Neuroanatomy in mouse models of Rett syndrome is related to the severity of Mecp2 mutation and behavioral phenotypes

Abstract

BackgroundRett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. The majority of RTT cases are caused by de novo mutations in methyl-CpG-binding protein 2 (MECP2), and several mouse models have been created to further understand the disorder. In the current literature, many studies have focused their analyses on the behavioral abnormalities and cellular and molecular impairments that arise from Mecp2 mutations. However, limited efforts have been placed on understanding how Mecp2 mutations disrupt the neuroanatomy and networks of the brain.MethodsIn this study, we examined the neuroanatomy of male and female mice from the Mecp2tm1Hzo, Mecp2tm1.1Bird/J, and Mecp2tm2Bird/J mouse lines using high-resolution magnetic resonance imaging (MRI) paired with deformation-based morphometry to determine the brain regions susceptible to Mecp2 disruptions.ResultsWe found that many cortical and subcortical regions were reduced in volume within the brains of mutant mice regardless of mutation type, highlighting regions that are susceptible to Mecp2 disruptions. We also found that the volume within these regions correlated with behavioral metrics. Conversely, regions of the cerebellum were differentially affected by the type of mutation, showing an increase in volume in the mutant Mecp2tm1Hzo brain relative to controls and a decrease in the Mecp2tm1.1Bird/J and Mecp2tm2Bird/J lines.ConclusionsOur findings demonstrate that the direction and magnitude of the neuroanatomical differences between control and mutant mice carrying Mecp2 mutations are driven by the severity of the mutation and the stage of behavioral impairments.

Surface‐ and voxel‐based brain morphologic study in Rett and Rett‐like syndrome with MECP2 mutation

“…Previous studies reported decreased volumes in the cerebrum (Reiss et al, 1993;Casanova et al, 1991;Murakami et al, 1992;Subramaniam et al, 1997;Carter et al, 2008), basal ganglia (Reiss et al, 1993;Casanova et al, 1991;Murakami et al, 1992), cerebellum (Casanova et al, 1991;Murakami et al, 1992), corpus callosum (Murakami et al, 1992), and brainstem (Reiss et al, 1993;Murakami et al, 1992) in RTT compared to those in NC. The volume reduction of the cerebrum and the cerebellum have been confirmed in brain MRI studies with a mecp2 hetero-or homozygousknockout mouse model (Ward et al, 2008;Allemang-Grand et al, 2017;Saywell et al, 2006). However, in our study, a statistically significant difference between RTT/RTT-l and NC was observed only in the cerebellar volume.…”

The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

“…Although Pcdhg GcKO mice are smaller, brain size can vary independently from body size (Allemang-Grand et al, 2017;Ellegood et al, 2013). To identify structure-specific differences, the brains were segmented into 182 regions and measured as percent volume differences from control.…”

MeCP2 in central nervous system glial cells: current updates

“…Diffusion tensor imaging (DTI) studies in Rett syndrome patients also found a significant reduction in fractional anisotropy (FA) in the corpus callosum (Mahmood et al 2010). MRI studies have also shown alterations in cerebellar white matter, and corpus callosum of all available MeCP2 mutant mice currently available (Allemang-Grand et al 2017). These results correlate with white matter impairment seen in human Rett syndrome patients.…”