J Physiol Volume 586, Number 7, 1921-1936, April 1, 2008 DOI: 10.1113/jphysiol.2008.150946
4-Aminopyridine-sensitive outward currents in preBötzinger complex neurons influence respiratory rhythm generation in neonatal mice
John A. Hayes1,
Jeffrey L. Mendenhall1,
Benjamin R. Brush1 and
Christopher A. Del Negro1
1 Department of Applied Science, McGlothlin-Street Hall, Room 318, The College of William and Mary, Williamsburg, VA 23187-8795, USA
We measured a low-threshold, inactivating K+ current, i.e. A-current (IA), in respiratory neurons of the preBötzinger complex (preBötC) in rhythmically active slice preparations from neonatal C57BL/6 mice. The majority of inspiratory neurons (21/34 = 61.8%), but not expiratory neurons (1/8 = 12.5%), expressed IA. In whole-cell and somatic outside-out patches IA activated at –60 mV (half-activation voltage measured –16.3 mV) and only fully inactivated above –40 mV (half-inactivation voltage measured –85.6 mV), indicating that IA can influence membrane trajectory at baseline voltages during respiratory rhythm generation in vitro. 4-Aminopyridine (4-AP, 2 mM) attenuated IA in both whole-cell and somatic outside-out patches. In the context of rhythmic network activity, 4-AP caused irregular respiratory-related motor output on XII nerves and disrupted rhythmogenesis as detected with whole-cell and field recordings in the preBötC. Whole-cell current-clamp recordings showed that 4-AP changed the envelope of depolarization underlying inspiratory bursts (i.e. inspiratory drive potentials) from an incrementing pattern to a decrementing pattern during rhythm generation and abolished current pulse-induced delayed excitation. These data suggest that IA opposes excitatory synaptic depolarizations at baseline voltages of approximately –60 mV and influences the inspiratory burst pattern. We propose that IA promotes orderly recruitment of constituent rhythmogenic neurons by minimizing the activity of these neurons until they receive massive coincident synaptic input, which reduces the periodic fluctuations of inspiratory activity.
(Received 10 January 2008;
accepted after revision 5 February 2008;
first published online 7 February 2008)
Corresponding author C. A. Del Negro: Department of Applied Science, McGlothlin-Street Hall, Room 318, The College of William and Mary, Williamsburg, VA 23187-8795, USA. Email: cadeln{at}wm.edu
Copyright © 2008 The Physiological Society.