Daily fluctuations in spinal adenosine determine mechanisms of respiratory motor plasticity

ABSTRACT Plasticity is a fundamental property of the neuromotor system controlling breathing. One key example of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a persistent increase in phrenic nerve activity after exposure to intermittent low oxygen or acute intermittent hypoxia (AIH). pLTF can arise from distinct intracellular signaling cascades initiated by serotonin and adenosine; these cascades interact via powerful crosstalk inhibition. We demonstrate the serotonin/adenosine balance varies dramatically with time-of-day and details of the AIH protocol. Using a “standard” AIH protocol, the mechanism driving pLTF shifts from serotonin-dominant, adenosine-constrained during rest, to adenosine-dominant, serotonin-constrained in the active phase. This mechanistic ‘flip’ results from daily changes in basal spinal adenosine levels across time-of-day combined with hypoxia-evoked spinal adenosine release. Since AIH is emerging as a promising therapeutic modality to restore respiratory (and non-respiratory) movements in people with spinal injury or ALS, new knowledge that time-of-day and protocol details impact mechanisms driving pLTF has experimental, biological and translational implications.