Rescue of behavioral and EEG deficits in male and female Mecp2-deficient mice by delayed Mecp2 gene reactivation

Abstract

Mutations of the X-linked gene encoding methyl CpG binding protein type 2 (MECP2) are the pred ominant cause of Rett syndrome, a severe neuro developmental condition that affects primarily females. Previous studies have shown that major phenotypic deficits arising from MeCP2-deficiency may be reversible,as the delayed reactivation of the Mecp2 gene in Mecp2-deficientmice improved aspects of their Rett-like phenotype.While encouraging for prospective gene replacement treatments, it remains unclear whether additional Rett syndrome co-morbidities recapitulated in Mecp2-deficient mice will be similarly responsive to the delayed reintroduction of functional Mecp2. Here, we show that the delayed reactivation of Mecp2 in both male and female Mecp2-deficient mice rescues established deficits in motor and anxiety-like behavior, epilepti form activity, cortical and hippocampal electroencephalogram patterning and thermoregulation. These findings indicate that neural circuitry deficits arising fromthe deficiency in Mecp2 are not engrained, and provide further evidence that delayed restoration of Mecp2 function can improve a wide spectrumof the Rett-like deficits recapitulated by Mecp2-deficientmice. © The Author 2013. Published by Oxford University Press. All rights reserved.