Synaptically activated burst-generating conductances may underlie a group-pacemaker mechanism for respiratory rhythm generation in mammals.

Breathing, chewing, and walking are critical life-sustaining behaviors in mammals that consist essentially of simple rhythmic movements. Breathing movements in particular involve the diaphragm, thorax, and airways but emanate from a network in the lower brain stem. This network can be studied in reduced preparations in vitro and using simplified mathematical models that make testable predictions. An iterative approach that employs both in vitro and in silico models argues against canonical mechanisms for respiratory rhythm in neonatal rodents that involve reciprocal inhibition and pacemaker properties. We present an alternative model in which emergent network properties play a rhythmogenic role. Specifically, we show evidence that synaptically activated burst-generating conductances-which are only available in the context of network activity-engender robust periodic bursts in respiratory neurons. Because the cellular burst-generating mechanism is linked to network synaptic drive we dub this type of system a group pacemaker.

4-Aminopyridine-sensitive outward currents in preBötzinger complex neurons influence respiratory rhythm generation in neonatal mice.

We measured a low-threshold, inactivating K+ current, i.e. A-current (I(A)), in respiratory neurons of the preBötzinger complex (preBötC) in rhythmically active slice preparations from neonatal C57BL/6 mice. The majority of inspiratory neurons (21/34 = 61.8%), but not expiratory neurons (1/8 = 12.5%), expressed I(A). In whole-cell and somatic outside-out patches I(A) activated at -60 mV (half-activation voltage measured -16.3 mV) and only fully inactivated above -40 mV (half-inactivation voltage measured -85.6 mV), indicating that I(A) can influence membrane trajectory at baseline voltages during respiratory rhythm generation in vitro. 4-Aminopyridine (4-AP, 2 mm) attenuated I(A) in both whole-cell and somatic outside-out patches. In the context of rhythmic network activity, 4-AP caused irregular respiratory-related motor output on XII nerves and disrupted rhythmogenesis as detected with whole-cell and field recordings in the preBötC. Whole-cell current-clamp recordings showed that 4-AP changed the envelope of depolarization underlying inspiratory bursts (i.e. inspiratory drive potentials) from an incrementing pattern to a decrementing pattern during rhythm generation and abolished current pulse-induced delayed excitation. These data suggest that I(A) opposes excitatory synaptic depolarizations at baseline voltages of approximately -60 mV and influences the inspiratory burst pattern. We propose that I(A) promotes orderly recruitment of constituent rhythmogenic neurons by minimizing the activity of these neurons until they receive massive coincident synaptic input, which reduces the periodic fluctuations of inspiratory activity.