4.6 Article

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

Journal

JOURNAL OF PHYSIOLOGY-LONDON
Volume 580, Issue 2, Pages 485-496

Publisher

WILEY
DOI: 10.1113/jphysiol.2006.124602

Keywords

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Funding

  1. NHLBI NIH HHS [R01 HL040959, HL-40959] Funding Source: Medline

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Breathing movements in mammals depend on respiratory neurons in the preBotzinger Complex (preBotC), which comprise a rhythmic network and generate robust bursts that form the basis for inspiration. Persistent Na+ current (I-NaP) is widespread in the preBotC 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 preBotC 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 mu M), and the intracellular Na+ channel antagonist QX-314 (2 mM). Here we show that I-NaP promotes intraburst spiking in preBotC neurons but surprisingly does not contribute to the depolarization that underlies inspiratory bursts, i.e. the inspiratory drive potential. Local microinjection in the preBotC of 10 mu M RIL or 20 nM TTX does not perturb respiratory frequency, even in the presence of bath-applied 100 mu M flufenamic acid (FFA), which attenuates a Ca2+-activated non-specific cation current (I-CAN) that may also have burst-generating functionality. These data contradict the hypothesis that I-NaP in preBotC neurons is obligatory for rhythmogenesis. However, in the presence of FFA, local microinjection of 10 mu M RIL in the raphe obscurus causes rhythm cessation, which suggests that I-NaP regulates the excitability of neurons outside the preBotC, including serotonergic raphe neurons that project to, and help maintain, rhythmic preBotC function.

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