The development of inhibitory cortical interneurons in the early fetal human telencephalon

Abstract

Higher order processing by circuits in the cerebral cortex is highly dependent on inhibitory interneurons; failure in their generation and/or functions is thought to lead to neurodevelopmental conditions. In rodents, interneurons are almost entirely generated in the ganglionic eminences (GE) and migrate into the cortex; however, it is still contentious to what degree this applies to the more complex human cerebral cortex. In this study, immunohistochemical analysis of early fetal human ventral telencephalon showed distinct (although overlapping) expression domains for several interneuron precursor transcription factors revealing the complex subdivisions of the GE; including three compartments for the CGE (medial, lateral, ventral) and septum (MGE-like, LGE-like, pallial septum). Two migratory pathways of interneurons from the CGE (anteriorly via LGE) and septum (medially) into the cortex, not previously reported in rodents, were also described. Cortically-derived cultures of fetal human neuroprogenitors contained considerable numbers of GABA+ and calretinin+ cells; significantly more so in anterior- versus posterior-derived cortical cultures. Many cells expressed either COUP-TFI or COUP-TFII, but not NKX2.1, characteristic of MGE-derived cells. Furthermore, RNA sequencing data from fetal human cortical samples found mRNA levels for DLX1, DLX2, GSH2, ASCL1, ARX, OLIG2 and CALB2, genes characteristic of GABAergic interneurons and their progenitors, to be significantly higher in samples derived from anterior than posterior cortical regions. As in mice, SP8 and COUP-TFI were expressed in counter-gradients across the cortex, but unlike in rodents, expression overlapped extensively in the ventricular zone (VZ) of parietal, occipital and dorso-temporal cortex. COUP-TFII was expressed widely throughout the ventral temporal and ventral posterior cortex overlapping extensively with COUP-TFI. VZ OLIG2 expression was confined to anteromedial cortex at early stages. Arealised expression of transcription factors in the cortical wall may, in turn, control expression of signalling pathways that attract migrating cells expressing the same transcription factors, setting up various pathways into the cortex for interneurons arriving from the GE. In conclusion, the early fetal human brain shares the fundamental mechanisms of protomap formation and interneuron generation with rodents; however, there may also be specific differences. The much larger human cortex may require additional migratory pathways for interneuron precursors. Interneuron generation in the anterior regions of developing human cortex in particular, along with more complex interplay between arealisation genes in the formation of the protomap, could be two mechanisms by which association cortex has become expanded and more specialised in human.