Spinal plasticity following intermittent hypoxia: implications for spinal injury

Abstract

Plasticity is a fundamental property of the neural system controlling breathing. One frequently studied model of respiratory plasticity is long-term facilitation of phrenic motor output (pLTF) following acute intermittent hypoxia (AIH). pLTF arises from spinal plasticity, increasing respiratory motor output through a mechanism that requires new synthesis of brain-derived neurotrophic factor, activation of its high-affinity receptor, tropomyosin-related kinase B, and extracellular-related kinase mitogen-activated protein kinase signaling in or near phrenic motor neurons. Because intermittent hypoxia induces spinal plasticity, we are exploring the potential to harness repetitive AIH as a means of inducing functional recovery in conditions causing respiratory insufficiency, such as cervical spinal injury. Because repetitive AIH induces phenotypic plasticity in respiratory motor neurons, it may restore respiratory motor function in patients with incomplete spinal injury.

Figures

Figure 1

Compressed phrenic neurogram showing phrenic long-term facilitation (pLTF; bracket) following acute intermittent hypoxia. Compressed 1.5 hr time scale shows the short-term hypoxic responses (dramatic increase in phrenic amplitude) during 3 hypoxic episodes (arrows). pLTF results from these intermittent hypoxic episodes and is an example of the Q pathway to PMF. 374×116mm (600 × 600 DPI)

Figure 2

Working model of cellular mechanisms giving rise to pLTF. Intermittent activation of serotonergic 5-HT2 receptors during hypoxic episodes activates protein kinase C (PKC). This, in turn, initiates new BDNF protein synthesis and increases NADPH oxidase (NOX) activity. After BDNF binds its high affinity receptor, TrkB, downstream signaling molecules include ERK MAP kinases. Although less clear, we suggest that ERK activity increases synaptic strength between descending respiratory pre-motor neurons and phrenic motor neurons, thereby expressing pLTF. Protein phosphatases (PP2A/5) normally constrain pLTF. However, ROS formation via NADPH oxidase activity inhibits these phosphatases and relieves their inhibitory constraint to pLTF. When this pathway is activated chronically, we propose that increased gene transcription occurs (i.e. in the cell nucleus), enhancing the expression of elements critical in this form of plasticity. For further detail, see ztext. 340×241mm (600 × 600 DPI)

Figure 3

Experimental protocols of intermittent hypoxia vary in their duration and intensity. The most limited protocol, acute intermittent hypoxia (AIH), elicits pLTF in short time domains. Daily AIH (dAIH) involves 10 hypoxic episodes per day for seven days. Thrice weekly AIH (3xwAIH) involves 10 episodes per day, three days per week for 4-10 weeks. These intermediate protocols of repetitive AIH upregulate key “plasticity proteins” involved in pLTF and confer metaplasticity to phrenic motor output. Whereas chronic intermittent hypoxia (CIH) also elicits spinal plasticity and metaplasticity, its intensity (72 episodes of hypoxia per day for 7-14 days) causes deleterious side effects such as hypertension and learning disabilities. 327×182mm (600 × 600 DPI)