IH‐dependent HIF1a signaling upregulates reactive oxygen species signaling to suppress expression of the hippocampal NMDA receptor by downregulating the NR1 subunit.

Abstract

When left untreated, the periodic cessation in breathing occurring with sleep apnea can cause oscillations in blood oxygenation leading to intermittent hypoxia (IH) and disrupted cognitive function. IH causes oxidative stress in the nervous system and impair spatial learning and memory. This study examines how IH influences synaptic physiology of principal neurons in the hippocampus. We hypothesize that IH‐dependent HIF1a signaling remodels the glutamatergic synapse by upregulating reactive oxygen species (ROS), weakening N‐methyl‐D‐aspartate receptor (NMDAR)‐dependent long‐term potentiation (LTP), and impairing cognitive performance on hippocampal based behavior. Wildtype mice (WT) and mice hemizygous for HIF1a (HIF1a+/−) were exposed to ten days of IH. While spatial memory in the Barnes maze was impaired in WT following IH (n=6), performance in the Barnes maze was unaffected by IH among HIF1a+/− (n=6). Electrophysiological recordings in brain slices from WT (n=6) and HIF1a+/−(n=6) exposed to IH also revealed that NMDAR‐dependent LTP was suppressed only in WT slices. While IH caused a down regulation of the NR1 subunit from WT, protein carbonylation and HIF1a regulated oxidase, NOX4, was increased by IH in the WT exposed to IH. No changes in NR1, protein carbonylation, or NOX4 were observed in HIF1a+/− exposed to IH. Furthermore, the administration of the superoxide anion scavenger MnTMPyP (5 mg/Kg i.p) during IH mitigated the downregulation of NR1 and suppression of NMDAR‐dependent LTP in WT. These results show that IH‐dependent HIF1a signaling causes targeted disruption to NMDAR‐dependent LTP through a ROS‐based mechanism that involves the downregulation of NR1 subunit. We provide new insight into the mechanistic basis by which sleep apnea may disrupt cognitive performance.Support or Funding InformationSupported by NIH Grant R01‐NS‐1074210100