Hif1a hemizygosity in vGlut1+ Cells mitigates the cellular and neurophysiological of Intermittent Hypoxia (IH)‐Dependent changes in the hippocampus

Abstract

Arias et al. (eNeuro, 2020) recently demonstrated that intermittent hypoxia (IH), a principal outcome of sleep apnea, increases hippocampal oxidative stress that in turn, contributes to IH‑mediated deficits in spatial memory and NMDAr-dependent LTP. These phenomena were mitigated in hemizygous HIF1a mice indicating that IH-dependent HIF1a signaling plays a central role in mediating neurophysiological changes associated with impaired spatial memory. However, it remains unclear where such signaling originates. As glutamatergic synaptic communication in the hippocampus and cortex is critical for learning and memory, we sought to determine whether hemizygosity of HIF1a among glutamatergic neurons could mediate the impact of IH on hippocampal synaptic plasticity and spatial memory. To address this, we generated Vglut1-HIF1a+/- mice using Cre/LoxP recombination technology. Vglut1‑HIF1a+/- mice were exposed to either room air (control) or ten days of IH (IH10). In the hippocampus of wild-type mice, IH10 decreased expression of the obligatory NMDAr subunit, GluN1. This correlated with deficient induction of NMDAr-dependent synaptic plasticity. IH10 also increased hippocampal oxidative stress and caused a two-fold increase in hippocampal expression of the pro-oxidant enzyme, NADPH oxidase 4 (NOX4). In contrast to the effects in wild type mice, IH10 neither increased oxidative stress nor increased NOX4 expression in the hippocampus of Vglut1-HIF1a+/- mice. IH10 did not suppress GluN1 expression or impair hippocampal NMDAr-dependent synaptic plasticity in Vglut1-HIF1a+/- mice. In conclusion, our findings show that hemizygosity of HIF1a in vGlut1+ cells mitigate IH-dependent changes to hippocampal synaptic plasticity and protein expression. Thus, HIF1a signaling in vGlut1+ glutamatergic neurons appear to be a significant contributor for perturbing NMDAr-dependent synaptic plasticity and the molecular profile of the hippocampus following IH.