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

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.

SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system

“…These showed alterations in local and global connectivity patterns in MRI, indicative for circuit abnormalities [ 50 ]. In addition, Shank3-deficient rats presented a reduced brain volume and impairments in white matter tracts [ 51 ]. These data support the hypothesis, that SHANK3 deficiency is another disorder of the autistic spectrum where the investigation of white matter changes and myelin might be essential to fully understand the disorder and its underlying mechanisms.…”

Gestational Buprenorphine Exposure Disrupts Dopamine Neuron Activity and Related Behaviors in Adulthood

“…While many neurodevelopmental milestones occur postbirth in rats ( Zeiss, 2021 ), the timing of our manipulation was selected to coincide with previous studies in which developmental disruptions between gestational day 11 and 21 produce robust neuropsychiatric alterations in adulthood, including autism-like and schizophrenia-like phenotypes ( Lodge, 2013 ; Perez et al, 2014 ; Donegan et al, 2018 , 2020 ). Indeed, lower total brain volume has been observed in rodent models of autism and early-life stress ( Golden et al, 2021 ; Reshetnikov et al, 2021 ). Further, loss of brain volume in specific brain regions is observed in a variety of psychiatric illnesses ( Angelescu et al, 2021 ; Steuber et al, 2021 ; Su et al, 2021 ).…”

Juvenile Shank3 KO Mice Adopt Distinct Hunting Strategies during Prey Capture Learning

“…It is possible that differences in superior colliculus or substantia nigra signaling or their connections might underlie some of the behavior differences reported here. While data are lacking in the literature as to the effect of Shank3 on SC function, Shank3 KO rats exhibit a lower relative volume of SC, suggesting that Shank3 loss may alter development of this brain region ( Golden et al, 2021 ).…”