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Early postnatal life represents a critical window of brain development that sets the foundation for neurophysiology later in adulthood. Apneas of Prematurity (AoP) is clinical condition that can emerge in neonates born less than 34 weeks and is hypothesized to have long-lasting impact on neurocognition. Untreated AoP produces periodic cessations in breathing leading to neonatal intermittent hypoxia (nIH). The objective of this study is to investigate how nIH impacts NMDAr-dependent synaptic plasticity during and following the critical period of development. To test this, neonatal mice (P4-5) were exposed to ten days of nIH. Biochemical analyses immediately following nIH, revealed that nIH caused oxidative stress corresponding with a greater GluN2B:GluN2A subunit ratio in the hippocampus. These effects were accompanied by a reduced contribution of GluN2A to LTP. Administration of the antioxidant MnTMPyP during nIH prevented these changes. In adult mice, six weeks after exposure to nIH, deficits in behavioral performance in spatial memory tasks were evident. These neurocognitive changes, correlated with a persistent increase in the GluN2B:GluN2A ratio and dysregulated LTP in the adult hippocampus. Administration of MnTMPyP, following nIH was not effective in mitigating the effects observed during adulthood. Our findings suggest that a narrow interventional window exists for mitigating oxidative stress that drive nIH‑dependent changes in hippocampal physiology and spatial memory during adulthood. This work was supported by NIH: R01NS107421 This work was supported by NIH: R01NS107421 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Underdeveloped breathing results from premature birth and causes intermittent hypoxia during the early neonatal period. Neonatal intermittent hypoxia (nIH) is a condition linked to the increased risk of neurocognitive deficit later in life. However, the underlying mechanistic consequences nIH-induced neurophysiological changes remains poorly resolved. Here, we investigated the impact of nIH on hippocampal synaptic plasticity and NMDA receptor (NMDAr) expression in neonatal mice. Our findings indicate that nIH induces a pro-oxidant state, leading to an imbalance in NMDAr subunit composition that favors GluN2A over GluN2B expression, and subsequently impairs synaptic plasticity. These consequences persist in adulthood and coincide with deficits in spatial memory. Treatment with the antioxidant, manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), during nIH effectively mitigated both immediate and long-term effects of nIH. However, MnTMPyP treatment post-nIH did not prevent the long-lasting changes in either synaptic plasticity or behavior. Our results underscore the central role of the pro-oxidant state in nIH-mediated neurophysiological and behavioral deficits and importance of stable oxygen homeostasis during early life. These findings suggest that targeting the pro-oxidant state during a discrete window may provide a potential avenue for mitigating long-term neurophysiological and behavioral outcomes when breathing is unstable during early postnatal life.HighlightsUntreated immature breathing leads neonatal intermittent hypoxia (nIH).nIH promotes a pro-oxidant state associated with increased HIF1a activity and NOX upregulation.nIH-dependent pro-oxidant state leads to NMDAr remodeling of the GluN2 subunit to impair synaptic plasticity.Impaired synaptic plasticity and NMDAr remodeling caused by nIH persists beyond the critical period of development.A discrete window for antioxidant administration exists to effectively mitigate neurophysiological and behavioral consequences of nIH.

Over one billion adults worldwide are estimated to suffer from sleep apnea, a condition with wide-reaching effects on brain health. Sleep apnea causes cognitive decline and is a risk factor for neurodegenerative conditions such as Alzheimer’s disease. Rodents exposed to intermittent hypoxia (IH), a hallmark of sleep apnea, exhibit spatial memory deficits associated with impaired hippocampal neurophysiology and dysregulated adult neurogenesis. We demonstrate that IH creates a pro-oxidant condition that reduces the Tbr2+ neural progenitor pool early in the process, while also suppressing terminal differentiation of adult born neurons during late adult neurogenesis. We further show that IH-dependent cell-autonomous hypoxia inducible factor 1-alpha (HIF1a) signaling is activated in early neuroprogenitors and enhances the generation of adult born neurons upon termination of IH. Our findings indicate that oscillations in oxygen homeostasis, such as those found in sleep apnea, have complex stage-dependent influence over hippocampal adult neurogenesis.

Changed NMDA receptor (NMDAr) physiology is implicated with cognitive deficit resulting from conditions ranging from normal aging to neurological disease. Using intermittent hypoxia (IH) to experimentally model untreated sleep apnea, a clinical condition whose comorbidities include neurocognitive impairment, we recently demonstrated that IH causes a pro-oxidant condition that contributes to deficits in spatial memory and in NMDAr-dependent long-term potentiation (LTP). However, the impact of IH on additional forms of synaptic plasticity remains ill-defined. Here we show that IH prevents the induction of NMDAr-dependent LTP and long-term depression (LTD) in hippocampal brain slices from mice exposed to ten days of IH (IH(10)) yet spares NMDAr-independent forms of synaptic plasticity. Deficits in synaptic plasticity were accompanied by a reduction in hippocampal GluN1 expression. Acute manipulation of redox state using the reducing agent, Dithiothreitol (DTT) stimulated the NMDAr-dependent fEPSP following IH(10). However, acute use of either DTT or MnTMPyP did not restore NMDAr-dependent synaptic plasticity after IH(10) or prevent the IH-dependent reduction in GluN1, the obligatory subunit of the NMDAr. In contrast, MnTMPyP during IH(10) (10-MnTMPyP), prevented the suppressive effects of IH on both NMDAr-dependent synaptic plasticity and GluN1 expression. These findings indicate that while the IH-dependent pro-oxidant state causes reversible oxidative neuromodulation of NMDAr activity, acute manipulation of redox state is ineffective in rescuing two key effects of IH related to the NMDAr within the hippocampus. These IH-dependent changes associated with the NMDAr may be a primary avenue by which IH enhances the vulnerability to impaired learning and memory when sleep apnea is left untreated in normal aging and in disease.

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.

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 wild-type mice, impaired performance in the Barnes maze caused by IH coincided with a loss of NMDA receptor (NMDAr)-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 (ROS) 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 forHif1a(HIF1a+/−) or wild-type mice treated with the antioxidant manganese (III) tetrakis(1-methyl-4-pyridyl) porphyrin (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.

In this review article, we address how activity-dependent Ca2+signaling is crucial for hippocampal synaptic/structural plasticity and discuss how changes in neuronal oxidative state affect Ca2+signaling and synaptic plasticity. We also analyze current evidence indicating that oxidative stress and abnormal Ca2+signaling contribute to age-related synaptic plasticity deterioration.

3,4-Methylenedioxymethamphetamine (MDMA), an important recreational psychostimulant drug, was examined for its ability to alter visuo-spatial learning and synaptic plasticity. Young rats received MDMA (0.2 and 2 mg/kg s.c.) twice per day for 6 days while their visuo-spatial learning was tested using the Morris Water Maze. After this, animals were sacrificed and LTP induced in hippocampal slices. Visuo-spatial learning was impaired and LTP reduced, both dose-dependently, without changes in serotonin levels or paired-pulse facilitation. We conclude that low, nontoxic doses of MDMA, applied during several days, slow learning by impairing postsynaptic plasticity.