Facilitation of phrenic motor output following sustained hypocapnia in rats

Abstract

Phrenic motoneurons exhibit serotonin-dependent synaptic plasticity, particularly following intermittent hypoxia. Another means of altering synaptic strength in the central nervous system is synaptic scaling, a process whereby efficacy is increased in inverse proportion to activity. We hypothesized that phrenic motoneuron inactivity increases synaptic efficacy, resulting in a long-lasting increase in phrenic motor output. Phrenic nerve inactivity was induced by modest hypocapnia in anesthetized, paralyzed, vagotomized and ventilated rats (4 to 6 mmHg below CO2-apneic threshold, 25 min). After restoring normocapnic arterial CO2 levels, an early and lasting facilitation in phrenic nerve burst amplitude was observed (n = 8; 15 min: 87%±21%; 60 min: 110%±29% baseline; p<0.05), a response significantly different from control rats (n=6; 15 min: −1%±3%; 60 min: 7%±7%). To confirm that inactivity versus respiratory alkalosis per se caused the facilitation, we restored baseline phrenic activity during hypocapnia with steady carotid sinus nerve (CSN) stimulation (2–5 Hz). This combination attenuated, but did not eliminate the phrenic facilitation (n = 5; 15 min: 39%±11%; 60 min: 45%±18%, both p<0.05). The results are consistent with the hypothesis that inactivity induces synaptic plasticity in the phrenic motor system, but do not rule out independent effects of hypocapnia and/or CSN stimulation. Inactivity-induced phrenic facilitation may have important implications: it may play a role in progressive central sleep apnea, since central apneas are among the few instances of spontaneous respiratory motor inactivity; and it may contribute to patient recovery following prolonged ventilatory support. Supported by NIH 69064 and CIHR (Canada).