Delayed Achievement of Developmental Milestones in a Mouse Model of Rett Syndrome
M.Santos; A.Silva-Fernandes; P.Oliveira; N.Sousa; P.Maciel.
Abstract
Rett syndrome (RTT) is a genetic neurodevelopmental disorder described to have an apparently normal pre- and perinatal developmental period lasting 6-18 months, following which, patients present a growth deceleration/arrest and a loss of motor, language and social acquisitions, leading to mental retardation, autistic behavior and motor deterioration. Mutations in the MECP2 gene are the cause of most of classical RTT cases and of about 30% of atypical cases. Mouse models have been developed that mimic RTT in many motor and behavioral aspects.
In spite of the classic RTT description, some researchers always questioned whether RTT patients could have subtle manifestations soon after birth, a theory that has recently been confirmed by the work of Einspieler et al. (2005), who analysed video records of the first six months of life of several RTT patients and were able to notice abnormalities in several behaviors.
In order to test whether the development during the perinatal period is also really normal in a mouse model of RTT (Mecp2tm1.1Bird), we performed a neurodevelopmental study, assessing milestone achievement for different maturational measures and neurological reflexes. A battery of tests was performed in male (n=13) and female (n=16) Mecp2 knock out mice from PND4 (postnatal day 4) through PND21, that were compared to wt littermates (females n=9, males n=11). We found statistically significant differences between ko and wt animals for anogenital distance, righting reflex, postural reflex and negative geotaxis, at specific timepoints, although at the end all milestones were achieved.
In conclusion, we detected delays in early neurodevelopment in the Mecp2-null mouse as had been described in human RTT patients. The observed differences in development are transient, and it is possible that compensatory mechanisms are activated which mask them; nevertheless, they can have significant effects on adult behaviors.
Lay Summary
It has been debated whether RTT patients display subtle signs of the condition soon after birth, prior to the development of classical RTT signs. In order to test whether the development during the first few weeks of life is affected in a mouse model of RTT, a number of tests for milestone achievement were assessed. A battery of tests were performed through the first three weeks of life in a mouse model of RTT - a time characteristically referred to as pre-symptomatic for the Rett condition. Interestingly, significant differences between MeCP2-null and non-affected animals for a number of neurological milestones and reflexes were observed. Most notably, at the end of this early developmental period all milestones were achieved for both groups - thus, the observed differences in development are transient at this very early stage. How this relates to the more "permanent" deficits at the adult stage, remain to be investigated.