AUTHOR=Sun Yuxiao , Jin Mei-fang , Li Lili , Liu Yueying , Wang Dandan , Ni Hong 

TITLE=Genetic Inhibition of Plppr5 Aggravates Hypoxic-Ischemie-Induced Cortical Damage and Excitotoxic Phenotype

JOURNAL=Frontiers in Neuroscience

VOLUME=16

YEAR=2022

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.751489

DOI=10.3389/fnins.2022.751489

ISSN=1662-453X

ABSTRACT=<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 <italic>Plppr5</italic> knockout exacerbated HI impairment in some aspects and partially attenuated the neuroprotective effects of melatonin, suggesting that <italic>Plppr5</italic> may be a novel intervention target for HI. The present study aimed to determine the long-term effects of gene knockout of <italic>Plppr5</italic> on HI brain injury, focusing on the neuronal excitability phenotype, and to determine the effect of <italic>Plppr5</italic> gene silencing on neuronal zinc metabolism and mitochondrial function <italic>in vitro</italic>. 10-day-old wild type (WT) mice and <italic>Plppr5</italic>-deficient (<italic>Plppr5</italic><sup>–/–</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–glucose deprivation/reoxygenation (OGD/R) treatment and was treated with medium containing LV-sh_<italic>Plppr5</italic> or control virus. Mitochondrial oxidative stress indicator ROS, mitochondrial ZnT1 protein expression and zinc ion content were detected.</p><sec><title>Results</title><p><italic>Plppr5</italic>-deficient mice subjected to hypoxia-ischemia at postnatal day 10 present significantly higher cerebral infarction. <italic>Plppr5</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 <italic>Plppr5</italic>-deficient mice as well as in mice subjected to HI excitotoxicity. <italic>Plppr5</italic> knockout <italic>in vivo</italic> exacerbates HI brain injury phenotypes, including infarct volume and seizure threshold. In addition, knockout of the <italic>Plppr5</italic> gene reduced the MFS score to some extent. <italic>In vitro Plppr5</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 <italic>Plppr5</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 <italic>Plppr5</italic>-mediated zinc and mitochondrial homeostasis in neonatal HIE.</p></sec>