Delayed Ventricular Repolarization and Sodium Channel Current Modification in a Mouse Model of Rett Syndrome

Rett syndrome (RTT) is a severe developmental disorder that is strongly linked to mutations in the MECP2 gene. RTT has been associated with sudden unexplained death and ECG QT interval prolongation. There are mixed reports regarding QT prolongation in mouse models of RTT, with some evidence that loss of Mecp2 function enhances cardiac late Na current, I-Na,I-Late. The present study was undertaken in order to investigate both ECG and ventricular AP characteristics in the Mecp2(Null/Y) male murine RTT model and to interrogate both fast I-Na and I-Na,I- Late in myocytes from the model. ECG recordings from 8-10-week-old Mecp2(Null/Y) male mice revealed prolongation of the QT and rate corrected QT (QTc) intervals and QRS widening compared to wild-type (WT) controls. Action potentials (APs) from Mecp2(Null/Y) myocytes exhibited longer APD(75) and APD(90) values, increased triangulation and instability. I-Na,I- Late was also significantly larger in Mecp2(Null/Y) than WT myocytes and was insensitive to the Nav1.8 inhibitor A-803467. Selective recordings of fast I-Na revealed a decrease in peak current amplitude without significant voltage shifts in activation or inactivation V-0.5. Fast I-Na `window current' was reduced in RTT myocytes; small but significant alterations of inactivation and reactivation time-courses were detected. Effects of two I-Na,I- Late inhibitors, ranolazine and GS-6615 (eleclazine), were investigated. Treatment with 30 mu M ranolazine produced similar levels of inhibition of I-Na,I- Late in WT and Mecp2(Null/Y) myocytes, but produced ventricular AP prolongation not abbreviation. In contrast, 10 mu M GS-6615 both inhibited I-Na,I- Late and shortened ventricular AP duration. The observed changes in I-Na and I-Na,I- Late can account for the corresponding ECG changes in this RTT model. GS-6615 merits further investigation as a potential treatment for QT prolongation in RTT.