The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice

Molecular Autism - Tập 10 - Trang 1-13 - 2019
Eleftheria Pervolaraki1, Adam L. Tyson2,3,4, Francesca Pibiri5, Steven L. Poulter5, Amy C. Reichelt6, R. John Rodgers7, Steven J. Clapcote1, Colin Lever5, Laura C. Andreae2,3, James Dachtler1,5
1School of Biomedical Sciences, University of Leeds, Leeds, UK
2Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
3MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK
4Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, UK
5Department of Psychology, Durham University, Durham, UK
6Robarts Research Institute, Western University, London, Canada
7School of Psychology, University of Leeds, Leeds, UK

Tóm tắt

Of the many genetic mutations known to increase the risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family of presynaptic proteins are the neurexins (NRXN), and recent genetic and mouse evidence has suggested a causative role for NRXN2 in generating altered social behaviours. Autism has been conceptualised as a disorder of atypical connectivity, yet how single-gene mutations affect such connectivity remains under-explored. To attempt to address this, we have developed a quantitative analysis of microstructure and structural connectivity leveraging diffusion tensor MRI (DTI) with high-resolution 3D imaging in optically cleared (CLARITY) brain tissue in the same mouse, applied here to the Nrxn2α knockout (KO) model. Fixed brains of Nrxn2α KO mice underwent DTI using 9.4 T MRI, and diffusion properties of socially relevant brain regions were quantified. The same tissue was then subjected to CLARITY to immunolabel axons and cell bodies, which were also quantified. DTI revealed increases in fractional anisotropy in the amygdala (including the basolateral nuclei), the anterior cingulate cortex, the orbitofrontal cortex and the hippocampus. Axial diffusivity of the anterior cingulate cortex and orbitofrontal cortex was significantly increased in Nrxn2α KO mice, as were tracts between the amygdala and the orbitofrontal cortex. Using CLARITY, we find significantly altered axonal orientation in the amygdala, orbitofrontal cortex and the anterior cingulate cortex, which was unrelated to cell density. Our findings demonstrate that deleting a single neurexin gene (Nrxn2α) induces atypical structural connectivity within socially relevant brain regions. More generally, our combined within-subject DTI and CLARITY approach presents a new, more sensitive method of revealing hitherto undetectable differences in the autistic brain.

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Molecular Autism

Tập 10

1-13

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