title: 4-Aminopyridine-sensitive outward currents in preBötzinger complex neurons influence respiratory rhythm generation in neonatal mice.
abstract: We measured a low-threshold, inactivating K+ current, i.e. A-current (I(A)), 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 I(A). In whole-cell and somatic outside-out patches I(A) 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 I(A) can influence membrane trajectory at baseline voltages during respiratory rhythm generation in vitro. 4-Aminopyridine (4-AP, 2 mm) attenuated I(A) 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 I(A) opposes excitatory synaptic depolarizations at baseline voltages of approximately -60 mV and influences the inspiratory burst pattern. We propose that I(A) 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.
authors.affiliation: Department of Applied Science, McGlothlin-Street Hall, Room 318, The College of William and Mary, Williamsburg, VA 23187-8795, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Hayes
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Mendenhall
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Brush
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Del Negro
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D001239:Inhalation / Q000502:physiology; D008526:Medulla Oblongata / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010507:Periodicity; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology*; D015656:Respiratory Mechanics / Q000502:physiology*
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D015761:4-Aminopyridine