A role for Hypoxia Inducible Factor 1a (HIF1a) in intermittent hypoxia-dependent changes to spatial memory and synaptic plasticity

Abstract

Intermittent hypoxia (IH), a key feature of sleep apnea, increases the oxygen regulated transcription factor Hypoxia Inducible Factor 1a (HIF1a). Although recognized for its role in IH-dependent changes in cardio-respiratory physiology, it remains unclear how IH-dependent HIF1a signaling affects neurophysiology underlying learning and memory. This study examines how IH affects hippocampal associated learning and memory in wildtype mice and mice heterozygous for the HIF1a gene (HIF1a+/-). In wild-type mice, ten days of IH impaired performance in the Barnes maze increased hippocampal HIF1a and elevated protein carbonyls. These behavioral and biochemical effects of IH were accompanied by a decrease in the N-Methyl-D-Aspartate receptor (NMDAr) and an attenuation of long-term potentiation (LTP) in area CA1. In HIF1a+/-, IH did not impair Barnes maze performance, increase hippocampal HIF1a, or enhance protein carbonyl content. At the network level, IH neither led to a decrease in NMDAr nor impaired LTP. Concurrent antioxidant treatment during IH mitigated the IH-dependent effects on the Barnes maze performance and LTP in wildtype mice. Our findings indicate that IH-dependent HIF1a signaling leads to oxidative stress and reduces NMDAr to impair LTP in area CA1, which contributes to IH-dependent deficits in learning and memory associated with the hippocampus.SignificanceIntermittent Hypoxia is a hallmark of sleep apnea and decreases the threshold for cognitive deficit. We demonstrate that intermittent hypoxia-dependent HIF1a signaling contributes to impairments in hippocampal associated memory. This is co-incidental with HIF1a-mediated alternations in synaptic physiology and increased oxidative stress.Key pointsIntermittent hypoxia (IH) is a hallmark of sleep apnea and is known to cause learning and memory deficits.Hypoxia Inducible Factor 1a (HIF1a), is associated with IH-dependent changes in physiology.IH exposure causes increased hippocampal HIF1a in wild type mice and is associated with elevated oxidative stress, impairments to spatial memory, and suppression of long term potentiation (LTP).IH-dependent suppression of LTP is co-incidental with diminished NMDA receptor contribution to glutamatergic transmission.Following IH, mice heterozygous for HIF1a (HIF1a+/-) do not show an increase in HIF1a and oxidative stress, or changes in either behavior or glutamatergic transmission.

Cholinergic basal forebrain degeneration due to obstructive sleep apnoea increases Alzheimer’s pathology in mice

“…Our conclusion is consistent with other reports in which rats exposed to intermittent hypoxia for 14 days (alternating 90s epochs of 21% and 10% O2 during sleep) developed deficits in water maze spatial memory performance and reductions in cBF neuron number that mirror the reduction in the OSA model (Row et al, 2007). Similarly, mice exposed to intermittent hypoxia during sleep (alternating 60s epochs of 21% and 0% O2 for 8 hours) developed hippocampal changes and cognitive impairment in the Barnes maze spatial memory test (Arias-Cavieres et al, 2019), which is sensitive to cBF function (Greferath et al, 2000;Barrett et al, 2010), and these phenotypes were prevented by heterozygous knockout of HIF1 (Arias-Cavieres et al, 2019).…”

Dysfunctional cerebrovascular tone contributes to cognitive impairment in a non-obese rat model of prediabetic challenge: Role of suppression of autophagy and modulation by anti-diabetic drugs

“…This was confirmed by the elevated expression of HIF-1α in MHC-fed rat hippocampus. Indeed, similar changes in HIF-1α expression were seen accompanied by a decline in hippocampal-associated memory following intermittent hypoxia(50). Consistent with the literature showing that cerebral hypoxia and accumulation of HIF-1α are associated with increased ROS levels(51), MHC-fed rat hippocampus demonstrated a high oxidative burden upon DHE staining.…”