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Seizures, ataxia and parvalbumin-expressing interneurons respond to selenium supply in Selenop-deficient mice.

Redox Biol. 2022 Sep 24;57:102490. doi: 10.1016/j.redox.2022.102490. Epub ahead of print. PMID: 36182809; PMCID: PMC9526222.

Authors/Editors: Schweizer U, Wirth EK, Klopstock T, Hölter SM, Becker L, Moskovitz J, Grune T, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Köhrle J, Schomburg L.
Publication Date: 2022

11_schweizer

Abstract

Mice with constitutive disruption of the Selenop gene have been key to delineate the importance of selenoproteins in neurobiology. However, the phenotype of this mouse model is exquisitely dependent on selenium supply and timing of selenium supplementation. Combining biochemical, histological, and behavioral methods, we tested the hypothesis that parvalbumin-expressing interneurons in the primary somatosensory cortex and hippocampus depend on dietary selenium availability in Selenop-/- mice. Selenop-deficient mice kept on adequate selenium diet (0.15 mg/kg, i.e. the recommended dietary allowance, RDA) developed ataxia, tremor, and hyperexcitability between the age of 4-5 weeks. Video-electroencephalography demonstrated epileptic seizures in Selenop-/- mice fed the RDA diet, while Selenop± heterozygous mice behaved normally. Both neurological phenotypes, hyperexcitability/seizures and ataxia/dystonia were successfully prevented by selenium supplementation from birth or transgenic expression of human SELENOP under a hepatocyte-specific promoter. Selenium supplementation with 10 μM selenite in the drinking water on top of the RDA diet increased the activity of glutathione peroxidase in the brains of Selenop-/- mice to control levels. The effects of selenium supplementation on the neurological phenotypes were dose- and time-dependent. Selenium supplementation after weaning was apparently too late to prevent ataxia/dystonia, while selenium withdrawal from rescued Selenop-/- mice eventually resulted in ataxia. We conclude that SELENOP expression is essential for preserving interneuron survival under limiting Se supply, while SELENOP appears dispensable under sufficiently high Se status.

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