Download Last Word on Point:Counterpoint “Medullary pacemaker neurons are

J Appl Physiol 103: 726, 2007;
doi:10.1152/japplphysiol.00436.2007.
Letters 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”
Jan-Marino Ramirez and Alfredo Garcia III
Department of Organismal Biology and Anatomy, Committee on Neurobiology, The University of Chicago, Chicago, Illinois
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: [email protected]).
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We predict that these projections also play roles under in
vivo conditions. For example, noradrenergic descending inputs
from the pons could endogenously activate ␣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.
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.
1a.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.
2. 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.
3. 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.
3a.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.
4. Ramirez JM, Tryba AK, Peña FP. Pacemaker neurons: an integrative
view. Curr Opin Neurobiol 14: 665– 674, 2004.
5. Tryba AK, Pena F, Ramirez JM. Gasping activity in vitro: a rhythm
dependent on 5-HT2A receptors. J Neurosci 26: 2623–2634, 2006.
8750-7587/07 $8.00 Copyright © 2007 the American Physiological Society
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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.