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Received November 8, 2006
Revised December 6, 2006
Accepted after revision January 31, 2007
1 The College of William and Mary
2 University of California, Los Angeles
3 The College of William and Mary, University of California, Los Angeles
* To whom correspondence should be addressed. E-mail: cadeln{at}wm.edu.
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 of INaP with 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 that INaP 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 µM RIL or 20 nM TTX does not perturb respiratory frequency, even in the presence of bath-applied 100 µM flufenamic acid (FFA), which attenuates a Ca2+-activated non-specific cation current (ICAN) that may also have burst-generating functionality. These data contradict the hypothesis that INaP in preBötC neurons is obligatory for rhythmogenesis. However, in the presence of FFA, local microinjection of 10 µM RIL in the raphé obscurus causes rhythm cessation, which suggests that INaP regulates the excitability of neurons outside the preBötC, including serotonergic raphé neurons that project to, and help maintain rhythmic preBötC function.
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