Microglial depletion rescues deficits in compensatory respiratory plasticity in adult offspring exposed to gestational intermittent hypoxia
Authors: Gumnit Maia G , Mickelson Carly , Meza Armand , Agbeh Abiye , Ewald Andrea , Braegelmann Kendra , Ouellette Jonathan , Watters Jyoti J , Baker Tracy L 
Published: June 2021

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 adult rat offspring exposed to gestational intermittent hypoxia (GIH) exhibit increased spontaneous apneas during sleep. Preliminary data also suggest that microglia isolated from adult GIH offspring exhibit enhanced inflammatory gene expression and primed responses to inflammatory stimuli. Since neuroinflammation impairs some forms of respiratory plasticity, we tested the hypothesis that adult GIH offspring have impaired compensatory plasticity in response to recurrent apnea. 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 GNX and GIH offspring. In GNX offspring, recurrent neural apnea (5, ~1 min neural apnea episodes, separated by 5 min) triggered a significant increase in phrenic burst amplitude (59±4% baseline, n=12, p<0.05), a form of plasticity known as inactivity‐induced inspiratory motor facilitation (iMF). By contrast, intermittent neural apnea did not trigger increased phrenic burst amplitude in GIH offspring (5±7% baseline, n=11, p>0.05), suggesting that in utero intermittent hypoxia impairs the capacity to elicit iMF. To determine if microglia participate in impairing iMF in GIH offspring, microglia were depleted with Pexidartinib (PLX3397; 80 mg/kg, 7 days po), a colony stimulating factor 1 receptor (CSFR1) inhibitor that results in microglial apoptosis. PLX3397 significantly reduced Iba1+ and CD11b+ cells throughout the brain and spinal cord (−82±8%, n=4, p<0.05), which were restored to control levels 7 days after PLX withdrawal (−6±17%, n=4, p>0.05). Preliminary data indicate that recurrent neural apnea triggered increased phrenic burst amplitude in GIH offspring receiving PLX (71±21 % baseline, n=5), suggesting that microglial depletion rescues the ability to trigger compensatory responses to recurrent neural apnea. iMF impairments in PLX‐treated GIH rats returned upon repopulation of microglia after PLX withdrawal (14±14 % baseline, n=5). PLX treatment had no impact on iMF in GNX offspring (75±11% baseline). Since iMF is hypothesized to be a compensatory form of plasticity that prevents recurrent apneas, the impact of restoring iMF on breathing stability during sleep in GIH offspring is currently being investigated.

Support or Funding Information

(Supported by NIH R01 HL105511 and NS085226).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.