Researchers have uncovered the molecular logic controlling the development of GABAergic neurons in the human telencephalon and found that this process is highly conserved through evolution. In an international collaboration between the laboratory led by Oscar Marín at the Centre for Developmental Neurobiology, Da Mi, alumnus of the Marín lab, and researchers from China, they have found that mice and humans share conserved transcriptional programmes for interneuron development. These results have been recently published in Science.
The organisation and cellular architecture of the telencephalon is broadly conserved between different mammalian species although both its size and complexity vary enormously between rodents and primates. Previous analyses have shown that the cellular composition of the cerebral cortex is relatively similar between mouse and human. However, extensive differences exist in the relative proportions, laminar distributions, and gene expression patterns of specific types of interneurons in the adult cortex of mice and humans. Do these fundamental differences arise through changes in the way cortical neurons are specified in mice and humans or through other mechanisms?
Understanding the mechanisms controlling the generation of human cortical GABAergic interneurons has important implications for human health. Neurodevelopmental conditions such autism spectrum disorder (ASD) and schizophrenia are caused, at least in part, by genetic variation. Genetic changes result in susceptibility to these disorders by affecting how specific cell types develop. For example, alterations in cortical and striatal GABAergic neurons are frequently observed in ASD and schizophrenia, but it is presently unclear whether the genes controlling the specification of these cells in humans are the same than those that have been studied in mice.
In their paper, Shi et al. used single-cell RNA sequencing to delineate the emergence of cell diversity in the ganglionic eminences – the place of origin of cortical GABAergic interneurons – in humans and found remarkable conservation between mouse and human in the genetic programmes controlling GABAergic neuronal development. Shi et al. constructed spatiotemporal maps of gene expression through the early second trimester (gestational weeks 9 - 18) of human development. This period covers the window of early development for the main classes of GABAergic neurons generated in the telencephalon, including olfactory bulb neurons, striatal and pallidal GABAergic projection neurons, and striatal and cortical GABAergic interneurons. Conserved mechanisms for the early diversification of subpallial neurons were observed, between mouse and human, as well as similar general cellular architecture of inhibitory cell types.
Professor Oscar Marín FMedSci commented:
“Understanding the fundamental mechanisms controlling the development of the human brain is terribly exciting and will have an important impact in the way we think about neurodevelopmental disorders.”
Shi et al.’s work elucidates the emergence of human GABAergic neurons and defines the commonalities and differences between us and rodents. Importantly, their work enables new levels of understanding of neurodevelopmental disorders. Many of these disorders have overlapping genetics and phenotypes and changes in striatal and cortical GABAergic neurons have been robustly documented in both ASD and schizophrenia. Shi et al. lays the foundations for understanding how and when genetic variations manifest in these cells and influence neurodevelopmental trajectories.