Gestational intermittent hypoxia induces neuroinflammation and impairs compensatory respiratory plasticity in adult offspring

Abstract

Sleep disordered breathing during pregnancy is increasing at an alarming rate, but virtually nothing is known about long‐lasting effects on adult offspring physiology. Preliminary data suggest that microglia isolated from adult rat offspring exposed to in utero intermittent hypoxia exhibit enhanced inflammatory gene expression and primed responses to inflammatory stimuli. Since neuroinflammation abrogates some forms of respiratory plasticity, we tested the hypothesis that gestational intermittent hypoxia (GIH) impairs respiratory plasticity in adult offspring. Pregnant rat dams were exposed to chronic intermittent hypoxia (8 hrs/day, 2 min 10.5% O2 separated by 2 min of 21% O2) or intermittent normoxia from gestation days 10–21 (GIH and GNX, respectively). Respiratory plasticity was assessed by measuring the response to recurrent neural apnea in urethane‐anesthetized, mechanically ventilated male and female GNX and GIH offspring. Recurrent neural apnea was induced by briefly hyperventilating below the CO2 apneic threshold for breathing (5, ~1 min neural apnea episodes, separated by 5 min). In GNX offspring, recurrent neural apnea triggered a significant increase in phrenic burst amplitude (45±3 %baseline, n=6, p<0.05), a form of plasticity known as inactivity‐induced phrenic motor facilitation (iPMF). By contrast, intermittent neural apnea did not trigger increased phrenic burst amplitude in GIH offspring (7±8 %baseline, n=10, p>0.05), suggesting that in utero intermittent hypoxia impairs the capacity to elicit iPMF. Further, the phrenic response to intermittent neural apnea was significantly different in GIH and GNX rats (p<0.05). A critical role for microglial neuroinflammation is suggested by preliminary data indicating that the capacity to elicit iPMF can be restored in adult GIH offspring in which microglia are depleted with Pexidartinib (PLX3397) or following administration of the non‐steroidal anti‐inflammatory drug ketoprofen. Since iPMF is hypothesized to be a compensatory form of respiratory plasticity that prevents recurrent apneas, the impact of impaired iPMF on breathing stability in adult GIH offspring during sleep is currently being investigated.Support or Funding InformationHL105511, NS085226This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.