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

Abstract

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations.

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

“…Cerebral white matter as a whole was significantly reduced, specifically 10 of 14 with matter regions were smaller. Dodero et al [151] replicated what was found in the study by Ellegood et al [133], similarly comparing BTBR with B6, but also reported resting-state fMRI connectivity differences in the BTBR mouse, including a significant reduction in the cerebral blood volume that is indicative of a reduced basal metabolism. The same group also examined dopaminergic neurotransmission in BTBR mice using fMRI, highlighting possible dysfunctions in the dopaminergic system [152].…”

“…This can be seen with the similarities between 2 independent studies of Nl3 KI [131,132], and the 2 independent BTBR studies [149,151]. However, perhaps the most significant overlap is seen in the similarities between the 16p11.2 models [28,54], in which the mice were created in 2 different laboratories, with 2 different techniques, and were inconsistent in age and sex, but still had strikingly similar findings.…”

“…Further, several different techniques are available for the assessment of the brain using MRI. Aside from the volume differences, the underlying tissue microstructure can be assessed with DTI [131,149,151], functional information can be assessed using fMRI [151], and metabolic differences can be assessed with magnetic resonance spectroscopy [116].…”

Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy

“…The effectiveness of ECT in BTBR mice is particularly remarkable considering that these animals have profound and irreversible deficiency in interhemispheric connectivity due to the missing corpus callosum and underdeveloped hippocampal commissure [41,42], which is congruent with compromised long-range connectivity in autism [43][44][45]. However, it should be noted that the lack of corpus callosum alone cannot explain the presence of autism-like behavior; indeed, postnatal mechanical lesion to the corpus callosum in LP/J mice (which are genetically close to BTBR mice but show no autism-like behavioral abnormalities) failed to produce autism-like impairments [46].…”

See-through Brains and Diffusion Tensor MRI Clarified Fiber Connections: A Preliminary Microstructural Study in a Mouse with Callosal Agenesis

“…5 Neuroanatomical studies of the BTBR mouse brain have shown total agenesis of corpus callosum (CC) connective tissues, lack of a hippocampal commissure, and a putative accessory interhemispheric white matter tract that is implicated in abnormal behaviors. [6][7][8] Here, to better characterize the inter-hemispheric commissure in the BTBR strain of mice, we performed a neuroanatomical analysis by using both 3D high-resolution twophoton images of the transparent mouse brain and DTI. To our knowledge, this is the first report on the use of this dual procedure in the mouse brain.…”