Author ORCID Identifier
Year of Publication
Doctor of Philosophy (PhD)
Dr. Warren J. Alilain
Dr. Edward D. Hall
There are over 17,000 new spinal cord injuries (SCIs) every year in the Unites States alone. Almost 60% of these injuries occur at the cervical level, potentially leading to loss of function in a variety of sensory and motor systems including upper and lower limbs, respiratory, and autonomics. In addition to the physical and emotional costs, individuals who experience these higher level injuries also face a massive financial burden, incurring over $1 million in expenses during the first year after injury in addition to substantial yearly costs for the rest of their lifetime. A myriad of therapeutic approaches targeting plasticity of spinal circuits have shown efficacy for improving functional recovery in preclinical animal models. However, translation of these strategies has proved less successful, leaving the SCI population with few effective therapeutic options to improve functional outcomes and alleviate the financial toll of their injury. We hypothesized that factors that are present in the human population, but difficult to model in preclinical studies, such as genetic diversity and sex differences, could determine how individuals respond to treatment strategies. Therefore, we investigated how sex and the human alleles of the APOE gene (ε2, ε3, and ε4), which encode unique isoforms of the lipid carrier apolipoprotein E (apoE), modulate a well-described form of spinally mediated respiratory motor plasticity that is sufficient to restore breathing function after cervical SCI.
To test whether E4, the isoform of apoE associated with deficits in synaptic plasticity in the brain, also impairs spinally mediated plasticity, we exposed rats to episodic serotonin (5-HT) dosing after they had been treated intrathecally with human apoE3 or E4. IH induces long term facilitation (LTF) of respiratory motor function, which is characterized as a prolonged augmentation of breathing in spinally intact rats. LTF also rescues breathing function in the paralyzed hemidiaphragm following unilateral cervical SCI. Although rats treated with E3 and E4 did not show significant differences in their respiratory response to episodic 5-HT as assessed through diaphragmatic EMG recordings, animals treated with E4 did demonstrate a downregulation of synaptic NMDA receptors. Interestingly, this effect was only present in animals that had received a cervical SCI. Due to the necessity of NMDA receptor signaling in synaptic strengthening and the induction of LTF, this indicates that human apoE4 may prevent therapeutic strategies from inducing spinal plasticity to mediate functional recovery after SCI.
To increase the clinical relevance of these studies and investigate how sex interacts with APOE genotype to modulate respiratory motor plasticity, we also evaluated LTF in male and female targeted replacement APOE mice that express the human alleles under the murine promotor. LTF was induced through exposure to therapeutic intermittent hypoxia (IH), which is currently in clinical trials for various functional outcomes in SCI subjects. There were significant effects of both genotype and sex on the respiratory response to IH. Although ε4 was inhibitory to plasticity in males, it was ε3 that proved detrimental in females in the absence of injury. In contrast, injured males showed no significant difference between genotypes while injured ε4 females experienced a decline in breathing activity compared to those expressing ε3.
Together, these results support the hypothesis that sex and genetic background may determine individuals’ propensity towards or against plasticity and functional recovery after SCI. By contributing to our understanding of translational barriers for SCI therapeutics, this investigation will inform the development of personalized medicine to overcome these obstacles.
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This study was supported by a National Science Foundation Graduate Research Fellowship awarded to Lydia Strattan (no.1839289) from 2018-2021. This research was also supported by a grant from the National Institutes of Health (R01 no. NS101105) from 2017-2021 awarded to Warren J. Alilain, PhD. Additionally, funding from the Craig H. Neilsen Foundation (no. 598741) awarded to Warren J. Alilain, PhD from 2019-2021 supported this study.
Strattan, Lydia Ella, "EXAMINING HUMAN APOE GENOTYPE AND SEX AS MODULATORS OF RESPIRATORY PLASTICITY IN THE PRESENCE AND ABSENCE OF SPINAL CORD INJURY" (2021). Theses and Dissertations--Neuroscience. 25.