Altered Astrocyte Function in a Murine Model of Rett Syndrome Michelle Olsen, Ph.D., Assistant Professor, University of Alabama at Birmingham, Department of Cell, Developmental and Integrative Biology
Rett syndrome has been considered almost exclusively a neuronal disease. Recent work demonstrated that restoration of MeCP2 function selectively to astrocytes reversed several phenotypes in a murine model of RTT, but the mechanism of this rescue is unknown. Astrocytes are the most numerous cells in the CNS and carry out many essential functions required for ‘normal’ brain functioning. One such task is the regulation of extracellular potassium, which when elevated leads to neuronal hyperexcitability. This process is mediated by a ‘glial’ specific potassium channel Kir4.1. The importance of this channel in human brain is underscored by recent studies in human patients that link mutations in the Kir4.1 gene (KCNJ10) to developmental disorders characterized by early onset seizures, ataxia, epilepsy, severe cognitive impairments and autism; all hallmarks of Rett syndrome. We demonstrate by ChIP assay that Kir4.1 is a direct molecular target of MeCP2 in wild type mice. Astrocytes from MeCP2 deficient mice express significantly less Kir4.1 mRNA and protein in cortex and brainstem; two brain structures affected in girls with RTT. The loss of Kir4.1 protein is associated with a >50% deficiency in Ba2+-sensitive Kir4.1 mediated currents, smaller astrocytic K+ currents, elevated [K+]o, . Potassium sensitive microelectrode recordings demonstrated that the baseline [K+]o was elevated by 1 mM in MeCP2-/y mice. These are the first data implicating a direct molecular target of MeCP2 in astrocytes and provide novel mechanistic insight explaining how astrocytic dysfunction may contribute to RTT.