Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

Background: Autism is a behaviourally defined neuro-developmental disorder of unknown etio-pathology. Human neuroimaging studies have begun to shed light on the neural substrate of this disorder, by revealing a number of subtle functional and structural alterations which may be related to specific behaviours and symptoms. A strong rationale exists for the extension of this approach to probe and assess the face- and construct-validity of preclinical models for the disorder.

Objectives: The BTBR T+tf/J mouse (BTBR) is an inbred line that shows robust behavioural phenotypes with analogies to all three diagnostics symptoms of autism, including selectively reduced social approach, low reciprocal social interactions and impaired juvenile play. These features have prompted its use as a high face-validity mouse model of autism. However, the extent to which the BTRB model replicates the morpho-anatomical and functional alterations observed in human imaging studies of autism remains unknown. We used a multi-parametric magnetic resonance imaging (MRI) protocol to assess multiple morphoanatomical and functional parameters in the brain of BTBR mice as compared with C57BL/6J (B6) controls. 

Methods:  Adult male BTBR (N=22) or B6 (N=24) underwent a series of structural and fucntional MRI scans at 7 tesla. We performed high-resolution white matter (WM) tractography using diffusion tensor imaging (DTI), assessed gray matter volume using voxel-based morphometry (VBM), and measured cortical thickness across strains. Moreover, we measured basal cerebral blood volume (bCBV), an established marker of resting brain function, and resting state functional connectivity using BOLD functional MRI (fMRI).

Results:  Intergroup maps of DTI fractional anisotropy using the TBSS method demonstrated the absence of the corpus callosum in BTBR subjects, and highlighted the presence of areas of altered fractional anisotropy in thalamic areas and postero-frontal regions. Tractographic analysis confirmed the lack of inter-hemispheric connections at the level of corpus callosum, forceps minor and dorsal hippocampal commissure and revealed major white matter reorganisation with the presence of major rostro-caudal bundles running alongside the inter-hemispheric cleft. The WM alterations were accompanied by a major reduction of gray matter density in frontal cerebral cortex as seen with VBM and cortical thickness measurements. Significant alterations in resting state bCBV and functional connectivity were also indentified.

Conclusions: Overall, these results highlight dramatic morpho-anatomical and functional abnormalities BTBR mice compared to B6 controls, with a particular involvement of fronto-cortical areas and WM architecture. The magnitude and nature of changes appear to be larger and more substantial than what typically observed in clinical studies, thus questioning the face-validity of the model, at least from a neuroimaging perspective. Our results also highlight the need to identify refined models of ASD capable to reproduce the more subtle functional and anatomical alterations observed in clinical research of autism.