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

亚板是一种暂时性胎儿结构，从怀孕后约13周(PCW)1，2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周)左右达到峰值厚度，并逐渐分解(从36 PCW开始)，根据皮质区域的不同1，2。亚板由多种细胞类型(如迁移神经元、亚板神经元、胶质细胞)、生长轴突(即纤维含量)组成，周围环绕着丰富的高度亲水性的细胞外基质(ECM)。该亚板富含硫酸软骨素蛋白多糖(CSPGs)(如NeuroCan、Verscan等凝集素)，已知可与纤维性ECM蛋白(如层粘连蛋白、纤维连接蛋白、胶原蛋白)相互作用2，3.富含CSPG的亚板是谷氨酸能神经元(径向)和GABA能中间神经元(切向)迁移的主要通道，也是轴突通路3。尽管它是暂时性的，但有越来越多的证据表明，该亚板在健康的皮质发生(例如，通过神经元分化、突触发生)和大脑电路的发展(即，长程和局部微循环)中发挥着重要作用3，4。最近，人们对该亚板重新产生了兴趣，因为现在假设，在神经发育的早期，对该隔区的干扰可能是各种神经精神和神经发育障碍的致病特征4。亚板的高亲水性环境在磁共振成像(MRI)5，6上发出可见的信号，该信号可以被分割和量化(例如，2D线性和3D体积测量)。亚板信号已经在体内胎儿(即宫内)和新生儿(即出生时)MRI以及体外(即尸检)MRI1、5、7上成功解析。然而，值得注意的是，由于MRI1分辨率的限制，亚板信号可能会延伸到真正的组织亚板之外。唐氏综合征(DS)，又称21三体，是由人类21号染色体部分或完全三倍体(Hsa21)引起的，是人类最常见的遗传发育障碍，每年全球新生儿中约有1人受到影响。DS的神经发育表型与不同程度的智力残疾和认知缺陷有关，包括言语、运动和语言功能的主要障碍9。除认知障碍外，其他常见的并发症包括先天性心脏病(CHD，40%-50%)、甲状腺功能减退、听力、视力和胃肠道并发症8。最近，与使用活体胎儿和新生儿MRI10的典型发育对照组(TDCs)相比，卢瑟福实验室已经能够识别DS患者皮质和小脑生长的早期变化。最值得注意的是，在怀孕中期以后，患有DS的胎儿和新生儿的全脑体积明显较小。然而，皮质体积在妊娠晚期(28周后)才开始偏离tDCs。最近，我们使用新生儿MRI(未发表的数据)发现，在妊娠晚期(GA 31.4-41.7周)，DS的亚板体积明显小于TDC。来自宫内胎儿MRI的子板体积(从大约20周妊娠到足月)仍有待分析。最后，已经有许多关于DS的ECM紊乱的报道，涉及CHD11-13(例如，VI型胶原和MMPs等12)，脐带和Wharton凝胶14，15(例如，VI型胶原和透明质酸过度表达)和胎儿颈部半透明16，17(例如，透明质酸和蛋白多糖增加)。然而，据我们所知，发育中的大脑亚板中特定的ECM干扰从未发表过，这代表着未来研究的机会。

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.