Reduced brain volume and white matter alterations in Shank3-deficient rats.
Shank3 rats mirror the brain-volume loss and white-matter changes seen in Phelan-McDermid syndrome, giving us an MRI yardstick for testing treatments.
01Research in Context
What this study did
Scientists scanned adult rats that lack the Shank3 gene. This gene causes Phelan-McDermid syndrome in people.
The team used MRI to measure whole-brain size and white-matter tracks. They compared the rats with normal controls.
What they found
Shank3 rats had smaller brains overall. Their white-matter fibers also showed weaker signals on diffusion scans.
The pattern matches what doctors see in Phelan-McDermid patients. The rats can serve as a picture-based model for future drug tests.
How this fits with other research
Fitzgerald et al. (2019) saw the same weak white-matter picture in living adults with autism. Both studies used DTI, so the rat data line up with human findings.
Roine et al. (2013) looked like a contradiction. They reported stronger white-matter signals in adults with Asperger syndrome. The difference is the group: Asperger adults have high IQ and mild traits, while Jacqueline’s mixed ASD group and the Shank3 rats show more disability. Direction of effect depends on whom you scan.
Van Hanegem et al. (2014) used MRI atlases in autism mice and also found gene-linked volume changes. Together these papers show that MRI can flag specific genetic hits across rodent models.
Why it matters
You now have an MRI marker that tracks Shank3 damage in rats. If you test a new drug, you can quickly see if brain volume or white-matter signals move back toward normal. Share the rat data with medical teams; it gives them a non-invasive endpoint before moving to human trials.
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02At a glance
03Original abstract
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.
Autism research : official journal of the International Society for Autism Research, 2021 · doi:10.1093/hmg/ddr212