Reduced brain volume and white matter alterations in Shank3‐deficient rats

• Published in: Autism research 2021-09, Vol.14 (9), p.1837-1842
• Main Authors: Golden, Carla E. M., Wang, Victoria X., Harony‐Nicolas, Hala, Hof, Patrick R., Buxbaum, Joseph D.
• Format: Article
• Language: English
• Subjects: Animals; Anisotropy; Anterior commissure; Assessments; Autism; Autism Spectrum Disorder; Axial diffusion; Biomarkers; Brain; Brain - anatomy & histology; Brain - diagnostic imaging; Cerebral cortex; Chromosome Disorders; Diffusion Tensor Imaging; Forebrain; Fornix; Glutamatergic transmission; Intellectual disabilities; Magnetic resonance imaging; Male; Medical imaging; Mutation; Neocortex; Nerve Tissue Proteins - genetics; Neuroimaging; Phenotypes; Piriform cortex; Rats; Rodents; Shank3; Short Report; Somatosensory cortex; Substantia alba; Superior colliculus; Synapses; Synaptogenesis; Tensors; Thalamus; White Matter - anatomy & histology; White Matter - diagnostic imaging
• ISSN: 1939-3792; 1939-3806
• DOI: 10.1002/aur.2568

Mutations and deletions in the SHANK3 gene cause the major neurodevelopmental features of Phelan–McDermid syndrome (PMS), which is characterized by intellectual disability, autism spectrum disorder, and sensory hyporeactivity. SHANK3 encodes a key structural component of excitatory synapses important for synaptogenesis. Clinical assessments and limited brain imaging studies of patients with PMS have uncovered regional volume reductions and white matter thinning. While these impairments have been replicated ex vivo in pups of a rat model, brain structure has not been assessed in rats in vivo or in adults. We assessed the brain structure of heterozygous and homozygous adult Shank3‐deficient male rats in comparison to wild‐type littermates with magnetic resonance imaging using both anatomical assessments and diffusion tensor imaging (DTI). Shank3‐deficient rats showed a reduction in overall brain size and the absolute volume of the neocortex, piriform cortex, thalamus, forebrain, inferior and superior colliculi, internal capsule, and anterior commissure. The superior colliculus was decreased in relative volume. DTI revealed that axial diffusion and fractional anisotropy were reduced in the external capsule and mean diffusion was increased in the fornix, suggesting that restriction of diffusion perpendicular to the axis of the axonal fibers was impaired in these white matter tracts. Therefore, Shank3‐deficient rats replicate the reduced brain volume and altered white matter phenotypes present in PMS. Our results indicate that the loss of a glutamatergic synaptic protein, Shank3, has structural consequences at the level of the whole brain. The brain regions that were altered represent potential cross‐species structural biomarkers that warrant further study. Lay Summary Phelan–McDermid syndrome can cause brain abnormalities. To investigate whether these could be replicated in a rat model, we assessed brain structure in rats lacking Shank3, the synaptic protein that is depleted in Phelan–McDermid syndrome. We found that Shank3‐deficient rats have smaller brains than littermate controls and deficits in their white matter pathways, similar to what is observed in people with Phelan–McDermid syndrome. This rat model can therefore be used in follow‐up studies to determine how a loss of Shank3 can lead to alterations in brain structure. Furthermore, our results indicate that this singular synaptic protein is important for the development of the whole brain.