title: Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration.
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.-Wirth, E. K., Conrad, M., Winterer, J., Wozny, C., Carlson, B. A., Roth, S., Schmitz, D., Bornkamm, G. W., Coppola, V., Tessarollo, L., Schomburg, L., Köhrle, J., Hatfield, D. L., Schweizer, U. Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration.
authors.affiliation: Institute for Experimental Endocrinology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Eva K
authors.initials: EK
authors.lastname: Wirth
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.forename: Jochen
authors.initials: J
authors.lastname: Winterer
authors.forename: Christian
authors.initials: C
authors.lastname: Wozny
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Carlson
authors.forename: Stephan
authors.initials: S
authors.lastname: Roth
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schmitz
authors.forename: Georg W
authors.initials: GW
authors.lastname: Bornkamm
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Lutz
authors.initials: L
authors.lastname: Schomburg
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
authors.forename: Dolph L
authors.initials: DL
authors.lastname: Hatfield
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schweizer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D064032:Calbindin 2; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004594:Electrophysiology; D005979:Glutathione Peroxidase / Q000378:metabolism / Q000502:physiology; D007150:Immunohistochemistry; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism* / Q000517:prevention & control*; D010320:Parvalbumins / Q000378:metabolism / Q000502:physiology; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D012346:RNA, Transfer, Amino Acyl / Q000235:genetics / Q000502:physiology; D064030:S100 Calcium Binding Protein G / Q000378:metabolism / Q000502:physiology; D012640:Seizures / Q000378:metabolism* / Q000517:prevention & control*; D012643:Selenium / Q000494:pharmacology; D051140:Selenoproteins / Q000378:metabolism / Q000502:physiology*; D014810:Vitamin E / Q000494:pharmacology
chemical_list: C576511:Calb2 protein, mouse; D064032:Calbindin 2; D010320:Parvalbumins; D012346:RNA, Transfer, Amino Acyl; D064030:S100 Calcium Binding Protein G; D051140:Selenoproteins; C112705:selenocysteinyl-tRNA; D014810:Vitamin E; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D012643:Selenium