title: Persistent Na+ and K+-dominated leak currents contribute to respiratory rhythm generation in the pre-Bötzinger complex in vitro.
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.
authors.affiliation: Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Koizumi
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Smith
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D008526:Medulla Oblongata / Q000502:physiology; D009415:Nerve Net / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010507:Periodicity; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D015656:Respiratory Mechanics / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism*; D012966:Sodium Cyanide / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D018377:Neurotransmitter Agents; D015221:Potassium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013373:Substance P; D013779:Tetrodotoxin; D012966:Sodium Cyanide