MeCP2 Deficiency Leads to Loss of Glial Kir4.1

• Published in: eNeuro 2018-01, Vol.5 (1), p.ENEURO.0194-17.2018
• Main Authors: Kahanovitch, Uri, Cuddapah, Vishnu A, Pacheco, Natasha L, Holt, Leanne M, Mulkey, Daniel K, Percy, Alan K, Olsen, Michelle L
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - metabolism; Gene Expression Regulation; Male; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice, Transgenic; New Research; Potassium Channels, Inwardly Rectifying - metabolism; Rett Syndrome - genetics; Rett Syndrome - metabolism
• ISSN: 2373-2822; 2373-2822
• DOI: 10.1523/ENEURO.0194-17.2018

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 -deficient mice express significantly less Kir4.1 mRNA and protein, which translates into a >50% deficiency in Ba -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 -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.