APOE Genotype Differentially Regulates Respiratory Motor Plasticity in the Active vs Rest phase

Acute intermittent hypoxia (AIH) elicits respiratory motor plasticity and is emerging as a promising strategy to improve breathing and other (non-respiratory) movements in clinical disorders that end life due to respiratory insuffciency ( e.g., spinal cord injury ApoE2 and E3 proteins are associated with neuroprotective and neuro-neutral phenotypes, respectively. ApoE4 impairs synaptic plasticity and is implicated in neurodegeneration, particularly Alzheimer’s Disease. Indeed, we recently discovered that specific APOE alleles predict human expression of mAIH-induced plasticity in cortico-spinal pathways to the phrenic/diaphragm motor system. Initial experiments using human APOE4 knock-in rats demonstrate a causal effect in limiting phrenic motor plasticity (vs APOE3) during the active phase. However, the impact of APOE genotype on respiratory plasticity across the daily rest/active cycle is unknown. We tested the hypothesis that APOE4 undermines AIH-induced pLTF vsAPOE3 in a time-of-day-dependent manner. Anesthetized, vagotomized, paralyzed and ventilated adult (3-4 months) male Sprague-Dawley rats with knock-in humanized (h) APOE3 and h APOE4 were presented with AIH (15,1 min hypoxic episodes; arterial PO 2 = 40-50mmHg). During the active phase, AIH-induced pLTF was significantly greater in h APOE3 (33±11%) vs h APOE4 rats (-26±7%; p<0.001; both n=6). In contrast, rest phase AIH-induced pLTF was similar in both h APOE3 and h APOE4 rats (121±12% and 122±5%, respectively; both n=7). These experiments demonstrate a causal relationship whereby APOE genotype and time-of-day interact to undermine AIH-induced pLTF in a manner that is unique to the active phase in rats. Since AIH has emerged as a promising neurotherapeutic to preserve/restore breathing in clinical disorders such as spinal cord injury and neuromuscular disease, understanding how genetic factors and time-of-day of AIH delivery impact phrenic motor plasticity will help identify individuals most/least likely to respond to treatment and reveal new targets for precision interventions of AIH. NIH R01HL148030 (GSM), NIH R01HL149800 (GSM), NIH T32HL134621-5 (ABM). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.