Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice.

Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice. Brain Res. 2018 Jun 11;: Authors: Matagne V, Wondolowski J, Frerking M, Shahidullah M, Delamere NA, Sandau US, Budden S, Ojeda SR Abstract Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2/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 FXYD1 may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if FXYD1 can rescue these RTT deficits, we studied the male progeny of Fxyd1 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 Fxyd1 allele, suggesting that NKA activity is under FXYD1 inhibitory control. Deletion of one Fxyd1 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 FXYD1 failed to rescue t...
Source: Brain Research - Category: Neurology Authors: Tags: Brain Res Source Type: research