Abstract
Sleep apnea causes cognitive deficits and is associated with several neurologic diseases. Intermittent hypoxia (IH) is recognized as a principal mediator of pathophysiology associated with sleep apnea, yet the basis by which IH contributes to impaired cognition remains poorly defined. Using a mouse model exposed to IH, this study examines how the transcription factor, Hypoxia Inducible Factor 1a (HIF1a), contributes to disrupted synaptic physiology and spatial memory. In wildtype mice, impaired performance in the Barnes maze caused by IH coincided with a loss of NMDA receptor dependent Long Term Potentiation (LTP) in area CA1 and increased nuclear HIF1a within the hippocampus. IH-dependent HIF1a signaling caused a two-fold increase in expression of the reactive oxygen species generating enzyme NADPH oxidase 4 (NOX4). These changes promoted a pro-oxidant state and the downregulation of GLUN1 within the hippocampus. The IH-dependent effects were not present in either mice heterozygous for Hif1a (HIF1a+/-) or wild type mice treated with the antioxidant MnTMPyP. Our findings indicate that HIF1a dependent changes in redox state are central to the mechanism by which IH disrupts hippocampal synaptic plasticity and impairs spatial memory. This mechanism may enhance the vulnerability for cognitive deficit and lower the threshold for neurologic diseases associated untreated sleep apnea.
Significance: Sleep apnea is associated with cognitive decline and neurological disease. Intermittent hypoxia, a hallmark consequence of sleep apnea, yet the mechanisms by which IH affects cognition is poorly understood. We show that a pro-oxidant state produced by HIF1a is a central factor causing IH-dependent impairment to spatial memory and synaptic plasticity. This work identifies potential targets for intervention in mitigating cognitive decline associated with sleep apnea.
Footnotes
The authors have no conflicts of interests related to this study.
This work was supported by NIH PO 1 HL 144454 (AJG), NIH R01 NS10742101 (AJG), a grant from The BSD Office of Diversity & Inclusion at The University of Chicago (AJG). GD was also supported by The University of Chicago Diabetes Research Center (P30 DK020595).
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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