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Selenoprotein T Deficiency Leads to Neurodevelopmental Abnormalities and Hyperactive Behavior in Mice

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Abstract

Selenoprotein T (SelT) is a newly discovered thioredoxin-like protein, which is abundantly but transiently expressed in the neural lineage during brain ontogenesis. Because its physiological function in the brain remains unknown, we developed a conditional knockout mouse line (Nes-Cre/SelTfl/fl) in which SelT gene is specifically disrupted in nerve cells. At postnatal day 7 (P7), these mice exhibited reduced volume of different brain structures, including hippocampus, cerebellum, and cerebral cortex. This phenotype, which is observed early during the first postnatal week, culminated at P7 and was associated with increased loss of immature neurons but not glial cells, through apoptotic cell death. This phenomenon was accompanied by elevated levels of intracellular reactive oxygen species, which may explain the increased neuron demise and reduced brain structure volumes. At the second postnatal week, an increase in neurogenesis was observed in the cerebellum of Nes-Cre/SelTfl/fl mice, suggesting the occurrence of developmental compensatory mechanisms in the brain. In fact, the brain volume alterations observed at P7 were attenuated in adult mice. Nevertheless, SelT mutant mice exhibited a hyperactive behavior, suggesting that despite an apparent morphological compensation, SelT deficiency leads to cerebral malfunction in adulthood. Altogether, these results demonstrate that SelT exerts a neuroprotective role which is essential during brain development, and that its loss impairs mice behavior.

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Acknowledgments

This work was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm, grant number U982); the University of Rouen; the Regional Council of Haute-Normandie; the European Community Interreg IV Program (grants PeReNE and TC2N); and the French Ministry for Higher Education and Research (Scholarship to M.T.C.). We thank Dorthe Cartier and Pr Pierrick Gandolfo of Inserm U982 for technical assistance and helpful comments. Part of the behavioral tests was done on the Service Commun d’Analyse Comportementale (SCAC). Images were acquired in PRIMACEN (http://primacen.crihan.fr), the Cell Imaging Facility of Normandy.

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Authors and Affiliations

  1. Inserm, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, University of Rouen, Normandy University, Mont-Saint-Aignan, 76821, France

    Matthieu T. Castex, Vadim Le Joncour, Gaëtan Prévost, Jean-Jacques Bonnet, Youssef Anouar & Anthony Falluel-Morel

  2. Sciences Faculty, University of Rouen, 76821, Mont-Saint-Aignan, France

    Arnaud Arabo

  3. PRIMACEN, Institute for Research and Innovation in Biomedicine, University of Rouen, 76821, Mont-Saint-Aignan, France

    Magalie Bénard

  4. PSY-NCA, EA4700, University of Rouen, 76821, Mont-Saint-Aignan, France

    Vincent Roy

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  1. Matthieu T. Castex
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Castex, M.T., Arabo, A., Bénard, M. et al. Selenoprotein T Deficiency Leads to Neurodevelopmental Abnormalities and Hyperactive Behavior in Mice. Mol Neurobiol 53, 5818–5832 (2016). https://doi.org/10.1007/s12035-015-9505-7

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