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TRPM4 mediates a subthreshold membrane potential oscillation in respiratory chemoreceptor neurons that drives pacemaker firing and breathing.

ABSTRACT: Brainstem networks that control regular tidal breathing depend on excitatory drive, including from tonically active, CO₂/H⁺-sensitive neurons of the retrotrapezoid nucleus (RTN). Here, we examine intrinsic ionic mechanisms underlying the metronomic firing activity characteristic of RTN neurons. In mouse brainstem slices, large-amplitude membrane potential oscillations are evident in synaptically isolated RTN neurons after blocking action potentials. The voltage-dependent oscillations are abolished by sodium replacement; blocking calcium channels (primarily L-type); chelating intracellular Ca²⁺; and inhibiting TRPM4, a Ca²⁺-dependent cationic channel. Likewise, oscillation voltage waveform currents are sensitive to calcium and TRPM4 channel blockers. Extracellular acidification and serotonin (5-HT) evoke membrane depolarization that augments TRPM4-dependent oscillatory activity and action potential discharge. Finally, inhibition of TRPM4 channels in the RTN of anesthetized mice reduces central respiratory output. These data implicate TRPM4 in a subthreshold oscillation that supports the pacemaker-like firing of RTN neurons required for basal, CO₂-stimulated, and state-dependent breathing.

SUBMITTER: Li K

PROVIDER: S-EPMC7888550 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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TRPM4 mediates a subthreshold membrane potential oscillation in respiratory chemoreceptor neurons that drives pacemaker firing and breathing.

Li Keyong K Abbott Stephen B G SBG Shi Yingtang Y Eggan Pierce P Gonye Elizabeth C EC Bayliss Douglas A DA

Cell reports 20210201 5

Brainstem networks that control regular tidal breathing depend on excitatory drive, including from tonically active, CO<sub>2</sub>/H<sup>+</sup>-sensitive neurons of the retrotrapezoid nucleus (RTN). Here, we examine intrinsic ionic mechanisms underlying the metronomic firing activity characteristic of RTN neurons. In mouse brainstem slices, large-amplitude membrane potential oscillations are evident in synaptically isolated RTN neurons after blocking action potentials. The voltage-dependent os ...[more]

PMID: 33535052

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Project description:Phasic neurons typically fire only for a fast-rising input, say at the onset of a step current, but not for steady or slow inputs, a property associated with type III excitability. Phasic neurons can show extraordinary temporal precision for phase locking and coincidence detection. Exemplars are found in the auditory brain stem where precise timing is used in sound localization. Phasicness at the cellular level arises from a dynamic, voltage-gated, negative feedback that can be recruited subthreshold, preventing the neuron from reaching spike threshold if the voltage does not rise fast enough. We consider two mechanisms for phasicness: a low threshold potassium current (subtractive mechanism) and a sodium current with subthreshold inactivation (divisive mechanism). We develop and analyze three reduced models with either divisive or subtractive mechanisms or both to gain insight into the dynamical mechanisms for the potentially high temporal precision of type III-excitable neurons. We compare their firing properties and performance for a range of stimuli. The models have characteristic non-monotonic input-output relations, firing rate vs. input intensity, for either stochastic current injection or Poisson-timed excitatory synaptic conductance trains. We assess performance according to precision of phase-locking and coincidence detection by the models' responses to repetitive packets of unitary excitatory synaptic inputs with more or less temporal coherence. We find that each mechanism contributes features but best performance is attained if both are present. The subtractive mechanism confers extraordinary precision for phase locking and coincidence detection but only within a restricted parameter range when the divisive mechanism of sodium inactivation is inoperative. The divisive mechanism guarantees robustness of phasic properties, without compromising excitability, although with somewhat less precision. Finally, we demonstrate that brief transient inhibition if properly timed can enhance the reliability of firing.

Dataset Information

TRPM4 mediates a subthreshold membrane potential oscillation in respiratory chemoreceptor neurons that drives pacemaker firing and breathing.

Publications

TRPM4 mediates a subthreshold membrane potential oscillation in respiratory chemoreceptor neurons that drives pacemaker firing and breathing.

Similar Datasets

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