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

Brainstem respiratory neurons express the glycine α(3) receptor (Glyα(3) R), which is a target of modulation by several serotonin (5-HT) receptor agonists. Application of the 5-HT(1A) receptor (5-HT(1A) R) agonist 8-OH-DPAT was shown (i) to depress cellular cAMP, leading to dephosphorylation of Glyα(3) R and augmentation of postsynaptic inhibition of neurons expressing Glyα(3) R (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 Glyα(3) R-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-HT(1A) R-Glyα(3) R 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-HT(1A) R activation can produce a disinhibition of inspiratory neurons, leading to the recovery of respiratory rhythm from opioid-induced apnoeas.