Abstract
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 inter-regional connectivity, yet how single-gene mutations affect such connectivity remains under-explored. For the first time, we have developed a within-subject, quantitative analysis of white matter microstructure and 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. DTI revealed decreases in fractional anisotropy and increases in apparent diffusion coefficient in the amygdala (including the basolateral nuclei), the anterior cingulate cortex, the orbitofrontal cortex and the hippocampus. Radial 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 connectivity within the social brain, likely underlying autism-related impairments. More generally, our combined within-subject DTI-plus-CLARITY approach presents a new, more sensitive method of revealing hitherto undetectable differences in the autistic brain.
Footnotes
Conflicts of Interest: The Authors declare no competing conflicts of interest.