Glutamate tone in preBötzinger complex rhythmogenesis: ambient extracellular glutamate as a candidate excitability bias

Abstract

The preBötzinger complex (preBötC) is essential for inspiratory rhythm generation, yet the biological processes that repeatedly establish the excitability state required for neuronal recruitment remain incompletely understood. This unresolved issue is reflected in computational models of respiratory rhythmogenesis, which rely on a phenomenological baseline excitability parameter, [Formula: see text], without a defined biological substrate. Ambient extracellular glutamate signaling is well established in other brain regions, but its relevance to the respiratory network remains largely untested. Here, we evaluate the hypothesis that ambient extracellular glutamate outside synaptic clefts-termed glutamate tone-represents one biologically plausible candidate for a distributed extracellular network-state variable in the preBötC. We define glutamate tone as a continuously maintained but dynamically regulated extracellular glutamate signal arising from the balance of glutamate release, diffusion, transporter-mediated clearance, and astrocyte-dependent metabolism. We critically review evidence that extracellular glutamate handling can influence respiratory network activity, while emphasizing that direct evidence for a compartment-specific, rhythmogenesis-relevant glutamate tone remains lacking. We then evaluate candidate glutamate-sensing mechanisms, including peri-/extrasynaptic NMDA receptors and metabotropic glutamate receptors, and place them within the established framework of recurrent excitation, intrinsic membrane conductances, and inhibitory circuitry. We propose that glutamate tone, if present, would not generate the inspiratory burst directly, but could bias the excitability landscape from which neuronal recruitment and synchronization emerge. Finally, we outline experimental criteria for distinguishing a causal excitability bias from glutamate signals that merely reflect ongoing network activity.

The authors' abstract, as published at the source. Pflügers Archiv - European Journal of Physiology, 2026 · DOI ↗