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.

AMPA and metabotropic glutamate receptors cooperatively generate inspiratory-like depolarization in mouse respiratory neurons in vitro.

Excitatory transmission mediated by AMPA receptors is critical for respiratory rhythm generation. However, the role of AMPA receptors has not been fully explored. Here we tested the functional role of AMPA receptors in inspiratory neurons of the neonatal mouse preBötzinger complex (preBötC) using an in vitro slice model that retains active respiratory function.

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 Ca(2+)-activated nonspecific cationic current (I(CAN)).

Phosphatidylinositol 4,5-bisphosphate regulates inspiratory burst activity in the neonatal mouse preBötzinger complex.

Neurons of the preBötzinger complex (preBötC) form local excitatory networks and synchronously discharge bursts of action potentials during the inspiratory phase of respiratory network activity. Synaptic input periodically evokes a Ca(2+)-activated non-specific cation current (I(CAN)) postsynaptically to generate 10-30 mV transient depolarizations, dubbed inspiratory drive potentials, which underlie inspiratory bursts. The molecular identity of I(CAN) and its regulation by intracellular signalling mechanisms during inspiratory drive potential generation remains unknown.

Inspiratory bursts in the preBötzinger complex depend on a calcium-activated non-specific cation current linked to glutamate receptors in neonatal mice.

Inspiratory neurons of the preBötzinger complex (preBötC) form local excitatory networks and display 10-30 mV transient depolarizations, dubbed inspiratory drive potentials, with superimposed spiking. AMPA receptors are critical for rhythmogenesis under normal conditions in vitro but whether other postsynaptic mechanisms contribute to drive potential generation remains unknown. We examined synaptic and intrinsic membrane properties that generate inspiratory drive potentials in preBötC neurons using neonatal mouse medullary slice preparations that generate respiratory rhythm.

Role of persistent sodium current in mouse preBötzinger Complex neurons and respiratory rhythm generation.

Breathing movements in mammals depend on respiratory neurons in the preBötzinger Complex (preBötC), which comprise a rhythmic network and generate robust bursts that form the basis for inspiration. Persistent Na(+) current (I(NaP)) is widespread in the preBötC and is hypothesized to play a critical role in rhythm generation because of its subthreshold activation and slow inactivation properties that putatively promote long-lasting burst depolarizations. In neonatal mouse slice preparations that retain the preBötC and generate a respiratory-related rhythm, we tested the role of I(NaP) with multiple Na(+) channel antagonists: tetrodotoxin (TTX; 20 nM), riluzole (RIL; 10 microM), and the intracellular Na(+) channel antagonist QX-314 (2 mM).

Sodium and calcium current-mediated pacemaker neurons and respiratory rhythm generation.

The breathing motor pattern in mammals originates in brainstem networks. Whether pacemaker neurons play an obligatory role remains a key unanswered question. We performed whole-cell recordings in the preBotzinger Complex in slice preparations from neonatal rodents and tested for pacemaker activity.