Sublaminar organization of the human subplate: developmental changes in the distribution of neurons, glia, growing axons and extracellular matrix

Abstract

The objective of this paper was to collect normative data essential for analyzing the subplate (SP) role in pathogenesis of developmental disorders, characterized by abnormal circuitry, such as hypoxic-ischemic lesions, autism and schizophrenia. The main cytological features of the SP, such as low cell density, early differentiation of neurons and glia, plexiform arrangement of axons and dendrites, presence of synapses and a large amount of extracellular matrix (ECM) distinguish this compartment from the cell-dense cortical plate (CP; towards pia) and large fiber bundles of external axonal strata of fetal white matter (towards ventricle). For SP delineation from these adjacent layers based on combined cytological criteria, we analyzed the sublaminar distribution of different microstructural elements and the associated maturational gradients throughout development, using immunocytochemical and histological techniques on postmortem brain material (Zagreb Neuroembryological Collection). The analysis revealed that the SP compartment of the lateral neocortex shows changes in laminar organization throughout fetal development: the monolayer in the early fetal period (presubplate) undergoes dramatic bilaminar transformation between 13 and 15 postconceptional weeks (PCW), followed by subtle sublamination in three 'floors' (deep, intermediate, superficial) of midgestation (15-21 PCW). During the stationary phase (22-28 PCW), SP persists as a trilaminar compartment, gradually losing its sublaminar organization towards the end of gestation and remains as a single layer of SP remnant in the newborn brain. Based on these sublaminar transformations, we have documented developmental changes in the distribution, maturational gradients and expression of molecular markers in SP synapses, transitional forms of astroglia, neurons and ECM, which occur concomitantly with the ingrowth of thalamo-cortical, basal forebrain and corticocortical axons in a deep to superficial fashion. The deep SP is the zone of ingrowing axons -'entrance (ingrowth) zone'. The process of axonal ingrowth begins with thalamo-cortical fibers and basal forebrain afferents, indicating an oblique geometry. During the later fetal period, deep SP receives long cortico-cortical axons exhibiting a tangential geometry. Intermediate SP ('proper') is the navigation and 'nexus' sublamina consisting of a plexiform arrangement of cellular elements providing guidance and substrate for axonal growth, and also containing transient connectivity of dendrites and axons in a tangential plane without radial boundaries immersed in an ECM-rich continuum. Superficial SP is the axonal accumulation ('waiting compartment') and target selection zone, indicating a dense distribution of synaptic markers, accumulation of thalamo-cortical axons (around 20 PCW), overlapping with dendrites from layer VI neurons. In the late preterm brain period, superficial SP contains a chondroitin sulfate non-immunoreactive band. The developmental dynamics for the distribution of neuronal, glial and ECM marker...

New insights into the development of the human cerebral cortex

“…), neuronal differentiation (Kostović et al. ), gliogenesis (Kostović et al. ), molecular specification of neurons (Bayatti et al.…”

“…), gliogenesis (Kostović et al. ), molecular specification of neurons (Bayatti et al. ; Hoerder‐Suabedissen & Molnár, ), development of columnar organization and microcircuitry (Allendoerfer & Shatz, ), spontaneous activity (Kanold & Luhmann, ), evoked activity (Allendoerfer & Shatz, ), neurosecretion (Kondo et al.…”

“…Accumulating evidence for the essential role of the subplate in development of large‐scale connectivity, microcircuitry and synaptogenesis in human fetal brain led to the view that disturbance of subplate may be a pathogenic factor in autism, schizophrenia and other circuitry disorders (Hoerder‐Suabedissen & Molnár, ; Kostović et al. ). Despite numerous studies, the subplate is still considered an enigmatic zone.…”

“…Golgi impregnated large neuron (B) with long smooth dendrites (with permission from Kostović et al. ). ‘Transient’ astroglia in the subplate (C) (with permission from Kostović et al.…”

“…‘Transient’ astroglia in the subplate (C) (with permission from Kostović et al. ). Electromicrograph (E) of the growth‐cone‐like dendritic profile forming a synaptic junction (arrow) in the subplate of 21‐week‐old human fetus (with permission from Kostović & Rakic, ).…”