Formation of functional areas in the cerebral cortex is disrupted in a mouse model of autism spectrum disorder.

Laura R Fenlon,Randal X Moldrich,Linda J Richards,Ilan Gobius,Skyle Murphy,Sha Liu,Nyoman D Kurniawan

doi:10.1186/s13064-015-0033-y

Abstract

BackgroundAutism spectrum disorders (ASD) are a group of poorly understood behavioural disorders, which have increased in prevalence in the past two decades. Animal models offer the opportunity to understand the biological basis of these disorders. Studies comparing different mouse strains have identified the inbred BTBR T + tf/J (BTBR) strain as a mouse model of ASD based on its anti-social and repetitive behaviours. Adult BTBR mice have complete agenesis of the corpus callosum, reduced cortical thickness and changes in early neurogenesis. However, little is known about the development or ultimate organisation of cortical areas devoted to specific sensory and motor functions in these mice that may also contribute to their behavioural phenotype.ResultsIn this study, we performed diffusion tensor imaging and tractography, together with histological analyses to investigate the emergence of functional areas in the cerebral cortex and their connections in BTBR mice and age-matched C57Bl/6 control mice. We found evidence that neither the anterior commissure nor the hippocampal commissure compensate for the loss of callosal connections, indicating that no interhemispheric neocortical connectivity is present in BTBR mice. We also found that both the primary visual and somatosensory cortical areas are shifted medially in BTBR mice compared to controls and that cortical thickness is differentially altered in BTBR mice between cortical areas and throughout development.ConclusionsWe demonstrate that interhemispheric connectivity and cortical area formation are altered in an age- and region-specific manner in BTBR mice, which may contribute to the behavioural deficits previously observed in this strain. Some of these developmental patterns of change are also present in human ASD patients, and elucidating the aetiology driving cortical changes in BTBR mice may therefore help to increase our understanding of this disorder.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-015-0033-y) contains supplementary material, which is available to authorized users.

Highlights

Autism spectrum disorders (ASD) are a group of poorly understood behavioural disorders, which have increased in prevalence in the past two decades
It is clear that BTBR T + tj/J (BTBR) mice have complete agenesis of the corpus callosum [22], the extent of neocortical disconnection through other commissures remains unclear
By selecting a region of interest (ROI) in the corpus callosum of C57Bl/6 mice we observed that streamlines generated through this ROI run mediolaterally, crossing the midline and connecting the left and right cortices (Figure 1G), whereas streamlines generated from ROIs of the Probst bundles form longitudinal tracts, which project caudally towards the hippocampus or ventrally to the basal forebrain (Figure 1H), as previously described in other acallosal mouse strains [32,34]

Summary

Introduction

Autism spectrum disorders (ASD) are a group of poorly understood behavioural disorders, which have increased in prevalence in the past two decades. Neuroanatomical studies using magnetic resonance imaging (MRI) and diffusion tensor MRI have demonstrated that BTBR mice display anatomical abnormalities that include volume changes in the cerebral white matter and grey matter and disruptions in the major white matter tracts of the brain [16,17,21,22] Most of these studies have focused on white matter malformations, revealing complete agenesis of the corpus callosum, thinning of the hippocampal commissure and the presence of ectopic interhemispheric connectivity above the third ventricle [16], subcortically through the posterior cerebrum [21] and excessively through the anterior commissure [17]. Despite the ASD-like traits commonly exhibited by humans with agenesis of the corpus callosum [23], the behavioural trait of low sociability in mouse models does not appear to be related to the presence or size of this commissure [24,25], indicating that other developmental changes in the brain may be associated with this trait

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