Genetic Effects on Cerebellar Structure Across Mouse Models of Autism Using a Magnetic Resonance Imaging Atlas

Abstract

Magnetic resonance imaging (MRI) of autism populations is confounded by the inherent heterogeneity in the individuals’ genetics and environment, two factors difficult to control for. Imaging genetic animal models that recapitulate a mutation associated with autism quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Here, we used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in, Methyl-CpG binding protein-2 (MECP2) 308-truncation and integrin β3 homozygous knockout. This study identified the morphological differences specific to the cerebellum, a structure repeatedly linked to autism in human neuroimaging and postmortem studies. To accomplish a comparative analysis, a segmented cerebellum template was created and used to segment each study image. This template delineated 39 different cerebellar structures. For Neuroligin-3 R451C male mutants, the gray (effect size (ES) = 1.94, FDR q = 0.03) and white (ES = 1.84, q = 0.037) matter of crus II lobule and the gray matter of the paraflocculus (ES = 1.45, q = 0.045) were larger in volume. The MECP2 mutant mice had cerebellar volume changes that increased in scope depending on the genotype: hemizygous males to homozygous females. The integrin β3 mutant mouse had a drastically smaller cerebellum than controls with 28 out of 39 cerebellar structures smaller. These imaging results are discussed in relation to repetitive behaviors, sociability, and learning in the context of autism. This work further illuminates the cerebellum’s role in autism.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

“…Regional volumes were determined using a pre‐existing classified MRI atlas encompassing 159 different structures throughout the brain (Dorr, Lerch, Spring, Kabani, & Henkelman, 2008; Steadman et al, 2014; Ullmann, Watson, Janke, Kurniawan, & Reutens, 2013). Statistical analyses were applied comparing the absolute and relative volume of these 159 different regions and on a voxel‐wise basis in the brains of control and Chd7 gt/+ mice.…”

Development of the cerebellum: simple steps to make a ‘little brain’

“…Furthermore, congenital deficits, in particular vermal agenesis, lead to later communicative and affective relational disorders (Tavano et al, 2007). Accordingly, a study of structural brain abnormalities in mouse models of autistic spectrum disorder (ASD) revealed cerebellar-specific disruptions (Steadman et al, 2013). Although this variety of sources suggests that early patterning defects might generate significant cognitive impairment, the most compelling evidence in support of this hypothesis is a recent analysis of a mouse model of human CHARGE syndrome.…”

Structural covariance of brain region volumes is associated with both structural connectivity and transcriptomic similarity

“…We used an atlas that defines 318 structures in total when considering bilateral structures separately; this atlas combined a high-resolution three-dimensional brain atlas of C57Bl/6J mice by Dorr et al (2008) with a segmentation of cerebellar structures by Steadman et al (2014) and a segmentation of the neocortex by Ullmann et al (2013) (the " Steadman-Ullmann" or DSU-atlas). To avoid spurious correlations driven by whole-brain volume, we considered for each mouse the normalized volumes of these structures, relative to the whole-brain volume (i.e.…”