RT Journal Article SR Electronic T1 MeCP2 Deficiency Leads to Loss of Glial Kir4.1 JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0194-17.2018 DO 10.1523/ENEURO.0194-17.2018 VO 5 IS 1 A1 Uri Kahanovitch A1 Vishnu A. Cuddapah A1 Natasha L. Pacheco A1 Leanne M. Holt A1 Daniel K. Mulkey A1 Alan K. Percy A1 Michelle L. Olsen YR 2018 UL http://www.eneuro.org/content/5/1/ENEURO.0194-17.2018.abstract AB Rett syndrome (RTT) is an X-linked neurodevelopmental disorder usually caused by mutations in methyl-CpG-binding protein 2 (MeCP2). RTT is typified by apparently normal development until 6–18 mo of age, when motor and communicative skills regress and hand stereotypies, autonomic symptoms, and seizures present. Restoration of MeCP2 function selectively to astrocytes reversed several deficits in a murine model of RTT, but the mechanism of this rescue is unknown. Astrocytes carry out many essential functions required for normal brain functioning, including extracellular K+ buffering. Kir4.1, an inwardly rectifying K+ channel, is largely responsible for the channel-mediated K+ regulation by astrocytes. Loss-of-function mutations in Kir4.1 in human patients result in a severe neurodevelopmental disorder termed EAST or SESAME syndrome. Here, we evaluated astrocytic Kir4.1 expression in a murine model of Rett syndrome. We demonstrate by chromatin immunoprecipitation analysis that Kir4.1 is a direct molecular target of MeCP2. Astrocytes from Mecp2-deficient mice express significantly less Kir4.1 mRNA and protein, which translates into a >50% deficiency in Ba2+-sensitive Kir4.1-mediated currents, and impaired extracellular potassium dynamics. By examining astrocytes in isolation, we demonstrate that loss of Kir4.1 is cell autonomous. Assessment through postnatal development revealed that Kir4.1 expression in Mecp2-deficient animals never reaches adult, wild-type levels, consistent with a neurodevelopmental disorder. These are the first data implicating a direct MeCP2 molecular target in astrocytes and provide novel mechanistic insight explaining a potential mechanism by which astrocytic dysfunction may contribute to RTT.