Serendipitous compound action potential oscillations reveal glycolytic astrocyte and oxidative axon interstitial K+ buffering in central white matter

The principal processes that govern interstitial K+ ([K+]o) buffering in mouse optic nerve (MON), a central white matter tract, either directly consume energy (Na+–K+‐ATPase) or use transmembrane ion gradients created by energy‐dependent pumps to enable the K+ fluxes that maintain a stable [K+]o, and thus ready availability of utilisable energy substrate is vital in supporting MON function. We switched the artificial cerebrospinal fluid (aCSF) bathing isolated ex vivo MON from a glucose and physiological [K+] (3 mM) formulation to one in which glucose was replaced by lactate and [K+] was increased to supra‐physiological concentrations (‘stress aCSF’), to test the ability of an oxidative fuel to support astrocyte function when faced with the buffering‐related increased energy demand that accompanies elevating [K+]o. We recorded simultaneously the compound action potential (CAP) and [K+]o with suction electrodes and ion‐sensitive microelectrodes, respectively. Increases in aCSF [K+] were not matched by equivalent increases in [K+]o, evidence of powerful buffering. The stress aCSF caused unexpected reciprocal CAP and [K+]o oscillations and exhaustion of astrocyte energy reserves coupled with elevation of [K+]o sufficient to activate axonal Na+ channels, the key factors required for their initiation. The oscillation profile was of a rise in [K+]o towards aCSF [K+], followed by a restoration of [K+]o towards baseline, driven by intermittent activation of the axonal Na+–K+‐ATPase, a cyclical process that continued for several hours. These oscillations exposed the contrasting utility of lactate, supporting axonal CAPs and axonal dominance of buffering during the oscillations, but incapable of fuelling astrocyte function.

• Publication year

  2025

• Venue

  Experimental Physiology

• Publication date

  2025-11-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1113/EP093107PMID 41214864PMCID PMC12949168
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2017cited by this paper
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  2012influential reference
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  2012cited by this paper
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  2012cited by this paper
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  2012influential reference
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  2011influential reference
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  2010influential reference
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• THE NEURONAL MICROENVIRONMENT

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  2009cited by this paper
• Uniquely Hominid Features of Adult Human Astrocytes

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  2008influential reference
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  2006cited by this paper
• Astrocyte activation in working brain: energy supplied by minor substrates.

  2006cited by this paper
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  2005cited by this paper
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  2004cited by this paper
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  2003cited by this paper
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  2000influential reference
• Regulation of intracellular sodium in cultured rat hippocampal neurones.

  1997cited by this paper
• Ion transport and membrane potential in CNS myelinated axons. II. Effects of metabolic inhibition.

  1997cited by this paper
• Intracellular sodium homeostasis in rat hippocampal astrocytes.

  1996influential reference
• Compound action potential of nerve recorded by suction electrode: a theoretical and experimental analysis.

  1991cited by this paper
• Characteristics of activity-dependent potassium accumulation in mammalian peripheral nerve in vitro.

  1991cited by this paper
• Fabrication and Implementation of Ion-Selective Microelectrodes

  1990cited by this paper
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  1990influential reference
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  1988cited by this paper
• Ion activities and potassium uptake mechanisms of glial cells in guinea‐pig olfactory cortex slices.

  1987cited by this paper
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  1987cited by this paper
• A simple method for making ion-selective microelectrodes suitable for intracellular recording in vertebrate cells.

  1985cited by this paper
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  1984cited by this paper
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  1984cited by this paper
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  1984cited by this paper
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  1984cited by this paper
• Extracellular K+ concentration during electrical stimulation of rat isolated sympathetic ganglia, vagus and optic nerves.

  1982influential reference
• Activity-dependent K+ accumulation in the developing rat optic nerve.

  1982cited by this paper
• Extracellular potassium in the mammalian central nervous system.

  1979influential reference
• Nerve fiber conduction-velocity distributions. I. Estimation based on the single-fiber and compound action potentials.

  1979cited by this paper
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  1975cited by this paper
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  1973cited by this paper
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  1972cited by this paper
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• Physiological properties of glial cells in the central nervous system of amphibia.

  1966cited by this paper
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• The transport of potassium between blood, cerebrospinal fluid and brain.

  1965cited by this paper
• The after‐effects of impulses in the giant nerve fibres of Loligo

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• Mechanism of spreading cortical depression.

  1956cited by this paper

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