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

Eva K Wirth, Marcus Conrad, Jochen Winterer, Christian Wozny, Bradley A. Carlson, Stephan Roth, Dietmar Schmitz, Georg W. Bornkamm, Vincenzo Coppola, Lino Tessarollo, Lutz Schomburg, Josef Köhrle, Dolph L. Hatfield, Ulrich Schweizer

Research output: Contribution to journalArticle

97 Citations (Scopus)

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.
LanguageEnglish
Pages844-852
Number of pages9
JournalFASEB Journal
Volume24
Issue number3
Early online date4 Nov 2009
DOIs
Publication statusPublished - 1 Mar 2010

Fingerprint

Selenoproteins
phospholipid-hydroperoxide glutathione peroxidase
Interneurons
Parvalbumins
Selenium
Seizures
Neurons
Calbindin 2
Ataxia
Vitamin E
RNA, Transfer, Ser
Cell death
Glutathione
Cell Death
Genes
Phenotype
Enzymes

Keywords

  • animals
  • blotting, western
  • Calbindin 2
  • cell differentiation
  • cells, cultured
  • electrophysiology
  • glutathione peroxidase
  • immunohistochemistry
  • interneurons
  • mice
  • mice, knockout
  • nerve degeneration
  • parvalbumins
  • RNA, transfer, amino acyl
  • S100 calcium binding protein G
  • seizures
  • selenium
  • selenoproteins
  • vitamin E

Cite this

Wirth, Eva K ; Conrad, Marcus ; Winterer, Jochen ; Wozny, Christian ; Carlson, Bradley A. ; Roth, Stephan ; Schmitz, Dietmar ; Bornkamm, Georg W. ; Coppola, Vincenzo ; Tessarollo, Lino ; Schomburg, Lutz ; Köhrle, Josef ; Hatfield, Dolph L. ; Schweizer, Ulrich. / Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration. In: FASEB Journal. 2010 ; Vol. 24, No. 3. pp. 844-852.
@article{1ba3e67e843940d2a0bbc3b609bae78f,
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., K{\"o}hrle, J., Hatfield, D. L., Schweizer, U. Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration.",
keywords = "animals, blotting, western, Calbindin 2, cell differentiation, cells, cultured, electrophysiology, glutathione peroxidase, immunohistochemistry, interneurons, mice, mice, knockout, nerve degeneration, parvalbumins, RNA, transfer, amino acyl, S100 calcium binding protein G, seizures, selenium, selenoproteins, vitamin E",
author = "Wirth, {Eva K} and Marcus Conrad and Jochen Winterer and Christian Wozny and Carlson, {Bradley A.} and Stephan Roth and Dietmar Schmitz and Bornkamm, {Georg W.} and Vincenzo Coppola and Lino Tessarollo and Lutz Schomburg and Josef K{\"o}hrle and Hatfield, {Dolph L.} and Ulrich Schweizer",
year = "2010",
month = "3",
day = "1",
doi = "10.1096/fj.09-143974",
language = "English",
volume = "24",
pages = "844--852",
journal = "FASEB Journal",
issn = "0892-6638",
number = "3",

}

Wirth, EK, Conrad, M, Winterer, J, Wozny, C, Carlson, BA, Roth, S, Schmitz, D, Bornkamm, GW, Coppola, V, Tessarollo, L, Schomburg, L, Köhrle, J, Hatfield, DL & Schweizer, U 2010, 'Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration' FASEB Journal, vol. 24, no. 3, pp. 844-852. https://doi.org/10.1096/fj.09-143974

Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration. / Wirth, Eva K; Conrad, Marcus; Winterer, Jochen; Wozny, Christian; Carlson, Bradley A.; Roth, Stephan; Schmitz, Dietmar; Bornkamm, Georg W.; Coppola, Vincenzo; Tessarollo, Lino; Schomburg, Lutz; Köhrle, Josef; Hatfield, Dolph L.; Schweizer, Ulrich.

In: FASEB Journal, Vol. 24, No. 3, 01.03.2010, p. 844-852.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration

AU - Wirth, Eva K

AU - Conrad, Marcus

AU - Winterer, Jochen

AU - Wozny, Christian

AU - Carlson, Bradley A.

AU - Roth, Stephan

AU - Schmitz, Dietmar

AU - Bornkamm, Georg W.

AU - Coppola, Vincenzo

AU - Tessarollo, Lino

AU - Schomburg, Lutz

AU - Köhrle, Josef

AU - Hatfield, Dolph L.

AU - Schweizer, Ulrich

PY - 2010/3/1

Y1 - 2010/3/1

N2 - 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.

AB - 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.

KW - animals

KW - blotting, western

KW - Calbindin 2

KW - cell differentiation

KW - cells, cultured

KW - electrophysiology

KW - glutathione peroxidase

KW - immunohistochemistry

KW - interneurons

KW - mice

KW - mice, knockout

KW - nerve degeneration

KW - parvalbumins

KW - RNA, transfer, amino acyl

KW - S100 calcium binding protein G

KW - seizures

KW - selenium

KW - selenoproteins

KW - vitamin E

U2 - 10.1096/fj.09-143974

DO - 10.1096/fj.09-143974

M3 - Article

VL - 24

SP - 844

EP - 852

JO - FASEB Journal

T2 - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 3

ER -