title: Correcting deregulated Fxyd1 expression ameliorates a behavioral impairment in a mouse model of Rett syndrome.
abstract: 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.
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center/Oregon Health & Science University, Beaverton, OR 97006, USA. valerie.matagne@univ-amu.fr
authors.forename: Valerie
authors.initials: V
authors.lastname: Matagne
authors.forename: Sarojini
authors.initials: S
authors.lastname: Budden
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Ojeda
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001526:Behavioral Symptoms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D001835:Body Weight / Q000235:genetics; D003072:Cognition Disorders / Q000235:genetics; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D020233:Gait Disorders, Neurologic / Q000209:etiology / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D018737:Hand Strength / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D015518:Rett Syndrome / Q000150:complications* / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D051783:Methyl-CpG-Binding Protein 2; D010750:Phosphoproteins; D012333:RNA, Messenger; C069141:phospholemman