Spinal Synaptic Enhancement with Acute Intermittent Hypoxia Improves Respiratory Function after Chronic Cervical Spinal Cord Injury

Abstract

Respiratory insufficiency is the leading cause of death after high-cervical spinal cord injuries (SCIs). Although respiratory motor recovery can occur with time after injury, the magnitude of spontaneous recovery is limited. We hypothesized that partial respiratory motor recovery after chronic cervical SCI could be strengthened using a known stimulus for spinal synaptic enhancement, intermittent hypoxia. Phrenic motor output was recorded before and after intermittent hypoxia from anesthetized, vagotomized, and pump-ventilated control and C2 spinally hemisected rats at 2, 4, and 8 weeks after injury. Weak spontaneous phrenic motor recovery was present in all C2-injured rats via crossed spinal synaptic pathways that convey bulbospinal inspiratory premotor drive to phrenic motoneurons on the side of injury. Intermittent hypoxia augmented crossed spinal synaptic pathways [phrenic long-term facilitation; pLTF] for up to 60 min after hypoxia at 8 weeks, but not 2 weeks, after injury. Ketanserin, a serotonin 2A receptor antagonist, administered before intermittent hypoxia at 8 weeks after injury prevented pLTF. Serotonergic innervation near phrenic motoneurons was assessed after injury. The limited magnitude of pLTF at 2 weeks was associated with an injury-induced reduction in serotonin-containing nerve terminals in the vicinity of phrenic motoneurons ipsilateral to C2 hemisection. Thereafter, pLTF magnitude progressively increased with the recovery of serotonergic innervation in the phrenic motor nucleus. Intermittent hypoxia (or pLTF) has intriguing possibilities as a therapeutic tool, because its greatest efficacy may be in patients with chronic SCI, a time when most patients have already achieved maximal spontaneous functional recovery.

Modest spontaneous recovery of ventilation following chronic high cervical hemisection in rats

“…These results conform to the hypothesis that endogenous "self-repair" mechanisms associated with the sCPP can impact breathing in the awake, freely behaving rat after chronic C2HS. It should be mentioned, however, that our hypoxia data contrast with prior reports (Golder and Mitchell, 2005;Fuller et al, 2006), but this appears to be due to different approaches employed. For example, Golder and Mitchell (2005) found that the IL phrenic hypoxic response did not change 2-8-week post-C2HS.…”

“…It should be mentioned, however, that our hypoxia data contrast with prior reports (Golder and Mitchell, 2005;Fuller et al, 2006), but this appears to be due to different approaches employed. For example, Golder and Mitchell (2005) found that the IL phrenic hypoxic response did not change 2-8-week post-C2HS. In that study, the hypoxic response was expressed relative to IL phrenic activity during a subsequent hypercapnic challenge.…”

“…This early onset is consistent with other reports Golder and Mitchell, 2005). However, other studies have noted a much longer delay between C2HS and the re-appearance of inspiratory IL PhMN activity.…”

“…The CPP also is expressed naturally (i.e., spontaneous CPP; sCPP) as ipsilateral phrenic inspiratory bursting which resumes weeks to months post-C2HS (Nantwi et al, 1999). This intrinsic recovery of PhMN activity can be manipulated in onset and magnitude thus indicating that targeted phrenic plasticity is a viable therapeutic goal after cervical SCI (Nantwi and Goshgarian, 2001Golder and Mitchell, 2005).…”

“…These studies were intended to provide a foundation for assessing future therapeutic manipulations of the sCPP (e.g. Nantwi and Goshgarian, 2001Golder and Mitchell, 2005;Alilain et al, 2007).…”