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Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration

Item Type:Article
Title:Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration
Creators Name:Wirth, E.K. and Conrad, M. and Winterer, J. and Wozny, C. and Carlson, B.A. and Roth, S. and Schmitz, D. and Bornkamm, G.W. and Coppola, V. and Tessarollo, L. and Schomburg, L. and Koehrle, J. and Hatfield, D.L. and Schweizer, U.
Abstract:Cerebral selenium (Se) deficiency is associated with neurological phenotypes including seizures and ataxia. We wanted to define whether neurons require selenoprotein expression and which selenoproteins are most important, and explore the possible pathomechanism. Therefore, we abrogated the expression of all selenoproteins in neurons by genetic inactivation of the tRNA[Ser](Sec) gene. Cerebral expression of selenoproteins was significantly diminished in the mutants, and histological analysis revealed progressive neurodegeneration. Developing interneurons failed to specifically express parvalbumin (PV) in the mutants. Electrophysiological recordings, before overt cell death, showed normal excitatory transmission, but revealed spontaneous epileptiform activity consistent with seizures in the mutants. In developing cortical neuron cultures, the number of PV(+) neurons was reduced on combined Se and vitamin E deprivation, while other markers, such as calretinin (CR) and GAD67, remained unaffected. Because of the synergism between Se and vitamin E, we analyzed mice lacking neuronal expression of the Se-dependent enzyme glutathione peroxidase 4 (GPx4). Although the number of CR(+) interneurons remained normal in Gpx4-mutant mice, the number of PV(+) interneurons was reduced. Since these mice similarly exhibit seizures and ataxia, we conclude that GPx4 is a selenoenzyme modulating interneuron function and PV expression. Cerebral SE deficiency may thus act via reduced GPx4 expression.
Keywords:Selenium, Parvalbumin, Excitability, Schizophrenia, {gamma} Oscillation, Animals, Mice
Source:FASEB Journal
Publisher:Federation of American Societies for Experimental Biology
Page Range:844-852
Date:March 2010
Official Publication:https://doi.org/10.1096/fj.09-143974
PubMed:View item in PubMed

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