Prenatal development of the human entorhinal cortex

Abstract

Little is known about the development of the human entorhinal cortex (EC), a major hub in a widespread network for learning and memory, spatial navigation, high‐order processing of object information, multimodal integration, attention and awareness, emotion, motivation, and perception of time. We analyzed a series of 20 fetal and two adult human brains using Nissl stain, acetylcholinesterase (AChE) histochemistry, and immunocytochemistry for myelin basic protein (MBP), neuronal nuclei antigen (NeuN), a pan‐axonal neurofilament marker, and synaptophysin, as well as postmortem 3T MRI. In comparison with other parts of the cerebral cortex, the cytoarchitectural differentiation of the EC begins remarkably early, in the 10th week of gestation (w.g.). The differentiation occurs in a superficial magnocellular layer in the deep part of the marginal zone, accompanied by cortical plate (CP) condensation and multilayering of the deep part of CP. These processes last until the 13–14th w.g. At 14 w.g., the superficial lamina dissecans (LD) is visible, which divides the CP into the lamina principalis externa (LPE) and interna (LPI). Simultaneously, the rostral LPE separates into vertical cell‐dense islands, whereas in the LPI, the deep LD emerges as a clear acellular layer. In the 16th w.g., the LPE remodels into vertical cell‐dense and cell‐sparse zones with a caudorostral gradient. At 20 w.g., NeuN immunoreactivity is most pronounced in the islands of layer II cells, whereas migration and differentiation inside‐out gradients are seen simultaneously in both the upper (LPE) and the lower (LPI) pyramidal layers. At this stage, the EC adopts for the first time an adult‐like cytoarchitectural organization, the superficial LD becomes discernible by 3T MRI, MBP‐expressing oligodendrocytes first appear in the fimbria and the perforant path (PP) penetrates the subiculum to reach its molecular layer and travels along through the Cornu Ammonis fields to reach the suprapyramidal blade of the dentate gyrus, whereas the entorhinal‐dentate branch perforates the hippocampal sulcus about 2–3 weeks later. The first AChE reactivity appears as longitudinal stripes at 23 w.g. in layers I and II of the rostrolateral EC and then also as AChE‐positive in‐growing fibers in islands of superficial layer III and layer II neurons. At 40 w.g., myelination of the PP starts as patchy MBP‐immunoreactive oligodendrocytes and their processes. Our results refute the possibility of an inside‐out pattern of the EC development and support the key role of layer II prospective stellate cells in the EC lamination. As the early cytoarchitectural differentiation of the EC is paralleled by the neurochemical development, these developmental milestones in EC structure and connectivity have implications for understanding its normal function, including its puzzling modular organization and potential contribution to consciousness content (awareness), as well as for its insufficiently explored deficits in developmental, psychiatric, and degenerative brain disorders.

Laminar dynamics of deep projection neurons and mode of subplate formation are hallmarks of histogenetic subdivisions of the human cingulate cortex before onset of arealization

“…While in the isocortical cingulate cortex SP expansion-deep CP cells "spread down" (Duque et al 2016) precedes by neocortical mode, the ventral primordial cingulate belt shows incomplete CP "delamination" and SP is extremely narrow at the border with a curved thin cortical sheet of the supracallosal archicortex-future indusium griseum ("dorsal hippocampus"). This new finding via DPN markers confirms histological observation of Kostović and Krmpotić (1976), synaptic distribution analysis in the interhemispheric cortex (Kostović and Krmpotić-Nemanić 1975;Kostović et al 2004), structural MRI (Bobić-Rasonja et al 2021, as well as the concept of the thin SP and MZ enlargement as a characteristic of the limbic allocortex (Kostović et al 1989;Supèr et al 1998;Šimić et al 2022). Using the atypical SP formation process in the ventral cingulate cortex, our study demonstrated that before the cingulate sulcus and callosal sulcus formation, mesocortex occupied a large portion of the interhemispheric cortical mantle (His 1904;Hochstetter 1919;Economo and Koskinas 1925), nicely summarized in Figure 121 by Stephan (1975).…”

Development of parvalbumin-immunoreactive neurons in the postnatal human hippocampal formation

“…Along with the maturation of excitatory neurons of the network, maturation-related increase in PV expression across the entire entorhinal-hippocampal complex is influenced by the activity of stellate cells in layer 2 of the medial entorhinal cortex (Donato et al, 2017 ). The coincidence of the postnatal development of PV-immunoreactive neurons found in the human entorhinal cortex by Grateron et al ( 2003 ) and the prolonged maturation of these cells found by us in the Ammon’s horn and the dentate gyrus, along with other developmental studies indicates the relevancy of the coupled and sequential maturation of the entorhinal-hippocampal network (Liu et al, 2021 ; Šimić et al, 2022 ).…”

Anterograde and Retrograde Propagation of Inoculated Human Tau Fibrils and Tau Oligomers in a Non-Transgenic Rat Tauopathy Model

“…The development of entorhinal to hippocampal neurofibrillary changes in both experimental conditions suggests the high vulnerability of the perforant path and hippocampus [ 89 , 90 , 91 , 92 , 93 ]. Therefore, our findings confirm that disruption of the perforant path is one of the key underlying pathophysiological events in the course of AD [ 94 , 95 ].…”