Exploring the subplate structure and function during typical and atypical neurodevelopment: the case study of Down syndrome.

亚板是一个短暂的胎儿结构，从大约13个怀孕周（pcw）开始，在皮质板（CP）下方和中间区（IZ）上方发育。它在妊娠中期（20 pcw）达到峰值厚度，并根据皮质区域以不同的速度逐渐消退（从36 pcw开始）1，2。 亚板由多种细胞类型（例如迁移神经元、亚板神经元、神经胶质）、生长的轴突（即纤维状内容物）组成，周围环绕着丰富的高度亲水性细胞外基质（ECM）。基板特别富含硫酸软骨素蛋白聚糖（CSPG）（例如，凝集素，如neurocan、versican），已知其与纤维状ECM蛋白（例如，层粘连蛋白、纤连蛋白、胶原蛋白）相互作用2，3。富含CSPG的亚板是迁移海马能神经元（即径向）和GABA能中间神经元（即切向）以及轴突寻路的主要通道3。尽管其短暂的性质，有越来越多的证据表明，基板在健康的皮质发生（例如，通过神经元分化，突触）和脑回路（即远程，以及局部微回路）的发展中起着至关重要的作用3，4。最近，有一个新的兴趣亚板，因为它现在假设，在早期的神经发育过程中，干扰这间室可能是一个致病的功能，在各种神经精神和神经发育障碍4。 基板的高度亲水性环境在磁共振成像（MRI）5，6上发出可见信号，其可以被分割和量化（例如，2D线性和3D体积测量）。在体内胎儿（即子宫内）和新生儿（即出生时）MRI以及离体（即死后）MRI上均成功解析了基板信号1，5，7。然而，值得注意的是，由于MRI 1的分辨率限制，亚板信号可能超出真正的组织学亚板。 唐氏综合征（DS），也称为21三体，是由人类21号染色体（Hsa 21）的部分或完全三倍引起的，是人类最常见的遗传发育障碍，全球每年约有1/1000的新生儿受到影响8。DS的神经发育表型与不同程度的智力残疾和认知缺陷相关，包括言语、运动和语言功能的严重损伤9。除认知困难外，其他常见的合并症包括先天性心脏缺陷（CHD，40-50%）、甲状腺功能减退症、听力、视力和胃肠道并发症8。最近，Rutherford实验室已经能够使用体内胎儿和新生儿MRI与典型发育对照（TDC）相比，识别DS中皮质和小脑脑生长的早期改变10。最值得注意的是，发现DS胎儿和新生儿在妊娠中期以后的全脑体积明显较小。然而，皮质体积仅在孕晚期（胎龄28周后，GA）开始偏离TDC。最近，我们使用新生儿MRI（未发表的数据）发现，与TDC相比，在妊娠晚期（GA 31.4 - 41.7周），DS的亚板体积显著较小。子宫内胎儿MRI（从大约20周龄GA到足月）的亚板体积仍有待分析。 最后，有许多关于DS中ECM紊乱的报告，这些ECM紊乱与CHD 11 -13（例如VI型胶原蛋白和MMPs等12）、脐带和沃顿氏韧带14，15（例如VI型胶原蛋白和透明质酸的过度表达）和胎儿颈部通透性16，17（例如透明质酸和蛋白聚糖增加）有关。然而，据我们所知，发育中大脑亚板中的特定ECM干扰从未发表过，这为未来的研究提供了机会。

The subplate is a transient fetal structure that develops beneath the cortical plate (CP) and above the intermediate zone (IZ) from approximately 13 post-conception weeks (pcw)1,2. It reaches its peak thickness around mid-gestation (20 pcw) and gradually resolves (from 36 pcw) at different rates depending on the cortical region1,2. The subplate is comprised of numerous cell types (e.g. migrating neurons, subplate neurons, glia), growing axons (i.e. fibrillar content) surrounded by an abundance of highly hydrophilic extracellular matrix (ECM). The subplate is particularly rich in chondroitin sulphate proteoglycans (CSPGs) (e.g. lecticans such as neurocan, versican), which are known to interact with fibrous ECM proteins (e.g. laminin, fibronectin, collagens)2,3. The CSPG-rich subplate is a major corridor for migrating glutamatergic neurons (i.e. radially) and GABAergic interneurons (i.e. tangentially), as well as axon pathfinding3. Despite its transient nature, there is accumulating evidence that the subplate plays an essential role in healthy corticogenesis (e.g. via neuronal differentiation, synaptogenesis) and development of brain circuitry (i.e. long-range, as well as local microcircuity)3,4. Recently, there has been a renewed interest in the subplate as it is now hypothesised that disturbance to this compartment during early neurodevelopment may be a pathogenic feature in a variety of neuropsychiatric and neurodevelopmental disorders4. The highly hydrophilic environment of the subplate gives off a visible signal on magnetic resonance imaging (MRI)5,6, which can be segmented and quantified (e.g. 2D linear and 3D volumetric measurements). The subplate signal has been successfully resolved on both in vivo fetal (i.e. in utero) and neonatal (i.e. at birth) MRI, as well as ex vivo (i.e. post-mortem) MRI1,5,7. However, it is worth noting that the subplate signal may extend beyond true histological subplate due to resolution limits on MRI1. Down Syndrome (DS), also known as Trisomy 21, is caused by the partial or complete triplication of human chromosome 21 (Hsa21) and is the most common genetic developmental disorder in humans affecting approximately 1 in 1000 births per annum globally8. The neurodevelopmental phenotype of DS is associated with varying degrees of intellectual disability and cognitive deficits, including major impairments in speech, motor and language functions9. In addition to cognitive difficulties, other common comorbidities include congenital heart defects (CHD, 40-50%), hypothyroidism, hearing, vision, and gastrointestinal complications8. Recently, the Rutherford lab have been able to identify early alterations in cortical and cerebellar brain growth in DS compared to typically-developing controls (TDCs) using in vivo fetal and neonatal MRI10. Most notably, fetuses and neonates with DS were found to have significantly smaller whole brain volumes in the second trimester onwards. However, cortical volumes only started to deviate from TDCs in the third trimester (after 28 weeks gestational age, GA). Most recently, we have identified that subplate volumes in DS are significantly smaller across the third trimester (GA 31.4 - 41.7 weeks) compared to TDCs using neonatal MRI (unpublished data). Subplate volumes from in utero fetal MRI (from approximately 20 weeks GA to term) remain to be analysed. Finally, there have been many reports of ECM disturbances in DS relating to CHD11-13 (e.g. collagen type VI and MMPs amongst others12), umbilical cord and Wharton's jelly14,15 (e.g. over-expression of collagen type VI and hyaluronan) and fetal nuchal translucency16,17 (e.g. increased hyaluronan and proteoglycans). However, specific ECM disturbances in the subplate of the developing brain have never been published to our knowledge, representing an opportunity for future research.