Selective elimination of respiratory motor neurons using intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) mimics motor neuron death and respiratory deficits observed in rat models of neuromuscular diseases . This CTB-SAP model allows us to study the impact of motor neuron death on the output of surviving phrenic motor neurons . After 7 (d) days of CTB-SAP, phrenic long-term facilitation (pLTF, a form of respiratory plasticity) is enhanced, but returns towards control levels at 28d . However, the mechanism responsible for this difference in magnitude of pLTF is unknown . In naïve rats, pLTF predominately requires 5-HT2 receptors, the new synthesis of BDNF, and MEK/ERK signaling; however, pLTF can alternatively be induced via A2A receptors, the new synthesis of TrkB, and PI3K/Akt signaling . Since A2A receptor-dependent pLTF is enhanced in naïve rats, we suggest that 7d CTB-SAP treated rats utilize the alternative mechanism for pLTF . Here, we tested the hypothesis that pLTF following CTB-SAP is : 1) TrkB and PI3K/Akt, not BDNF and MEK/ERK, dependent at 7d; and 2) BDNF and MEK/ERK, not TrkB and PI3K/Akt, dependent at 28d . Adult Sprague Dawley male rats were anesthetized, paralyzed, ventilated, and were exposed to acute intermittent hypoxia (AIH; 3 , 5â¯min bouts of 10.5% O2) following bilateral, intrapleural injections at 7d and 28d of : 1) CTB-SAP (25â¯µg), or 2) un-conjugated CTB and SAP (control). Intrathecal C4 delivery included either : 1) small interfering RNA that targeted BDNF or TrkB mRNA; 2) UO126 (MEK/ERK inhibitor); or 3) PI828 (PI3K/Akt inhibitor). Our data suggest that pLTF in 7d CTB-SAP treated rats is elicited primarily through TrkB and PI3K/Akt-dependent mechanisms, whereas BDNF and MEK/ERK-dependent mechanisms induce pLTF in 28d CTB-SAP treated rats . This project increases our understanding of respiratory plasticity and its implications for breathing following motor neuron death.