scholarly journals The effect of lamotrigine and other antiepileptic drugs on respiratory rhythm generation in the pre‐Bötzinger complex

Epilepsia ◽  
2021 ◽  
Author(s):  
Nikolas Layer ◽  
Janine Brandes ◽  
Philipp Justus Lührs ◽  
Thomas V. Wuttke ◽  
Henner Koch
Keyword(s):  
Antiepileptic Drugs ◽  
Respiratory Rhythm ◽  
Rhythm Generation ◽  
Bötzinger Complex ◽  
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.

Isolation of the Kernel for Respiratory Rhythm Generation in a Novel Preparation: The Pre-Bötzinger Complex “Island”

2001 ◽  
Vol 85 (4) ◽  
pp. 1772-1776 ◽  
Author(s):  
Shereé M. Johnson ◽  
Naohiro Koshiya ◽  
Jeffrey C. Smith
Keyword(s):  
Respiratory Rhythm ◽  
Fluorescent Imaging ◽  
Extracellular Potassium ◽  
Synaptic Inhibition ◽  
Rhythm Generation ◽  
Population Activity ◽  
Thin Slices ◽  
Bötzinger Complex ◽  
Population Burst ◽  
Respiratory Rhythm Generation

The pre-Bötzinger complex (pre-BötC), a bilaterally distributed network of rhythmogenic neurons within the ventrolateral medulla, has been proposed to be the critical locus for respiratory rhythm generation in mammals. To date, thin transverse medullary slice preparations that capture the pre-BötC have served as the optimal experimental model to study the region's inherent cellular and network properties. We have reduced the thin slices to isolated pre-BötC “islands” to further establish whether the pre-BötC has intrinsic rhythmicity and is the kernel for rhythmogenesis in the slice. We recorded neuron population activity locally in the pre-BötC with macroelectrodes and fluorescent imaging of Ca2+ activities with Calcium Green-1AM dye before and after excising the island. The isolated island remained rhythmically active with a population burst profile similar to the inspiratory burst in the slice. Rhythmic population activity persisted in islands after block of GABAAergic and glycinergic synaptic inhibition. The loci of pre-BötC Ca2+ activity imaged in thin slices and islands were similar, and imaged pre-BötC neurons exhibited synchronized flashing after blocking synaptic inhibition. Population burst frequency increased monotonically as extracellular potassium concentration was elevated, consistent with mathematical models consisting entirely of an excitatory network of synaptically coupled pacemaker neurons with heterogeneous, voltage-dependent bursting properties. Our results provide further evidence for a rhythmogenic kernel in the pre-BötC in vitro and demonstrate that the islands are ideal preparations for studying the kernel's intrinsic properties.

Postnatal Development Differentially Affects Voltage-Activated Calcium Currents in Respiratory Rhythmic Versus Nonrhythmic Neurons of the Pre-Bötzinger Complex

2005 ◽  
Vol 94 (2) ◽  
pp. 1423-1431 ◽  
Author(s):  
Frank P. Elsen ◽  
Jan-Marino Ramirez
Keyword(s):  
Postnatal Development ◽  
Calcium Current ◽  
Respiratory Rhythm ◽  
Calcium Currents ◽  
Postnatal Life ◽  
Rhythm Generation ◽  
Patch Clamp Technique ◽  
Early Postnatal Development ◽  
Bötzinger Complex ◽  
Respiratory Rhythm Generation

The mammalian respiratory network reorganizes during early postnatal life. We characterized the postnatal developmental changes of calcium currents in neurons of the pre-Bötzinger complex (pBC), the presumed site for respiratory rhythm generation. The pBC contains not only respiratory rhythmic (R) but also nonrhythmic neurons (nR). Both types of neurons express low- and high-voltage-activated (LVA and HVA) calcium currents. This raises the interesting issue: do calcium currents of the two co-localized neuron types have similar developmental profiles? To address this issue, we used the whole cell patch-clamp technique to compare in transverse slices of mice LVA and HVA calcium current amplitudes of the two neuron populations (R and nR) during the first and second postnatal week (P0–P16). The amplitude of HVA currents did not significantly change in R pBC-neurons (P0–P16), but it significantly increased in nR pBC-neurons during P8–P16. The dehydropyridine (DHP)-sensitive current amplitudes did not significantly change during the early postnatal development, suggesting that the observed amplitude changes in nR pBC-neurons are caused by (DHP) insensitive calcium currents. The ratio between HVA calcium current amplitudes dramatically changed during early postnatal development: At P0–P3, current amplitudes were significantly larger in R pBC-neurons, whereas at P8–P16, current amplitudes were significantly larger in nR pBC-neurons. Our results suggest that calcium currents in pBC neurons are differentially altered during postnatal development and that R pBC-neurons have fully expressed calcium currents early during postnatal development. This may be critical for stable respiratory rhythm generation in the underlying rhythm generating network.

Transition Mechanisms of Bursting in a Two-Cell Network Model of the Pre-Bötzinger Complex

2015 ◽  
Vol 25 (05) ◽  
pp. 1550069 ◽  
Author(s):  
Lixia Duan ◽  
Dandan Yuan ◽  
Xi Chen ◽  
Xiangying Meng
Keyword(s):  
Network Model ◽  
Parameter Space ◽  
Respiratory Rhythm ◽  
Rhythm Generation ◽  
Synaptic Coupling ◽  
Cell Network ◽  
Bötzinger Complex ◽  
Respiratory Rhythm Generation ◽  
Two Parameter ◽  
Slow Decomposition

Persistent sodium and calcium activated nonspecific cationic currents play important roles in the respiratory rhythm generation of the pre-Bötzinger complex. In this paper, we study the bursting patterns and their transition mechanisms in the two-parameter space of a two-cell network model of the pre-Bötzinger complex with synaptic coupling. Using the methods of fast/slow decomposition and two-parameter bifurcation analysis, we divide the two-parameter space into four different regions according to the multiphase oscillations, and reveal the possible transition mechanisms of bursting between these different regions. We also study the dynamics of the system with varying synaptic coupling strength. This work provides insights of how currents and synaptic coupling work on the respiratory rhythm generation.

Medullary regions for neurogenesis of gasping: noeud vital or noeuds vitals?

1996 ◽  
Vol 81 (5) ◽  
pp. 1865-1877 ◽  
Author(s):  
Walter M. St. John
Keyword(s):  
Mammalian Species ◽  
Respiratory Rhythm ◽  
Rhythmic Activity ◽  
Neonatal Rat ◽  
Rhythm Generation ◽  
Bötzinger Complex ◽  
Per Se ◽  
Respiratory Rhythm Generation

St. John, Walter M. Medullary regions for neurogenesis of gasping: noeud vital or noeuds vitals? J. Appl. Physiol. 81(5): 1865–1877, 1996.—Gasping is a critical mechanism for survival in that it serves as a mechanism for autoresuscitation when eupnea fails. Eupnea and gasping are separable patterns of automatic ventilatory activity in all mammalian species from the day of birth. The neurogenesis of the gasp is dependent on the discharge of neurons in the rostroventral medulla. This gasping center overlaps a region termed “the pre-Bötzinger complex.” Neuronal activities of this complex, characterized in an in vitro brain stem spinal cord preparation of the neonatal rat, have been hypothesized to underlie respiratory rhythm generation. Yet, the rhythmic activity of this in vitro preparation is markedly different from eupnea but identical with gasping in vivo. In eupnea, medullary neuronal activities generating the gasp and the identical rhythm of the in vitro preparation are incorporated into a portion of the pontomedullary circuit defining eupneic ventilatory activity. However, these medullary neuronal activities do not appear critical for the neurogenesis of eupnea, per se.

CO2/H+ chemoreception in the cat pre-Bötzinger complex in vivo

2000 ◽  
Vol 88 (6) ◽  
pp. 1996-2007 ◽  
Author(s):  
Irene C. Solomon ◽  
Norman H. Edelman ◽  
Marvin H. O'Neal
Keyword(s):  
Phrenic Nerve ◽  
Respiratory Rhythm ◽  
High Amplitude ◽  
Rhythm Generation ◽  
Bötzinger Complex ◽  
Tissue Acidosis ◽  
Respiratory Rhythm Generation ◽  
Additional Support ◽  
Nerve Discharge

We examined the effects of focal tissue acidosis in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) on phrenic nerve discharge in chloralose-anesthetized, vagotomized, paralyzed, mechanically ventilated cats. Focal tissue acidosis was produced by unilateral microinjection of 10–20 nl of the carbonic anhydrase inhibitors acetazolamide (AZ; 50 μM) or methazolamide (MZ; 50 μM). Microinjection of AZ and MZ into 14 sites in the pre-BötC reversibly increased the peak amplitude of integrated phrenic nerve discharge and, in some sites, produced augmented bursts (i.e., eupneic breath ending with a high-amplitude, short-duration burst). Microinjection of AZ and MZ into this region also reversibly increased the frequency of eupneic phrenic bursts in seven sites and produced premature bursts (i.e., doublets) in five sites. Phrenic nerve discharge increased within 5–15 min of microinjection of either agent; however, the time to the peak increase and the time to recovery were less with AZ than with MZ, consistent with the different pharmacological properties of AZ and MZ. In contrast to other CO2/H+ brain stem respiratory chemosensitive sites demonstrated in vivo, which have only shown increases in amplitude of integrated phrenic nerve activity, focal tissue acidosis in the pre-BötC increases frequency of phrenic bursts and produces premature (i.e., doublet) bursts. These data indicate that the pre-BötC has the potential to play a role in the modulation of respiratory rhythm and pattern elicited by increased CO2/H+ and lend additional support to the concept that the proposed locus for respiratory rhythm generation has intrinsic chemosensitivity.

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