Glutamate tone in preBötzinger complex rhythmogenesis: ambient extracellular glutamate as a candidate excitability bias.
4 affiliations
- 1Doctorado en Investigaciones Cerebrales, Universidad Veracruzana, Dr. Castelazo Ayala s/n, Xalapa, 91190, Veracruz, Mexico.
- 2Instituto de Investigaciones Cerebrales, Universidad Veracruzana, Dr. Castelazo Ayala s/n, Xalapa, 91190, Veracruz, Mexico.
- 3Instituto de Investigaciones Cerebrales, Universidad Veracruzana, Dr. Castelazo Ayala s/n, Xalapa, 91190, Veracruz, Mexico. [email protected].
- 4Instituto de Investigaciones Cerebrales, Universidad Veracruzana, Dr. Castelazo Ayala s/n, Xalapa, 91190, Veracruz, Mexico. [email protected].
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.
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BibTeX
@article{vazquezmendoza2026glutamate,
title = {{Glutamate tone in preBötzinger complex rhythmogenesis: ambient extracellular glutamate as a candidate excitability bias.}},
author = {Enrique Vázquez-Mendoza and Carol Alejandra Olmos-Pastoresa and Donají Chí-Castañeda and María Leonor López-Meraz and Luis Beltran-Parrazal and Consuelo Morgado-Valle},
journal = {Pflugers Archiv : European journal of physiology},
year = {2026},
month = oct,
doi = {10.1007/s00424-026-03223-7},
url = {https://europepmc.org/article/MED/42888295},
note = {CC BY},
}
RIS
TY - JOUR
TI - Glutamate tone in preBötzinger complex rhythmogenesis: ambient extracellular glutamate as a candidate excitability bias.
AU - Enrique Vázquez-Mendoza
AU - Carol Alejandra Olmos-Pastoresa
AU - Donají Chí-Castañeda
AU - María Leonor López-Meraz
AU - Luis Beltran-Parrazal
AU - Consuelo Morgado-Valle
PY - 2026
DA - 2026/10/17
JO - Pflugers Archiv : European journal of physiology
DO - 10.1007/s00424-026-03223-7
UR - https://europepmc.org/article/MED/42888295
AB - 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.
SN - 0031-6768
SN - 1432-2013
ER -