Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death

Respir Physiol Neurobiol. 2018 Oct;256:43-49. doi: 10.1016/j.resp.2017.08.003. Epub 2017 Aug 16.

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to progressive motor neuron degeneration and death by ventilatory failure. In a rat model of ALS (SOD1G93A), phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) is enhanced greater than expected at disease end-stage but the mechanism is unknown. We suggest that one trigger for this enhancement is motor neuron death itself. Intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) selectively kill respiratory motor neurons and mimic motor neuron death observed in SOD1G93A rats. This CTB-SAP model allows us to study the impact of respiratory motor neuron death on breathing without many complications attendant to ALS. Here, we tested the hypothesis that phrenic motor neuron death is sufficient to enhance pLTF. pLTF was assessed in anesthetized, paralyzed and ventilated Sprague Dawley rats 7 and 28 days following bilateral intrapleural injections of: 1) CTB-SAP (25 μg), or 2) un-conjugated CTB and SAP (control). CTB-SAP enhanced pLTF at 7 (CTB-SAP: 162 ± 18%, n = 8 vs. Control: 63 ± 3%; n = 8; p < 0.05), but not 28 days post-injection (CTB-SAP: 64 ± 10%, n = 10 vs. Control: 60 ± 13; n = 8; p > 0.05). Thus, pLTF at 7 (not 28) days post-CTB-SAP closely resembles pLTF in end-stage ALS rats, suggesting that processes unique to the early period of motor neuron death enhance pLTF. This project increases our understanding of respiratory plasticity and its implications for breathing in motor neuron disease.

Keywords: ALS; Breathing; Neurodegenerative disease; Phrenic motor neurons; Respiratory motor output; Ventilatory control.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Blood Gas Analysis
  • Blood Pressure / drug effects
  • Cell Death / drug effects*
  • Cholera Toxin / toxicity*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hypoxia / physiopathology
  • Male
  • Motor Neurons / drug effects*
  • Phrenic Nerve / drug effects*
  • Phrenic Nerve / physiology
  • Poisons / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Center / cytology*
  • Ribosome Inactivating Proteins, Type 1 / toxicity*
  • Saporins
  • Time Factors

Substances

  • Poisons
  • Ribosome Inactivating Proteins, Type 1
  • cholera toxin B-saporin conjugate
  • Cholera Toxin
  • Saporins