Journal of Applied Physiology
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J Appl Physiol 103: 726, 2007. First published April 26, 2007; doi:10.1152/japplphysiol.00436.2007
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LETTER TO THE EDITOR

Last Word on Point:Counterpoint "Medullary pacemaker neurons are essential for both eupnea and gasping in mammals vs. medullary pacemaker neurons are essential for gasping, but not eupnea, in mammals"

The majority of pacemaker recordings were obtained in vitro.   This approach allowed careful identification of different pacemaker types. Numerous in vitro studies characterized pacemaker responses to synaptic inputs, neuromodulators, and hypoxia (2, 4, 5). The emerging picture is complex and reveals multiple and highly plastic ways to regulate pacemaker activity (2). In contrast to the large amount of in vitro evidence, only very few and not well-identified pacemakers were recorded in situ (1), and no pacemaker has been recorded so far in vivo. Nothing is known about their modulation by synaptic inputs, neuromodulators, nor how they interact with other areas in any in vivo or in situ setting. The existing indirect in situ and in vivo evidence thus far confirms concepts first established in vitro (1, 3). Therefore, until we are able to collect detailed in situ and in vivo evidence, we depend only on in vitro data to make testable predictions how pacemakers may behave in vivo.

Predictions based on in vitro data.   1) Synaptic inhibition is a powerful mechanism that regulates degree and type of pacemaker bursting (4). In hypoxia, synaptic inhibition is decreased through shut down of inhibitory neurons, which facilitates bursting in some, but not all, pacemakers.

We predict that this is also the case in vivo. There will be hypoxic and normoxic conditions where changes in the activation of inhibitory neurons will alter the relative contribution of pacemakers and bursting properties. The deeply rooted belief that inhibition plays a role only in adult animals and only in vivo and in situ is pure speculation.

2) Neuromodulation is an equally powerful mechanism to regulate pacemaker properties (4, 5). Neuromodulators amplify and weaken bursting and turn pacemaker properties on and off. The nervous system is equipped with an impressive arsenal of noradrenergic, serotonergic, and peptidergic inputs projecting from numerous brain regions onto pacemaker neurons.

We predict that these projections also play roles under in vivo conditions. For example, noradrenergic descending inputs from the pons could endogenously activate {alpha}1-receptors, which in vitro produce an augmenting burst shape characteristic for eupnea. The belief that pons suppresses pacemaker activity is pure speculation.

Last words.   In vitro research has demonstrated that bursting produced by pacemakers is not a rigid cellular property incompatible with the high degree of regulation necessary to generate a complex behavior such as eupnea. Multiple synaptic and modulatory processes prevent pacemakers from being simple "autorhythmic" cells when embedded in a network (4). Instead, bursting of pacemakers is a highly plastic nonlinear property that is useful in synchronizing, escaping inhibitory processes, amplifying excitatory processes, influencing timing, and stabilizing or destabilizing network activity (4).

We hope that some day our data will be able to eradicate the deeply rooted and undocumented belief that pacemakers are simple phylogenetic backup mechanisms useful only under emergency situations such as gasping. Overly simplistic statements, such as "pacemakers are suppressed during eupnea" are not based on evidence and only hamper progress in unraveling the roles of pacemakers in the respiratory network.

FOOTNOTES


Address for reprint requests and other correspondence: J.-M. Ramirez, Dept. of Organismal Biology and Anatomy, Committee on Neurobiology, The Univ. of Chicago, Chicago, IL 60637 (e-mail: jramire{at}uchicago.edu)

REFERENCES

  1. Paton JF, Abdala AP, Koizumi H, Smith JC, St-John WM. Respiratory rhythm generation during gasping depends on persistent sodium current. Nat Neurosci 9: 311–313, 2006.[CrossRef][ISI][Medline]
  2. Paton JFR, St-John MW. Counterpoint: Medullary pacemaker neurons are essential for gasping, but not eupnea, in mammals. J Appl Physiol. doi:10.1152/japplphysiol.00003a.2007.
  3. Pena F, Parkis MA, Tryba AK, Ramirez JM. Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia. Neuron 43: 105–117, 2004.[CrossRef][ISI][Medline]
  4. Pena F, Aguileta MA. Effects of riluzole and flufenamic acid on eupnea and gasping of neonatal mice in vivo. Neurosci Lett 415: 288–293, 2007.[CrossRef][ISI][Medline]
  5. Ramirez JM, Garcia A III. Point: Medullary pacemaker neurons are essential for both eupnea and gasping in mammals. J Appl Physiol. doi:10.1152/japplphysiol.00003.2007.
  6. Ramirez JM, Tryba AK, Peña FP. Pacemaker neurons: an integrative view. Curr Opin Neurobiol 14: 665–674, 2004.[CrossRef][ISI][Medline]
  7. Tryba AK, Pena F, Ramirez JM. Gasping activity in vitro: a rhythm dependent on 5-HT2A receptors. J Neurosci 26: 2623–2634, 2006.[Abstract/Free Full Text]

Jan-Marino Ramirez
Alfredo Garcia, III
 Department of Organismal Biology and Anatomy, Committee on Neurobiology, The University of Chicago, Chicago, Illinois





This Article
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103/2/726    most recent
00436.2007v1
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