Computational modelling of 5-HT receptor-mediated reorganization of the brainstem respiratory network

Authors

  • Natalia A. Shevtsova,

    1. Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA
    Search for more papers by this author
  • Till Manzke,

    1. Department of Neuro- and Sensory Physiology, University of Göttingen, Göttingen, Germany
    2. DFG Research Center of Molecular Physiology of the Brain, Göttingen, Germany
    Search for more papers by this author
  • Yaroslav I. Molkov,

    1. Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA
    Search for more papers by this author
  • Anne Bischoff,

    1. Department of Neuro- and Sensory Physiology, University of Göttingen, Göttingen, Germany
    2. DFG Research Center of Molecular Physiology of the Brain, Göttingen, Germany
    Search for more papers by this author
  • Jeffrey C. Smith,

    1. Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
    Search for more papers by this author
  • Ilya A. Rybak,

    1. Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA
    Search for more papers by this author
  • Diethelm W. Richter

    1. Department of Neuro- and Sensory Physiology, University of Göttingen, Göttingen, Germany
    2. DFG Research Center of Molecular Physiology of the Brain, Göttingen, Germany
    Search for more papers by this author

Ilya A. Rybak, as above.
E-mail: rybak@drexel.edu

Abstract

Brainstem respiratory neurons express the glycine α3 receptor (Glyα3R), which is a target of modulation by several serotonin (5-HT) receptor agonists. Application of the 5-HT1A receptor (5-HT1AR) agonist 8-OH-DPAT was shown (i) to depress cellular cAMP, leading to dephosphorylation of Glyα3R and augmentation of postsynaptic inhibition of neurons expressing Glyα3R (Manzke et al., 2010) and (ii) to hyperpolarize respiratory neurons through 5-HT-activated potassium channels. These processes counteract opioid-induced depression and restore breathing from apnoeas often accompanying pharmacotherapy of pain. The effect is postulated to rely on the enhanced Glyα3R-mediated inhibition of inhibitory neurons causing disinhibition of their target neurons. To evaluate this proposal and investigate the neural mechanisms involved, an established computational model of the brainstem respiratory network (Smith et al., 2007), was extended by (i) incorporating distinct subpopulations of inhibitory neurons (glycinergic and GABAergic) and their synaptic interconnections within the Bötzinger and pre-Bötzinger complexes and (ii) assigning the 5-HT1AR-Glyα3R complex to some of these inhibitory neuron types in the network. The modified model was used to simulate the effects of 8-OH-DPAT on the respiratory pattern and was able to realistically reproduce a number of experimentally observed responses, including the shift in the onset of post-inspiratory activity to inspiration and conversion of the eupnoeic three-phase rhythmic pattern into a two-phase pattern lacking the post-inspiratory phase. The model shows how 5-HT1AR activation can produce a disinhibition of inspiratory neurons, leading to the recovery of respiratory rhythm from opioid-induced apnoeas.

Ancillary