Neonatal intermittent hypoxia-dependent oxidative stress prevents NMDAr subunit remodeling during the critical period producing deficits in synaptic plasticity and spatial memory during adulthood

Abstract

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.