title: 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.
authors.affiliation: Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Steadman
authors.forename: Jacob
authors.initials: J
authors.lastname: Ellegood
authors.forename: Kamila U
authors.initials: KU
authors.lastname: Szulc
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Turnbull
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Joyner
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lerch
mesh_terms: D000818:Animals; D001931:Brain Mapping; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002531:Cerebellum / Q000473:pathology*; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D005838:Genotype; D006720:Homozygote; D039661:Integrin beta3 / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009929:Organ Size / Q000235:genetics; D012016:Reference Values; D012737:Sex Factors
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D039661:Integrin beta3; C497393:Mecp2 protein, mouse; D008565:Membrane Proteins; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; C098004:neuroligin 3
keywords: animal models; genetics; neuroanatomy; neuroimaging; structural MRI