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). Here we show that I(NaP) promotes 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 microM RIL or 20 nM TTX does not perturb respiratory frequency, even in the presence of bath-applied 100 microM flufenamic acid (FFA), which attenuates a Ca(2+)-activated non-specific cation current (I(CAN)) that may also have burst-generating functionality. These data contradict the hypothesis that I(NaP) in preBötC neurons is obligatory for rhythmogenesis. However, in the presence of FFA, local microinjection of 10 microM RIL in the raphe obscurus causes rhythm cessation, which suggests that I(NaP) regulates the excitability of neurons outside the preBötC, including serotonergic raphe neurons that project to, and help maintain, rhythmic preBötC function.
Pace
Ryland W
RW
Department of Applied Science, The College of William and Mary, Williamsburg, VA 23187-8795, USA.
Mackay
Devin D
DD
Feldman
Jack L
JL
Del Negro
Christopher A
CA
D000779:Anesthetics, Local; D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D001239:Inhalation; D008012:Lidocaine / Q000031:analogs & derivatives; D008526:Medulla Oblongata / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009474:Neurons / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*
D000779:Anesthetics, Local; C012647:QX-314; D008012:Lidocaine; D012964:Sodium