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The Journal of Neuroscience, January 12, 2005, 25(2):446-453; doi:10.1523/JNEUROSCI.2237-04.2005
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Behavioral/Systems/Cognitive
Sodium and Calcium Current-Mediated Pacemaker Neurons and Respiratory Rhythm Generation
Christopher A. Del Negro,1,2 * Consuelo Morgado-Valle,1 * John A. Hayes,2 Devin D. Mackay,1 Ryland W. Pace,2 Erin A. Crowder,2 andJack L. Feldman1 1Systems Neurobiology Laboratory, Department of Neurobiology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California 90095-1763, and 2Department of Applied Science, The College of William and Mary, Williamsburg, Virginia 23187-8795
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 preBötzinger Complex in slice preparations from neonatal rodents and tested for pacemaker activity. We observed persistent Na+ current (INaP)-mediated bursting in
5% of inspiratory neurons in postnatal day 0 (P0)-P5 and in P8-P10 slices. INaP-mediated bursting was voltage dependent and blocked by 20 µM riluzole (RIL). We found Ca2+ current (ICa)-dependent bursting in 7.5% of inspiratory neurons in P8-P10 slices, but in P0-P5 slices these cells were exceedingly rare (0.6%). This bursting was voltage independent and blocked by 100 µM Cd2+ or flufenamic acid (FFA) (10-200 µM), which suggests that a Ca2+-activated inward cationic current (ICAN) underlies burst generation. These data substantiate our observation that P0-P5 slices exposed to RIL contain few (if any) pacemaker neurons, yet maintain respiratory rhythm. We also show that 20 nM TTX or coapplication of 20 µM RIL + FFA (100-200 µM) stops the respiratory rhythm, but that adding 2 µM substance P restarts it. We conclude that INaP and ICAN enhance neuronal excitability and promote rhythmogenesis, even if their magnitude is insufficient to support bursting-pacemaker activity in individual neurons. When INaP and ICAN are removed pharmacologically, the rhythm can be maintained by boosting neural excitability, which is inconsistent with a pacemaker-essential mechanism of respiratory rhythmogenesis by the preBötzinger complex.
Key words: breathing; preBötzinger Complex; brainstem; bursting; central pattern generator; calcium-activated nonspecific cation current (ICAN)
Received June 8, 2004; revised November 29, 2004; accepted November 29, 2004.
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