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 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.

Models of Respiratory Rhythm Generation in the Pre-Bötzinger Complex. I. Bursting Pacemaker Neurons

1999 ◽  
Vol 82 (1) ◽  
pp. 382-397 ◽  
Author(s):  
Robert J. Butera ◽  
John Rinzel ◽  
Jeffrey C. Smith
Keyword(s):  
Membrane Potential ◽  
Respiratory Rhythm ◽  
Rhythm Generation ◽  
Minimal Models ◽  
Dynamic Features ◽  
Bursting Neurons ◽  
Wide Range ◽  
Bötzinger Complex ◽  
Voltage Dependent ◽  
Respiratory Rhythm Generation

A network of oscillatory bursting neurons with excitatory coupling is hypothesized to define the primary kernel for respiratory rhythm generation in the pre-Bötzinger complex (pre-BötC) in mammals. Two minimal models of these neurons are proposed. In model 1, bursting arises via fast activation and slow inactivation of a persistent Na+ current I NaP-h. In model 2, bursting arises via a fast-activating persistent Na+ current INaP and slow activation of a K+ current IKS. In both models, action potentials are generated via fast Na+ and K+currents. The two models have few differences in parameters to facilitate a rigorous comparison of the two different burst-generating mechanisms. Both models are consistent with many of the dynamic features of electrophysiological recordings from pre-BötC oscillatory bursting neurons in vitro, including voltage-dependent activity modes (silence, bursting, and beating), a voltage-dependent burst frequency that can vary from 0.05 to >1 Hz, and a decaying spike frequency during bursting. These results are robust and persist across a wide range of parameter values for both models. However, the dynamics of model 1 are more consistent with experimental data in that the burst duration decreases as the baseline membrane potential is depolarized and the model has a relatively flat membrane potential trajectory during the interburst interval. We propose several experimental tests to demonstrate the validity of either model and to differentiate between the two mechanisms.

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