Characterization of the MeCP2R168X Knockin Mouse Model for Rett Syndrome

Abstract

Rett syndrome, one of the most common causes of mental retardation in females, is caused by mutations in the X chromosomal gene MECP2. Mice deficient for MeCP2 recapitulate some of the symptoms seen in patients with Rett syndrome. It has been shown that reactivation of silent MECP2 alleles can reverse some of the symptoms in these mice. We have generated a knockin mouse model for translational research that carries the most common nonsense mutation in Rett syndrome, R168X. In this article we describe the phenotype of this mouse model. In male MeCP2R168X mice life span was reduced to 12–14 weeks and bodyweight was significantly lower than in wild type littermates. First symptoms including tremor, hind limb clasping and inactivity occurred at age 27 days. At age 6 weeks nest building, rotarod, open-field and elevated plus maze experiments showed impaired motor performance, reduced activity and decreased anxiety-like behavior. Plethysmography at the same time showed apneas and irregular breathing with reduced frequency. Female MeCP2R168X mice showed no significant abnormalities except decreased performance on the rotarod at age 9 months. In conclusion we show that the male MeCP2R168X mice have a phenotype similar to that seen in MECP2 knockout mouse models and are therefore well suited for translational research. The female mice, however, have a much milder and less constant phenotype making such research with this mouse model more challenging.

MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

“…In XY males, however, mutations in MECP2 result in fatal neonatal encephalopathy due to the x-linked nature of the disease, or, rarely, a more classical RTT presentation (47–49). Paralleling findings in humans, Mecp2 ZFN/y rats became symptomatic within weeks of birth and died early, all findings that are corroborated by earlier reports in various mouse models (10–12,20–22,37,50,51). …”

“…These findings may be related to previous reports of altered aggressive or defensive behaviours (17,18,99,102) and anxiety-like behaviours (19,20,22,37,38, 44,50,61) in RTT mouse models as well as in patients (reviewed in (53)). This aggressive behaviour was not observed in Mecp2 ZFN/+  females.…”

Systemic Radical Scavenger Treatment of a Mouse Model of Rett Syndrome: Merits and Limitations of the Vitamin E Derivative Trolox

“…Motor problems and insufficient motor skills are evident in various MeCP2-mutant mice (Guy et al, 2001; Shahbazian et al, 2002; Moretti et al, 2005; Wegener et al, 2014). Compared to WTs, the treated Mecp2 −/y mice failed markedly earlier on the rotarod, and their impaired motor function was not ameliorated by Trolox.…”

“…The individual respiratory cycles were detected by the threshold crossing method (Clampfit 10.3, Molecular Devices), and breathing frequencies calculated as the reciprocal of the averaged inspiratory interval. The irregularity score was determined as the normalized difference between a pair of subsequent breaths (Barthe and Clarac, 1997; Telgkamp et al, 2002; Wegener et al, 2014). …”

The postnatal development of ultrasonic vocalization‐associated breathing is altered in glycine transporter 2‐deficient mice

“…Irregularity scores (IrrScore) were calculated to assess the cycle‐to‐cycle variability of the interval (int) as IrrScore Int = 100·|(Int (n) − Int (n−1) )/Int (n−1) | and of the tidal volume ( V T ) as IrrScore VT = 100·|( V T(n) − V T(n−1) )/ V T(n−1) | (Barthe & Clarac, ; Wegener et al . ; Mesuret et al . ).…”