ concentration ([Ca2+]i). Here, we aimed to functionally characterize human microglia obtained from cortices of subjects with temporal lobe epilepsy, focusing on the Ca2+-mediated response triggered by purinergic signaling.MethodsFura-2 based fluorescence microscopy was used to measure [Ca2+]i in primary cultures of human microglial cells obtained from surgical specimens. The perforated patch-clamp technique, which preserves the cytoplasmic milieu, was used to measure ATP-evoked Ca2+-dependent whole-cell currents.ResultsIn human microglia extracellular ATP evoked [Ca2+]i increases depend on Ca2+ entry from the extracellular space and on Ca2+ mobilization from intracellular compartments. Extracellular ATP also induced a transient fivefold potentiation of the total transmembrane current, which was completely abolished when [Ca2+]i increases were prevented by removing external Ca2+ and using an intracellular Ca2+ chelator. TRAM-34, a selective KCa3.1 blocker, significantly reduced the ATP-induced current potentiation but did not abolish it. The removal of external Cl- in the presence of TRAM-34 further lowered the ATP-evoked effect. A direct comparison between the ATP-evoked mean current potentiation and mean Ca2+ transient amplitude revealed a linear correlation. Treatment of microglial cells with LPS for 48 h did not prevent the ATP-induced Ca2+ mobilization but completely abolished the ATP-mediated current potentiation. The absence of the Ca2+-evoked K+ current led to a less sustained ATP-evoked Ca2+ entry, as shown by the faster Ca2+ transient kinetics observed in LPS-treated microglia.ConclusionsOur study confirms a functional role for KCa3.1 channels in human microglia, linking ATP-evoked Ca2+ transients to changes in membrane conductance, with an inflammation-dependent mechanism, and suggests that during brain inflammation the KCa3.1-mediated microglial response to purinergic signaling may be reduced.

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Astrocyte Ca²⁺-evoked ATP release regulates myelinated axon excitability and conduction speed.

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Astrocyte Ca<sup>2+</sup>-evoked ATP release regulates myelinated axon excitability and conduction speed.

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