The pacemaker hypothesis that specialized neurons with conditional oscillatory- bursting properties are obligatory for respiratory rhythm generation in vitro has gained widespread acceptance, despite lack of direct proof. Here we critique the pacemaker hypothesis and provide an alternative explanation for rhythmogenesis based on emergent network properties. Pacemaker neurons in the preBötC depend on either persistent Na+ current I nap or Ca2+-activated nonspecific cationic current (I can ). Activity in slice preparations and synaptically- isolated pacemaker neurons undergo similar frequency modulation by perturbations including hypoxia and changes in external K+. These data have been used to argue that pacemaker cells must be rhythmogenic, but may simply reflect the action of these perturbations on intrinsic membrane properties throughout the preBötC and does not constitute proof that pacemakers necessarily drive the rhythm with synaptic coupling in place. Likewise, bath-applied drugs, such as riluzole (RIL) and flufenamic acid (FFA), attenuate I nap and I can , respectively, throughout the slice. Thus, when these drugs stop the rhythm, a widespread depression of excitability is likely the underlying cause, not selective blockade of bursting-pacemaker activity. We propose that rhythmogenesis is an emergent network property, wherein recurrent synaptic excitation initiates a positive feedback cycle among interneurons and that intrinsic currents like I can and I nap promote inspiratory burst generation by augmenting synaptic excitation in the context of network activity. In this group-pacemaker framework, individual pacemaker neurons can be embedded but play the same role as every other network constituent.
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References
Brockhaus, J. and Ballanyi, K. (1998) Synaptic inhibition in the isolated respiratory network of neonatal rats. Eur. J. Neurosci. 10, 3823–3839.
Butera, R.J., Jr., Rinzel, J. and Smith J.C. (1999) Models of respiratory rhythm generation in the pre-Botzinger complex. I. Bursting pacemaker neurons. J. Neurophysiol. 82, 382–397.
Darbon, P., Scicluna, L., Tscherter, A. and Streit, J. (2002) Mechanisms controlling bursting activity induced by disinhibition in spinal cord networks. Eur. J. Neurosci. 15, 671–683.
Del Negro, C.A., Johnson, S.M., Butera, R.J. and Smith J.C. (2001) Models of respiratory rhythm generation in the pre-Bötzinger complex. III. Experimental tests of model predictions. J. Neurophysiol. 86, 59–74.
Del Negro, C.A., Koshiya, N., Butera, R.J. Jr. and Smith J.C. (2002a) Persistent sodium current, membrane properties and bursting behavior of pre-Botzinger complex inspiratory neurons in vitro. J. Neurophysiol. 88, 2242–2250.
Del Negro, C.A., Morgado-Valle, C. and Feldman, J.L. (2002b) Respiratory rhythm: an emergent network property? Neuron 34, 821–830.
Del Negro, C.A., Morgado-Valle, C., Hayes, J.A., Mackay, D.D., Pace, R.W., Crowder, E.A. and Feldman, J.L. (2005) Sodium and calcium dependent pacemaker neurons and respiratory rhythm generation. J. Neurosci. 25, 446–453.
Feldman, J.L. and Smith J.C. (1989) Cellular mechanisms underlying modulation of breathing pattern in mammals. Ann. N.Y. Acad. Sci. 563, 114–130.
Koshiya, N. and Smith, J.C. (1999) Neuronal pacemaker for breathing visualized in vitro. Nature 400, 360–363.
Kosmidis, E.K., Pierrefiche, O. and Vibert J.F. (2004) Respiratory-like rhythmic activity can be produced by an excitatory network of non-pacemaker neuron models. J. Neurophysiol. 92, 686–699.
Pace, R.W., MacKay, D.D., Feldman, J.L. and Del Negro, C.A. (2007a) Inspiratory bursts in the preBötzinger complex depend on a calcium-activated nonspecific cationic current linked to glutamate receptors. J. Physiol, in press.
Pace, R.W., MacKay, D.D., Feldman, J.L. and Del Negro, C.A. (2007b) Role of persistent sodium current in mouse preBötzinger complex neurons and respiratory rhythm generation. J. Physiol. 580(2):485–496.
Pena, F., Parkis, M.A., Tryba, A.K. and Ramirez, J.M. (2004) Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia. Neuron 43, 105–117.
Ptak, K., Zummo, G.G., Alheid, G.F., Tkatch, T., Surmeier, D.J. and McCrimmon, D.R. (2005) Sodium currents in medullary neurons isolated from the pre-Botzinger complex region. J. Neurosci. 25, 5159–5170.
Rekling, J.C., Champagnat, J. and Denavit-Saubie, M. (1996) Electroresponsive properties and membrane potential trajectories of three types of inspiratory neurons in the newborn mouse brain stem in vitro. J. Neurophysiol. 75, 795–810.
Rekling, J.C. and Feldman, J.L. (1998) Prebötzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. Annu. Rev. Physiol. 60, 385–405.
Smith, J.C., Butera, R.J., Koshiya, N., Del Negro, C., Wilson, C.G. and Johnson, S.M. (2000) Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker-network model. Respir. Physiol. 122, 131–147.
Smith, J.C., Ellenberger, H.H., Ballanyi, K., Richter, D.W. and Feldman, J.L. (1991) Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science 254, 726–729.
Thoby-Brisson, M. and Ramirez, J.M. (2001) Identification of two types of inspiratory pacemaker neurons in the isolated respiratory neural network of mice. J. Neurophysiol. 86, 104–112.
Thoby-Brisson, M. and Ramirez, J.M. (2000) Role of inspiratory pacemaker neurons in mediating the hypoxic response of the respiratory network in vitro. J. Neurosci. 20, 5858–5866.
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Negro, C.A.D., Pace, R.W., Hayes, J.A. (2008). What Role Do Pacemakers Play in the Generation of Respiratory Rhythm?. In: Poulin, M.J., Wilson, R.J.A. (eds) Integration in Respiratory Control. Advances in Experimental Medicine and Biology, vol 605. Springer, New York, NY. https://doi.org/10.1007/978-0-387-73693-8_15
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