AUTHOR=Arias-Cavieres Alejandra , Garcia Alfredo J. TITLE=A consequence of immature breathing induces persistent changes in hippocampal synaptic plasticity and behavior: a role of prooxidant state and NMDA receptor imbalance JOURNAL=Frontiers in Molecular Neuroscience VOLUME=Volume 16 - 2023 YEAR=2023 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2023.1192833 DOI=10.3389/fnmol.2023.1192833 ISSN=1662-5099 ABSTRACT=

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 mechanistic basis of nIH-induced changes to neurophysiology remains poorly resolved. 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 prooxidant state that leads to an imbalance in NMDAr subunit composition favoring GluN2B over GluN2A expression and impairs synaptic plasticity. These consequences persist in adulthood and coincide with deficits in spatial memory. Treatment with an 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 long-lasting changes in either synaptic plasticity or behavior. In addition to demonstrating that the prooxidant state has a central role in nIH-mediated neurophysiological and behavioral deficits, our results also indicate that targeting the prooxidant state during a discrete therapeutic window may provide a potential avenue for mitigating long-term neurophysiological and behavioral outcomes that result from unstable breathing during early postnatal life.