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PERSPECTIVES |
1 Department of Comparative Biosciences, School of Veterinary Medicine, 2015 Linden Drive, Madison, WI 53706, USA
Email: johnsons{at}svm.vetmed.wisc.edu
The mammalian respiratory control system in the brainstem produces a robust rhythm that drives respiratory muscles and maintains blood gas homeostasis from birth to death. Unfortunately, there is a great deal that is still not known with respect to how key cellular and synaptic mechanisms contribute to this fundamental rhythm. Among the models currently being debated (Fig. 1), the pacemaker-network hypothesis proposes that some respiratory neurons have intrinsic membrane conductances that cause the membrane potential to spontaneously oscillate (i.e. pacemaker properties). Synaptic inputs modulate pacemaker neuron excitability, but ultimately the breathing rhythm is derived from pacemaker properties (Smith et al. 2000; Ramirez & Viemari, 2005). In contrast, the network hypothesis proposes that the breathing rhythm is due to neurons that are reciprocally coupled by inhibitory synaptic connections, thereby establishing a straightforward oscillatory neural network (Richter et al. 1992). Finally, the group-pacemaker hypothesis proposes that inspiratory bursts of action potentials are an emergent property of non-pacemaker neurons that are interconnected by chemical and electrotonic excitatory synaptic interactions; pacemaker neurons are not required (Rekling & Feldman, 1998; Feldman & Del Negro, 2006). The pacemaker-network and network hypotheses incorporate the interaction between synaptic inputs and intrinsic membrane conductances into their models, but these interactions are at the heart of the group-pacemaker model.
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In this issue of The Journal of Physiology, Pace et al. (2007) extend this line of research by investigating potential mechanisms underlying the group-pacemaker hypothesis at the cellular level. With whole-cell recordings of inspiratory neurons in rhythmically active medullary slices, Pace et al. (2007) show that large inspiratory drive potentials (i.e. 10–30 mV depolarizations occurring during the inspiratory phase) are due to activation of ICAN. They also show that ICAN activation requires activation of NMDA or group I metabotropic glutamate (mGluR1) receptors. The authors conclude that glutamatergic excitatory synaptic inputs are required to evoke the ICAN-dependent inspiratory drive potentials, rather than ICAN alone being the main source of inspiratory drive potentials (as suggested by the pacemaker hypothesis). The importance of this study is that, once again, it demonstrates the plausibility of the group-pacemaker hypothesis for respiratory rhythm generation.
Does this mean that pacemaker neurons are not involved in rhythm generation? Of course not! Other investigators suggest that pacemaker neurons may still play a critical role in rhythm generation (Ramirez et al. 2007). Also, the respiratory control system is multifunctional, state-dependent, highly modulated, and capable of significant plasticity. Thus, the relative contribution of pacemaker properties and synaptic inputs to rhythm generation is likely to be very dynamic. During normal quiet breathing, the respiratory rhythm may be predominantly due to inhibitory synaptic transmission (network hypothesis) and glutamatergic–ICAN interactions (group-pacemaker hypothesis). During hypoxia, however, the respiratory control network may shift to a different operating mode that is more dependent on pacemaker properties and produce gasping behaviour (Paton et al. 2006).
To an outside observer, the debate regarding the cellular and synaptic mechanisms underlying respiratory rhythm generation may appear to be an exercise in hair-splitting semantics. However, understanding precisely how the brain produces the breathing rhythm is not only a fascinating biological problem, but it may also lead to critical insights for treating respiratory-related diseases and pathological conditions, such as sleep-disordered breathing, spinal cord injury, sudden infant death syndrome, Rett syndrome and congenital hypoventilation.
References
Del Negro C, Morgado-Valle C & Feldman J (2002). Neuron 34, 821–830.[CrossRef][Medline]
Del Negro CA, Morgado-Valle C, Hayes JA, Mackay DD, Pace RW, Crowder EA & Feldman JA (2005). J Neurosci 25, 446–453.
Feldman JL & Del Negro CA (2006). Nat Rev Neurosci 7, 232–242.[CrossRef][Medline]
Pace RW, Mackay DD, Feldman JL & Del Negro CA (2007). J Physiol 582, 113–125.
Paton JFR, Abdala APL, Koizumi H, Smith JC & St-John WM (2006). Nat Neurosci 9, 311–313.[CrossRef][Medline]
Ramirez JM, St John WM, Paton JF & Garcia A (2007). J Appl Physiol; (in press):
Ramirez JM & Viemari JC (2005). Respir Physiol Neurobiol 147, 145–157.[CrossRef][Medline]
Rekling JC & Feldman JL (1998). Annu Rev Physiol 60, 385–405.[CrossRef][Medline]
Richter DW, Ballanyi K & Schwarzacher S (1992). Curr Opin Neurobiol 2, 788–793.[CrossRef][Medline]
Smith JC, Butera RJ Jr, Koshiya N, Del Negro C, Wilson CG & Johnson SM (2000). Respir Physiol 122, 131–147.[CrossRef][Medline]
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