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

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Abstract
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 (INaP) 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 ofINaPwith multiple Na+channel antagonists: tetrodotoxin (TTX; 20 nm), riluzole (RIL; 10 μm), and the intracellular Na+channel antagonist QX‐314 (2 mm). Here we show thatINaPpromotes intraburst spiking in preBötC neurons but surprisingly does not contribute to the depolarization that underlies inspiratory bursts, i.e. the inspiratory drive potential. Local microinjection in the preBötC of 10 μmRIL or 20 nmTTX does not perturb respiratory frequency, even in the presence of bath‐applied 100 μmflufenamic acid (FFA), which attenuates a Ca2+‐activated non‐specific cation current (ICAN) that may also have burst‐generating functionality. These data contradict the hypothesis thatINaPin preBötC neurons is obligatory for rhythmogenesis. However, in the presence of FFA, local microinjection of 10 μmRIL in the raphe obscurus causes rhythm cessation, which suggests thatINaPregulates the excitability of neurons outside the preBötC, including serotonergic raphe neurons that project to, and help maintain, rhythmic preBötC function.