Arias-Cavieres, A. | Search bioRxiv

bioRxiv2023

A Consequence of Immature Breathing induces Persistent Changes in Hippocampal Synaptic Plasticity and Behavior: A Role of Pro-Oxidant State and NMDA Receptor Imbalance

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. HighlightsO_LIUntreated immature breathing leads neonatal intermittent hypoxia (nIH). C_LIO_LInIH promotes a pro-oxidant state associated with increased HIF1a activity and NOX upregulation. C_LIO_LInIH-dependent pro-oxidant state leads to NMDAr remodeling of the GluN2 subunit to impair synaptic plasticity. C_LIO_LIImpaired synaptic plasticity and NMDAr remodeling caused by nIH persists beyond the critical period of development. C_LIO_LIA discrete window for antioxidant administration exists to effectively mitigate neurophysiological and behavioral consequences of nIH. C_LI

neuroscience↗

bioRxiv2019

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

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.\n\nSignificanceIntermittent 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.\n\nKey pointsO_LIIntermittent hypoxia (IH) is a hallmark of sleep apnea and is known to cause learning and memory deficits.\nC_LIO_LIHypoxia Inducible Factor 1a (HIF1a), is associated with IH-dependent changes in physiology.\nC_LIO_LIIH 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).\nC_LIO_LIIH-dependent suppression of LTP is co-incidental with diminished NMDA receptor contribution to glutamatergic transmission.\nC_LIO_LIFollowing IH, mice heterozygous for HIF1a (HIF1a+/-) do not show an increase in HIF1a and oxidative stress, or changes in either behavior or glutamatergic transmission.\nC_LI

neuroscience↗