What Role Do Pacemakers Play in the Generation of Respiratory Rhythm?

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.