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

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.