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
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/early/2018/02/12/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 months 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 results 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 ChIP 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.Significance Statement Rett Syndrome (RTT) is a devastating neurodevelopmental disorder that affects 1 in 10 000-25 000 females. Mutations in Methyl-CpG-binding protein 2 (MeCP2), a transcriptional regulator, are responsible for over 95% of Rett cases. Recent work has shown that astrocytes contribute significantly to the disorder, although their contribution to this disease is not known. Here we demonstrate that the critical astrocyte K+ channel Kir4.1 is a novel molecular target of MeCP2. MeCP2 deficiency leads to decreased Kcnj10/Kir4.1 mRNA levels, protein expression, and currents. These findings provide novel mechanistic insight and begin to elucidate the role of astrocytes in this disorder.