Interneuron Diversity, Early Emergence

 

Science  06 Apr 2018: Vol. 360, Issue 6384, pp. 81-85

Early emergence of cortical interneuron diversity in the mouse embryo

Da Mi, et.al.

Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London SE1 1UL, UK.

Medical Research Council Centre for Neurodevelopmental Disorders, King’s College London, London SE1 1UL, UK.

Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.

Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.

Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02446, USA.

Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.

[paraphrase]

GABAergic interneurons (GABA, γ-aminobutyric acid) regulate neural-circuit activity in the mammalian cerebral cortex. These cortical interneurons are structurally and functionally diverse. Here, we use single-cell transcriptomics to study the origins of this diversity in the mouse. We identify distinct types of progenitor cells and newborn neurons in the ganglionic eminences, the embryonic proliferative regions that give rise to cortical interneurons. These embryonic precursors show temporally and spatially restricted transcriptional patterns that lead to different classes of interneurons in the adult cerebral cortex. Our findings suggest that shortly after the interneurons become postmitotic, their diversity is already patent in their diverse transcriptional programs, which subsequently guide further differentiation in the developing cortex.

The mammalian cerebral cortex contains more than two dozen GABAergic cell types (GABA, γ-aminobutyric acid) with particular morphological, electrophysiological, and molecular characteristics. Interneuron diversity has evolved to increase the repertoire of cortical computational motifs through a division of labor that allows individual classes of interneurons to control information flow in cortical circuits. Although a picture about cortical interneuron cell types is emerging, the mechanisms that generate interneuron diversity remain controversial. One model proposes that interneurons acquire the potential to differentiate into a distinct subtype at the level of progenitors or shortly after becoming postmitotic, before they migrate; the competing model postulates that interneuron identity is established relatively late in development, after they have migrated to their final location, through interactions with the cortical environment.

To study cell diversity in the germinal regions of cortical interneurons, we dissected tissue from three regions in the mouse subpallium, the dorsal and ventral medial ganglionic eminence (dMGE and vMGE, respectively) and the caudal ganglionic eminence (CGE), across two stages that coincide with the peak of neurogenesis for cortical interneurons. We prepared single-cell suspensions and sequenced the transcriptome of individual cells, which, following quality control, led to a final data set of 2003 cells, covering on average of about 3200 genes per cell. We performed regression analysis on these cells to remove the influence of cell cycle–dependent genes in cell type identification.

We used principal components analysis (PCA) to identify the most prominent sources of variation. These analyses revealed gene expression patterns that distinguish progenitor cells and neurons at each developmental stage. The adult mouse cerebral cortex contains more than 20 distinct classes of interneurons with characteristic transcriptional profiles,  Analysis of progenitor cell clusters confirmed that radial glial cells and intermediate progenitors have distinct identities across different regions of the subpallium, Altogether, these results strongly suggested that interneurons exhibit a great diversity of transcriptional signatures shortly after becoming postmitotic in the GE.

Our study reveals that GABAergic interneurons have a propensity toward a defined fate long before they occupy their final position in the cerebral cortex during early postnatal development. This suggests that interneuron diversity does not emerge in response to activity-dependent mechanisms in the cortex but rather is established early, before these cells reach the cortex, by specific transcriptional programs that then unfold over the course of several weeks. Activity-dependent mechanisms undoubtedly influence development, maturation, and plasticity of cortical interneurons, but most aspects that are directly linked to the functional diversity of cortical interneurons seem to be intrinsically determined.

Our analysis identifies early markers for many different classes of cortical interneurons, whose functional validation may eventually illuminate the mechanisms regulating the differentiation of GABAergic interneurons into specific subtypes and, through comparative analyses, inform the use of stem cell biology for the generation of distinct classes of human cortical interneurons. Thus, core aspects of interneuron identity are drafted early in development, forming the foundation on which later interactions with other neurons must function.

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