Department of Psychiatry, Stanford University School of Medicine, Stanford, California, 94305, USA.
J Neurosci. 2011 Apr 13;31(15):5764-76. doi: 10.1523/JNEUROSCI.6015-10.2011.
Down syndrome (DS) is a developmental disorder caused by a third chromosome 21 in humans (Trisomy 21), leading to neurological deficits and cognitive impairment. Studies in mouse models of DS suggest that cognitive deficits in the adult are associated with deficits in synaptic learning and memory mechanisms, but it is unclear whether alterations in the early wiring and refinement of neuronal circuits contribute to these deficits. Here, we show that early developmental refinement of visual circuits is perturbed in mouse models of Down syndrome. Specifically, we find excessive eye-specific segregation of retinal axons in the dorsal lateral geniculate nucleus. Indeed, the degree of refinement scales with defects in the "Down syndrome critical region" (DSCR) in a dose-dependent manner. We further identify Dscam (Down syndrome cell adhesion molecule), a gene within the DSCR, as a regulator of eye-specific segregation of retinogeniculate projections. Although Dscam is not the sole gene in the DSCR contributing to enhanced refinement in trisomy, Dscam dosage clearly regulates cell spacing and dendritic fasciculation in a specific class of retinal ganglion cells. Thus, altered developmental refinement of visual circuits that occurs before sensory experience is likely to contribute to visual impairment in individuals with Down syndrome.
唐氏综合征（DS）是一种由人类 21 号染色体三体（Trisomy 21）引起的发育障碍，导致神经功能缺陷和认知障碍。DS 小鼠模型的研究表明，成年认知缺陷与突触学习和记忆机制缺陷有关，但尚不清楚神经元回路的早期布线和细化改变是否导致这些缺陷。在这里，我们表明，唐氏综合征小鼠模型中视觉回路的早期发育细化受到干扰。具体来说，我们发现背外侧膝状体核中的视网膜轴突过度特异性分离。实际上，这种细化程度与“唐氏综合征关键区域”（DSCR）中的缺陷呈剂量依赖性相关。我们进一步确定 Dscam（唐氏综合征细胞粘附分子），DSCR 内的一个基因，是视放射投射的眼特异性分离的调节剂。尽管 Dscam 不是导致三倍体中增强细化的 DSCR 中的唯一基因，但 Dscam 剂量明显调节特定视网膜神经节细胞类别的细胞间距和树突丛集。因此，在感觉体验之前发生的视觉回路发育细化改变可能导致唐氏综合征个体的视力障碍。
