Although neuroplasticity is an important property of the respiratory motor control system, its existence has been appreciated only in recent years and, as a result, its functional significance is not completely understood. The most frequently studied models of respiratory plasticity is respiratory long-term facilitation (LTF) following acute intermittent hypoxia and enhanced LTF following chronic intermittent hypoxia. Since intermittent hypoxia is a prominent feature of sleep-disordered breathing, LTF and/or enhanced LTF may compensate for factors that predispose to sleep-disordered breathing, particularly during obstructive sleep apnoea (OSA). Long-term facilitation has been studied most frequently in rats, and exhibits interesting properties consistent with a role in stabilizing breathing during sleep. Specifically, LTF: (1) is prominent in upper airway respiratory motor activity, suggesting that it stabilizes upper airways and maintains airway patency; (2) is most prominent during sleep in unanaesthetized rats; and (3) exhibits sexual dimorphism (greatest in young male and middle-aged female rats; smallest in middle-aged male and young female rats). Although these features are consistent with the hypothesis that upper airway LTF minimizes the prevalence of OSA in humans, there is little direct evidence for such an effect. Here we review advances in our understanding of LTF and its underlying mechanisms and present evidence concerning a potential role for LTF in maintaining upper airway patency, stabilizing breathing and preventing OSA in humans. Regardless of the relationship between LTF and OSA, a detailed understanding of cellular and synaptic mechanisms that underlie LTF may guide the development of new drugs to regulate upper airway tone, thereby offsetting the tendency for upper airway collapse characteristic of heavy snoring and OSA.

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Phrenic long term facilitation (pLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia. pLTF requires spinal serotonin receptor activation, new BDNF synthesis and TrkB receptor activation. Spinal adenosine 2A (A 2A ) receptor activation also elicits phrenic motor facilitation, but by a distinct mechanism involving new TrkB synthesis. Because extracellular adenosine increases during hypoxia, we hypothesized that A 2A receptor activation contributes to acute intermittent hypoxia (AIH)-induced pLTF. A selective A 2A receptor antagonist (MSX-3, 8 μg kg −1 , 12 μl) was administered intrathecally (C4) to anaesthetized, vagotomized and ventilated male Sprague-Dawley rats before AIH (three 5 min episodes, 11% O 2 ). Contrary to our hypothesis, pLTF was greater in MSX-3 versus vehicle (aCSF) treated rats (97 ± 6% vs. 49 ± 4% at 60 min post-AIH, respectively; P < 0.05). MSX-3 and aCSF treated rats did not exhibit facilitation without AIH (time controls; 7 ± 5% and 9 ± 9%, respectively; P > 0.05). A second A 2A receptor antagonist (ZM2412385, 7 μg kg −1 , 7 μl) enhanced pLTF (85 ± 11%, P < 0.05), but an adenosine A 1 receptor antagonist (DPCPX, 3 μg kg −1 , 10 μl) had no effect (51% ± 8%, P > 0.05), indicating specific A 2A receptor effects. Intrathecal methysergide (306 μg kg −1 , 15μl) blocked AIH-induced pLTF in both MSX-3 and aCSF treated rats, confirming that enhanced pLTF is serotonin dependent. Intravenous MSX-3 (140 μg kg −1 , 1 ml) enhanced both phrenic (104 ± 7% vs. 57 ± 5%, P < 0.05) and hypoglossal LTF (46 ± 13% vs. 28 ± 10%; P < 0.05). In conclusion, A 2A receptors constrain the expression of serotonin-dependent phrenic and hypoglossal LTF following AIH. A 2A receptor antagonists (such as caffeine) may exert beneficial therapeutic effects by enhancing the capacity for AIH-induced respiratory plasticity.

We hypothesized that reduced respiratory neural activity elicits compensatory mechanisms of plasticity that enhance respiratory motor output. In urethane-anesthetized and ventilated rats, we reversibly reduced respiratory neural activity for 25–30 min using: hypocapnia (end tidal CO2 = 30 mmHg), isoflurane (~ 1%) or high frequency ventilation (HFV; ~100 breaths/min). In all cases, increased phrenic burst amplitude was observed following restoration of respiratory neural activity (hypocapnia: 92 ± 22%; isoflurane: 65 ± 22%; HFV: 54 ± 13% baseline), which was significantly greater than time controls receiving the same surgery, but no interruptions in respiratory neural activity (3 ± 5% baseline, p<0.05). Hypocapnia also elicited transient increases in respiratory burst frequency (9 ± 2 versus 1 ± 1 bursts/min, p<0.05). Our results suggest that reduced respiratory neural activity elicits a unique form of plasticity in respiratory motor control which we refer to as inactivity-induced phrenic motor facilitation (iPMF). iPMF may prevent catastrophic decreases in respiratory motor output during ventilatory control disorders associated with abnormal respiratory activity.

Long-term facilitation (LTF) is a form of respiratory neuroplasticity frequently induced by acute intermittent isocapnic hypoxia (AIH, three 5 min isocapnic hypoxic episodes). Although repetitive apnoeas are a frequent natural occurrence producing brief (< 30 s) episodes of hypoxia and hypercapnia, it is unknown if repetitive apnoeas also elicit LTF. Apnoea-induced LTF may preserve upper airway patency during sleep, thereby limiting further apnoeic events. We tested the hypothesis that repeated, brief ventilator-induced apnoeas are sufficient to induce serotonin-dependent phrenic and hypoglossal (XII) LTF in anaesthetized rats. Anaesthetized, male Sprague-Dawley rats were exposed to three or six 25 s ventilator apnoeas with 5 min intervals, and compared to time control and AIH-treated rats. Three and six ventilator apnoeas induced phrenic and XII LTF with a magnitude similar to AIH. Both apnoea-induced and AIH-induced LTF were associated with a decreased CO 2 recruitment threshold for phrenic and XII activity (∼4 mmHg). Spinal methysergide, a serotonin receptor antagonist, blocked apnoea-induced LTF but not changes in the CO 2 -recruitment threshold. Thus, brief ventilator apnoeas elicit phrenic and XII LTF. Similar to AIH-induced LTF, apnoea-induced LTF is serotonin dependent, and the relevant serotonin receptors for phrenic LTF are located in the cervical spinal cord. Apnoea-induced LTF may have implications for the maintenance of breathing stability, particularly during sleep.