International Meeting for Autism Research: Neuroanatomical Abnormalities In the Mecp2(308) Mouse Model of Rett Syndrome

Neuroanatomical Abnormalities In the Mecp2(308) Mouse Model of Rett Syndrome

Thursday, May 12, 2011
Elizabeth Ballroom E-F and Lirenta Foyer Level 2 (Manchester Grand Hyatt)
3:00 PM
J. Ellegood, J. P. Lerch and R. M. Henkelman, Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada
Background: Rett Syndrome (RTT) is an X-linked disorder located under the Autism Spectrum of Disorders (ASD). RTT is caused by mutations in the Mecp2 gene.  A commonly used mouse model of RTT involves a truncation of the Mecp2 gene at codon 308.  The behavioural phenotype of the Mecp2308 mouse includes abnormalities in social interaction and home-cage behaviours (Moretti et al. 2005), as well as learning and memory impairments (Moretti et al. 2006).  Recently, anatomical phenotyping in the fixed mouse brain using MRI has been shown in a number of mutants to be useful in determining specific volumetric changes, which has helped to localize and aid further research in these mutants (Nieman et al. 2006).

Objectives: The purpose of this study was to examine the volume changes in the Mecp2308 RTT mouse model with high resolution MRI.

Methods: Fifty-one C57/B6 fixed mouse brains were examined, 17 wild-type and 34 knockdown Mecp2308 mice.  Of the Mecp2308 mice, 12 were heterozygous females, 12 were homozygous females, and 10 were hemizygous males.  

MRI Acquisition - A multi-channel 7.0 Tesla MRI scanner (Varian Inc., Palo Alto, CA) with a 6-cm inner bore diameter insert gradient set (max gradient strength 100 G/cm) was used to acquire anatomical images of brains within skulls. A T2- weighted, 3-D fast spin-echo sequence was used, with a TR of 325 ms, and TEs of 10 ms per echo for 6 echos, four averages, field-of-view of 14 × 14 × 25 mm3 and matrix size = 432 × 432 × 780 giving an image with 0.032 mm isotropic voxels. Total imaging time was ~11 h.

Data Analysis – We use image registration to align a previously developed neuroanatomical atlas (Dorr et al. 2008) defining 62 separate brain regions towards each scan.  Volumes of individual structures for each mouse were calculated in mm3.  Group differences in volume were calculated using linear models; multiple comparisons were controlled using the false discovery rate (FDR).

Results: Of the 62 different regions assessed 26 were found to be significantly different (q<0.01, q is defined as the FDR corrected version of the p-value) when comparing the Mecp2308 with the wild type.  Notable regions of decrease in the brain were the parieto-temporal lobe (4%, q<0.01), the corpus callosum (5%, q<0.001), the internal capsule (6%, q<0.001), the striatum (5%, q<0.01), and the thalamus (7%, q<0.001).  Notable regions of increase were the cerebellar cortex (5%, q<0.01), the inferior of the cerebellar peduncle (5%, q<0.01), the cuneate nucleus (20%, q=0.001), and the third and fourth ventricles (7 and 15%, q<0.01 and q<0.001, respectively).

Conclusions: This study reports volumetric changes in different regions in the brain of the Mecp2308 mouse.  Regions such as the partieo-temporal lobe, striatum, thalamus, corpus callosum, and cerebellum are all affected in human Rett syndrome and significant differences were found in each of these regions in the Mecp2308 mouse as well.   Along with the behavioural characteristics shown in previous studies of the Mecp2308 mouse, this model seems to be an accurate behavioural and neuroanatomical model of human Rett syndrome.

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