scholarly journals Role of persistent sodium current in mouse preBötzinger Complex neurons and respiratory rhythm generation

2007 ◽  
Vol 580 (2) ◽  
pp. 485-496 ◽  
Author(s):  
Ryland W. Pace ◽  
Devin D. Mackay ◽  
Jack L. Feldman ◽  
Christopher A. Del Negro
Keyword(s):  
Sodium Current ◽  
Respiratory Rhythm ◽  
Persistent Sodium Current ◽  
Rhythm Generation ◽  
Respiratory Rhythm Generation ◽  
Prebotzinger Complex ◽  
Prebötzinger Complex

Respiratory rhythm generation during gasping depends on persistent sodium current

2006 ◽  
Vol 9 (3) ◽  
pp. 311-313 ◽  
Author(s):  
Julian F R Paton ◽  
Ana P L Abdala ◽  
Hidehiko Koizumi ◽  
Jeffrey C Smith ◽  
Walter M St-John
Keyword(s):  
Sodium Current ◽  
Respiratory Rhythm ◽  
Persistent Sodium Current ◽  
Rhythm Generation ◽  
Respiratory Rhythm Generation

scholarly journals Putting the theory into 'burstlet theory': A biophysical model of bursts and burstlets in the respiratory preBötzinger complex

2021 ◽  
Author(s):  
Ryan S Phillips ◽  
Jonathan E Rubin
Keyword(s):  
Neuronal Activity ◽  
Respiratory Rhythm ◽  
Motor Output ◽  
Biophysical Model ◽  
Extracellular Potassium ◽  
Rhythm Generation ◽  
Cationic Current ◽  
Respiratory Rhythm Generation ◽  
Prebotzinger Complex ◽  
Prebötzinger Complex

Inspiratory breathing rhythms arise from synchronized neuronal activity in a bilaterally distributed brainstem structure known as the preBötzinger complex (preBötC). In in vitro slice preparations containing the preBötC, extracellular potassium must be elevated above physiological levels (to 7-9mM) to observe regular rhythmic respiratory motor output in the hypoglossal nerve to which the preBötC projects. Reexamination of how extracellular K+ affects preBötC neuronal activity has revealed that low amplitude oscillations persist at physiological levels. These oscillatory events are sub-threshold from the standpoint of transmission to motor output and are dubbed burstlets. Burstlets arise from synchronized neural activity in a rhythmogenic neuronal subpopulation within the preBötC that in some instances may fail to recruit the larger network events, or bursts, required to generate motor output. The fraction of subthreshold preBötC oscillatory events (burstlet fraction) decreases sigmoidally with increasing extracellular potassium. These observations underlie the burstlet theory of respiratory rhythm generation. Experimental and computational studies have suggested that recruitment of the non-rhythmogenic component of the preBötC population requires intracellular Ca2+ dynamics and activation of a calcium-activated non-selective cationic current. In this computational study, we show how intracellular calcium dynamics driven by synaptically triggered Ca2+ influx as well as Ca2+ release/uptake by the endoplasmic reticulum in conjunction with a calcium-activated non-selective cationic current can explain all of the key observations underlying the burstlet theory of respiratory rhythm generation. Thus, we provide a mechanistic basis to unify the experimental findings on rhythm generation and motor output recruitment in the preBötC.

scholarly journals Effects of persistent sodium current blockade in respiratory circuits depend on the pharmacological mechanism of action and network dynamics

2019 ◽  
Author(s):  
Ryan S. Phillips ◽  
Jonathan E. Rubin
Keyword(s):  
Experimental Data ◽  
Sodium Current ◽  
Respiratory Rhythm ◽  
Experimental Results ◽  
Respiratory Neurons ◽  
Persistent Sodium Current ◽  
Rhythm Generation ◽  
Respiratory Network ◽  
Respiratory Rhythm Generation

AbstractThe mechanism(s) of action of most commonly used pharmacological blockers of voltage-gated ion channels are well understood; however, this knowledge is rarely considered when interpreting experimental data. Effects of blockade are often assumed to be equivalent, regardless of the mechanism of the blocker involved. Using computer simulations, we demonstrate that this assumption may not always be correct. We simulate the blockade of a persistent sodium current (INaP), proposed to underlie rhythm generation in pre-Bötzinger complex (pre-BötC) respiratory neurons, via two distinct pharmacological mechanisms: (1) pore obstruction mediated by tetrodotoxin and (2) altered inactivation dynamics mediated by riluzole. The reported effects of experimental application of tetrodotoxin and riluzole in respiratory circuits are diverse and seemingly contradictory and have led to considerable debate within the field as to the specific role ofINaPin respiratory circuits. The results of our simulations match a wide array of experimental data spanning from the level of isolated pre-BötC neurons to the level of the intact respiratory network and also generate a series of experimentally testable predictions. Specifically, in this study we: (1) provide a mechanistic explanation for seemingly contradictory experimental results from in vitro studies ofINaPblock, (2) show that the effects ofINaPblock in in vitro preparations are not necessarily equivalent to those in more intact preparations, (3) demonstrate and explain why riluzole application may fail to effectively blockINaPin the intact respiratory network, and (4) derive the prediction that effective block ofINaPby low concentration tetrodotoxin will stop respiratory rhythm generation in the intact respiratory network. These simulations support a critical role forINaPin respiratory rhythmogenesis in vivo and illustrate the importance of considering mechanism when interpreting and simulating data relating to pharmacological blockade.Author summaryThe application of pharmacological agents that affect transmembrane ionic currents in neurons is a commonly used experimental technique. A simplistic interpretation of experiments involving these agents suggests that antagonist application removes the impacted current and that subsequently observed changes in activity are attributable to the loss of that current’s effects. The more complex reality, however, is that different drugs may have distinct mechanisms of action, some corresponding not to a removal of a current but rather to a changing of its properties. We use computational modeling to explore the implications of the distinct mechanisms associated with two drugs, riluzole and tetrodotoxin, that are often characterized as sodium channel blockers. Through this approach, we offer potential explanations for disparate findings observed in experiments on neural respiratory circuits and show that the experimental results are consistent with a key role for the persistent sodium current in respiratory rhythm generation.

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