Evidence for abnormal early development in a mouse model of Rett syndrome

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder that affects mainly females, associated in most cases to mutations in the MECP2 gene. After an apparently normal prenatal and perinatal period, patients display an arrest in growth and in psychomotor development, with autistic behaviour, hand stereotypies and mental retardation. Despite this classical description, researchers always questioned whether RTT patients did have subtle manifestations soon after birth. This issue was recently brought to light by several studies using different approaches that revealed abnormalities in the early development of RTT patients. Our hypothesis was that, in the mouse models of RTT as in patients, early neurodevelopment might be abnormal, but in a subtle manner, given the first descriptions of these models as initially normal. To address this issue, we performed a postnatal neurodevelopmental study in the Mecp2(tm1.1Bird) mouse. These animals are born healthy, and overt symptoms start to establish a few weeks later, including features of neurological disorder (tremors, hind limb clasping, weight loss). Different maturational parameters and neurological reflexes were analysed in the pre-weaning period in the Mecp2-mutant mice and compared to wild-type littermate controls. We found subtle but significant sex-dependent differences between mutant and wild-type animals, namely a delay in the acquisition of the surface and postural reflexes, and impaired growth maturation. The mutant animals also show altered negative geotaxis and wire suspension behaviours, which may be early manifestations of later neurological symptoms. In the post-weaning period the juvenile mice presented hypoactivity that was probably the result of motor impairments. The early anomalies identified in this model of RTT mimic the early motor abnormalities reported in the RTT patients, making this a good model for the study of the early disease process.