Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome

Abstract

Rett syndrome (RTT) is caused by mutations in the X-linked gene MECP2. While patients with RTT show widespread changes in brain function, relatively few studies document changes in brain structure and none examine in detail whether mutations causing more severe clinical phenotypes are linked to more marked changes in brain structure. To study the influence of MeCP2-deficiency on the morphology of brain areas and axonal bundles, we carried out an extensive morphometric study of two Mecp2-mutant mouse models (Mecp2B and Mecp2J) of RTT. Compared to wildtype littermates, striking changes included reduced brain weight ( approximately 13% and approximately 9%) and the volumes of cortex ( approximately 11% and approximately 7%), hippocampus (both by approximately 8%), and cerebellum ( approximately 12% and 8%) in both mutant mice. At 3 weeks of age, most (24 of 47) morphological parameters were significantly altered in Mecp2B mice; fewer (18) were abnormal in Mecp2J mice. In Mecp2B mice, significantly lower values for cortical area were distributed along the rostrocaudal axis, and there was a reduced length of the olfactory bulb ( approximately 10%) and periaqueductal gray matter ( approximately 16%). In Mecp2J mice, while there was significant reduction in rostrocaudal length of cortex, this parameter was also abnormal in hippocampus ( approximately 10%), periaqueductal gray matter ( approximately 13%), fimbria ( approximately 18%), and anterior commissure ( approximately 10%). Our findings define patterns of Mecp2 mutation-induced changes in brain structure that are widespread and show that while some changes are present in both mutants, others are not. These observations provide the underpinning for studies to further define microarchitectural and physiological consequences of MECP2 deficiency.

Early Behavioural Alterations in Mouse Models of Autism Spectrum Disorders: A Step Forward Towards the Discovery of New Therapeutic Approaches

“…In contrast with null mutant mice, impaired emotional communicative behaviour in this mouse model involved a significant decrease in ultrasound vocalizations emission. This discrepancy suggests that the behavioural phenotype of models carrying different mutations in the Mecp2 gene do not necessarily overlaps, thus supporting previous reports (Belichenko et al, 2008;Ricceri et al, 2008). Indeed, BDNF levels, a gene-target of Mecp2 (Chang et al, 2006), are decreased in Mecp2-null mice (Schaevitz et al, 2010), while appear not altered in Mecp2-308 mice , suggesting that the truncated form of Mecp2 could retain some of its functions, thus contributing to the milder neurobehavioural phenotype of Mecp2-308 mice.…”

A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations

“…While the association is widespread, there do appear to be regions of increased MECP2 association. Based on mouse and human MECP2 mutation studies, we expected to see reductions in frontal and motor cortex size, and we do indeed observe this (6,9,12,17). Studies of females with Rett syndrome generally show occipital cortex preservation and dorsal-parietal cortical volume reduction (9), and we do not observe this.…”

“…While rare mutations in several genes result in reduced brain size, common polymorphisms in these genes have shown little or no replicated association with brain structure measures (4,5). We examined the association of brain structure measures with variants in and around the gene MECP2, chosen because of its role as a determinant of brain morphology in both humans and mice (6)(7)(8)(9). Located on Xq28, MECP2 encodes the methyl CpG binding protein 2, and mutations in this gene cause Rett syndrome (10), and are associated with other neurodevelopmental disorders including autism (11), mental retardation (12), and mild learning disabilities (13).…”

“…Murine Rett syndrome models exhibit a 25% reduction in whole brain volume (17) and show significant reductions in cortical surface area and volume of subcortical structures when Mecp2 exon 3 is either partially or entirely deleted (6). In humans, a classic symptom of Rett syndrome in females is head-growth deceleration (18), and severe MECP2 mutations in males result in neonatal progressive encephalopathy with disproportionate reduction in frontal and temporal lobes (8).…”

Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

“…Mouse models with different mutations in the MeCP2 gene all show symptoms that are characteristic of the disease (6)(7)(8), although the severity of the phenotype relates to the kind of mutation (44). In this study, we have examined MeCP2 mutant mice with an in-frame deletion of exon 3 (6), and we provide evidence that (1-3)IGF-1 ameliorates symptoms of RTT in these mice.…”