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.

中文翻译：

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Shank3缺陷大鼠的脑容量和白质改变减少

SHANK3基因的突变和缺失导致了 Phelan-McDermid 综合征 (PMS) 的主要神经发育特征，其特征是智力障碍、自闭症谱系障碍和感觉低反应性。SHANK3编码对突触发生很重要的兴奋性突触的关键结构成分。对 PMS 患者的临床评估和有限的脑成像研究发现了局部体积减少和白质变薄。虽然这些损伤已在大鼠模型的幼崽中体外复制，但尚未在大鼠体内或成人体内评估大脑结构。我们评估了杂合子和纯合子成年Shank3的大脑结构- 与使用解剖评估和扩散张量成像 (DTI) 的磁共振成像的野生型同窝仔鼠相比，缺乏雄性大鼠。Shank3 缺陷大鼠显示整体脑大小和新皮质、梨状皮质、丘脑、前脑、下丘和上丘、内囊和前连合的绝对体积减小。上丘相对体积减小。DTI 显示，外囊中的轴向扩散和分数各向异性减少，穹窿中的平均扩散增加，表明在这些白质束中垂直于轴突纤维轴的扩散限制受损。因此，Shank3- 缺陷大鼠复制减少的脑容量和改变的 PMS 中存在的白质表型。我们的研究结果表明，谷氨酸能突触蛋白 Shank3 的缺失在整个大脑水平上具有结构性后果。被改变的大脑区域代表了潜在的跨物种结构生物标志物，值得进一步研究。