Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by 
mutations in the MECP2. Several genes have been shown to be MECP2 targets. We 
previously identified FXYD1 (encoding phospholemman; a protein containing the 
motif phenylalanine-X-tyrosine-aspartate), a gene encoding a transmembrane 
modulator of the Na, K-ATPase (NKA) enzyme, as one of them. In the absence of 
MECP2, FXYD1 expression is increased in the frontal cortex (FC) of both RTT 
patients and Mecp2(Bird) null mice. Here, we show that Fxyd1 mRNA levels are 
also increased in the FC and hippocampus (HC) of male mice carrying a truncating 
mutation of the Mecp2 gene (Mecp2(308)). To test the hypothesis that some of the 
behavioral phenotypes seen in these Mecp2 mutants could be ameliorated by 
genetically preventing the Fxyd1 response to MECP2 deficiency, we crossed Fxyd1 
null male mice with Mecp2(308) heterozygous females and behaviorally tested the 
adult male offspring. Mecp2(308) mice had impaired HC-dependent novel location 
recognition, and this impairment was rescued by deletion of both Fxyd1 alleles. 
No other behavioral or sensorimotor impairments were rescued. These results 
indicate that reducing FXYD1 levels improves a specific cognitive impairment in 
MECP2-deficient mice.