Persistent Na+ and K+-dominated leak currents contribute to respiratory rhythm generation in the pre-Bötzinger complex in vitro

J Neurosci. 2008 Feb 13;28(7):1773-85. doi: 10.1523/JNEUROSCI.3916-07.2008.

Abstract

A central problem in analyzing neural circuit function is establishing how intrinsic neuronal conductances contribute to the generation of network activity. We used real-time calcium activity imaging combined with whole-cell patch-clamp recording to analyze contributions of subthreshold conductances in the excitatory rhythm-generating network in the respiratory pre-Bötzinger complex (pre-BötC) of neonatal rat in vitro brainstem slice preparations. Voltage-clamp ramp recordings from imaged pre-BötC neurons revealed that persistent sodium (NaP) and K+-dominated leak currents primarily contribute to subthreshold I-V relations. We quantified NaP and leak conductance densities (g/C(m)) in intrinsic oscillatory bursters and intrinsically nonbursters, the two main electrophysiological phenotypes of inspiratory neurons within the pre-BötC. Densities of g(NaP) were significantly higher for intrinsic bursters, whereas leak conductance densities were not significantly different between intrinsic bursters and nonbursters. By pharmacologically manipulating g(NaP) and/or g(Leak) directly within the pre-BötC, we could modulate network oscillation frequency over a wide dynamic range and cause transitions between oscillatory and quiescent states. These results were consistent with models of the pre-BötC excitatory network consisting of heterogeneous mixtures of intrinsic bursters and nonintrinsic bursters incorporating g(NaP) and g(Leak) with parameter values found experimentally. We propose a paradigm whereby NaP and Leak represent a functional set of subthreshold conductances that endow the pre-BötC with rhythmogenic properties and represent targets for modulatory control of inspiratory rhythm generation.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Medulla Oblongata / physiology
  • Nerve Net / physiology*
  • Neurons / metabolism
  • Neurotransmitter Agents / pharmacology
  • Patch-Clamp Techniques
  • Periodicity*
  • Potassium Channels / metabolism*
  • Rats
  • Respiratory Mechanics / physiology*
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / metabolism*
  • Sodium Cyanide / pharmacology
  • Substance P / pharmacology
  • Tetrodotoxin / pharmacology

Substances

  • Neurotransmitter Agents
  • Potassium Channels
  • Sodium Channel Blockers
  • Sodium Channels
  • Substance P
  • Tetrodotoxin
  • Sodium Cyanide