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The Journal of Neuroscience, February 13, 2008, 28(7):1773-1785; doi:10.1523/JNEUROSCI.3916-07.2008

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 Previous Article

Behavioral/Systems/Cognitive
Persistent Na⁺ and K⁺-Dominated Leak Currents Contribute to Respiratory Rhythm Generation in the Pre-Bötzinger Complex In Vitro

Hidehiko Koizumi and Jeffrey C. Smith

Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892

Correspondence should be addressed to Dr. Jeffrey C. Smith, Porter Neuroscience Research Center, 35 Convent Drive, Room 3C-917, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Email: jsmith{at}helix.nih.gov

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.

Key words: oscillations; brainstem; breathing; bursting neurons; membrane conductances; neuromodulation

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Received Jan. 28, 2007; revised Dec. 30, 2007; accepted Dec. 31, 2007.

Correspondence should be addressed to Dr. Jeffrey C. Smith, Porter Neuroscience Research Center, 35 Convent Drive, Room 3C-917, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Email: jsmith{at}helix.nih.gov

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