{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T19:06:35Z","timestamp":1785783995967,"version":"3.56.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T00:00:00Z","timestamp":1648080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Hypoxia-ischemia (HI) is the most common acute brain threat in neonates and a leading cause of neurodevelopmental impairment. Exploring the new molecular mechanism of HI brain injury has important clinical translational significance for the next clinical intervention research. Lipid phosphatase-related proteins (PLPPRs) are regulators of mitochondrial membrane integrity and energy metabolism. We recently found that <jats:italic>Plppr5<\/jats:italic> knockout exacerbated HI impairment in some aspects and partially attenuated the neuroprotective effects of melatonin, suggesting that <jats:italic>Plppr5<\/jats:italic> may be a novel intervention target for HI. The present study aimed to determine the long-term effects of gene knockout of <jats:italic>Plppr5<\/jats:italic> on HI brain injury, focusing on the neuronal excitability phenotype, and to determine the effect of <jats:italic>Plppr5<\/jats:italic> gene silencing on neuronal zinc metabolism and mitochondrial function <jats:italic>in vitro<\/jats:italic>. 10-day-old wild type (WT) mice and <jats:italic>Plppr5<\/jats:italic>-deficient (<jats:italic>Plppr5<\/jats:italic><jats:sup>\u2013\/\u2013<\/jats:sup>) mice were subjected to hypoxia-ischemia. Lesion volumes and HI-induced neuroexcitotoxic phenotypes were quantified together with ZnT1 protein expression in hippocampus. In addition, HT22 (mouse hippocampal neuronal cells) cell model was established by oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) treatment and was treated with medium containing LV-sh_<jats:italic>Plppr5<\/jats:italic> or control virus. Mitochondrial oxidative stress indicator ROS, mitochondrial ZnT1 protein expression and zinc ion content were detected.<\/jats:p><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Plppr5<\/jats:italic>-deficient mice subjected to hypoxia-ischemia at postnatal day 10 present significantly higher cerebral infarction. <jats:italic>Plppr5<\/jats:italic>-deficient mice were endowed with a more pronounced superexcitability phenotype at 4 weeks after HI, manifested as a reduced seizure threshold. ZnT1 protein was also found reduced in <jats:italic>Plppr5<\/jats:italic>-deficient mice as well as in mice subjected to HI excitotoxicity. <jats:italic>Plppr5<\/jats:italic> knockout <jats:italic>in vivo<\/jats:italic> exacerbates HI brain injury phenotypes, including infarct volume and seizure threshold. In addition, knockout of the <jats:italic>Plppr5<\/jats:italic> gene reduced the MFS score to some extent. <jats:italic>In vitro Plppr5<\/jats:italic> silencing directly interferes with neuronal zinc metabolism homeostasis and exacerbates hypoxia-induced mitochondrial oxidative stress damage. Taken together, our findings demonstrate for the first time that <jats:italic>Plppr5<\/jats:italic>-deficient mouse pups exposed to neuronal hypoxia and ischemia exhibit aggravated acute brain injury and long-term brain excitability compared with the same treated WT pups, which may be related to the disruption of zinc and mitochondria-dependent metabolic pathways in the hippocampus. These data support further investigation into novel approaches targeting <jats:italic>Plppr5<\/jats:italic>-mediated zinc and mitochondrial homeostasis in neonatal HIE.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2022.751489","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T02:06:22Z","timestamp":1648519582000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Genetic Inhibition of Plppr5 Aggravates Hypoxic-Ischemie-Induced Cortical Damage and Excitotoxic Phenotype"],"prefix":"10.3389","volume":"16","author":[{"given":"Yuxiao","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-fang","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueying","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.lfs.2016.03.008","article-title":"Selenium and zinc protect brain mitochondrial antioxidants and electron transport chain enzymes following postnatal protein malnutrition.","volume":"152","author":"Adebayo","year":"2016","journal-title":"Life Sci."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2015.00157","article-title":"Replacement of asymmetric synaptic profiles in the molecular layer of dentate gyrus following cycloheximide in the pilocarpine model in rats.","volume":"6","author":"Bittencourt","year":"2015","journal-title":"Front. 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