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• W4366133639 endingPage "106128" @default.
• W4366133639 startingPage "106128" @default.
• W4366133639 abstract "RGS14 is a complex multifunctional scaffolding protein that is highly enriched within pyramidal cells (PCs) of hippocampal area CA2. In these neurons, RGS14 suppresses glutamate-induced calcium influx and related G protein and ERK signaling in dendritic spines to restrain postsynaptic signaling and plasticity. Previous findings show that, unlike PCs of hippocampal areas CA1 and CA3, CA2 PCs are resistant to a number of neurological insults, including degeneration caused by temporal lobe epilepsy (TLE). While RGS14 is protective against peripheral injury, similar roles for RGS14 during pathological injury in hippocampus remain unexplored. Recent studies showed that area CA2 modulates hippocampal excitability, generates epileptiform activity and promotes hippocampal pathology in animal models and patients with TLE. Because RGS14 suppresses CA2 excitability and signaling, we hypothesized that RGS14 would moderate seizure behavior and early hippocampal pathology following seizure activity, possibly affording protection to CA2 PCs. Using kainic acid (KA) to induce status epilepticus (KA-SE) in mice, we show that the loss of RGS14 (RGS14 KO) accelerated onset of limbic motor seizures and mortality compared to wild type (WT) mice, and that KA-SE upregulated RGS14 protein expression in CA2 and CA1 PCs of WT. Our proteomics data show that the loss of RGS14 impacted the expression of a number of proteins at baseline and after KA-SE, many of which associated unexpectedly with mitochondrial function and oxidative stress. RGS14 was shown to localize to the mitochondria in CA2 PCs of mice and reduce mitochondrial respiration in vitro. As a readout of oxidative stress, we found that RGS14 KO dramatically increased 3- nitrotyrosine levels in CA2 PCs, which was greatly exacerbated following KA-SE and correlated with a lack of superoxide dismutase 2 (SOD2) induction. Assessing for hallmarks of seizure pathology in RGS14 KO, we unexpectedly found no differences in neuronal injury in CA2 PCs. However, we observed a striking and surprising lack of microgliosis in CA1 and CA2 of RGS14 KO compared to WT. Together, our data demonstrate a newly appreciated role for RGS14 in limiting intense seizure activity and pathology in hippocampus. Our findings are consistent with a model where RGS14 limits seizure onset and mortality and, after seizure, is upregulated to support mitochondrial function, prevent oxidative stress in CA2 PCs, and promote microglial activation in hippocampus." @default.
• W4366133639 created "2023-04-19" @default.
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• W4366133639 date "2023-06-01" @default.
• W4366133639 modified "2023-10-03" @default.
• W4366133639 title "RGS14 limits seizure-induced mitochondrial oxidative stress and pathology in hippocampus" @default.
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