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Correcting deregulated Fxydl expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice

Abstract : Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxydl may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxydl can rescue these RTT deficits, we studied the male progeny of Fxydl null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxydl allele, suggesting that NKA activity is under Fxydl inhibitory control. Deletion of one Fxydl allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxydl failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxydl in the absence of MeCP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth. (C) 2018 Elsevier B.V. All rights reserved.
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https://hal-amu.archives-ouvertes.fr/hal-01991342
Contributor : Valérie Gall <>
Submitted on : Wednesday, January 23, 2019 - 6:00:30 PM
Last modification on : Thursday, February 7, 2019 - 3:41:08 PM

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Valerie Matagne, Joyce Wondolowski, Matthew Frerking, Mohammad Shahidullah, Nicholas A. Delamere, et al.. Correcting deregulated Fxydl expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice. Brain Research, 2018, 1697, pp.45-52. ⟨hal-01991342⟩

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