On GABAergic interneuron diversity and maturation

Abstract: GABAergic interneurons provide finely, distinct styles of inhibition granted by their unique targeting preferences, molecular profiles, and morphological silhouettes. A central quest of my thesis was to explore what constitutes such diversity, touching upon how this di- versity is reached and preserved during development and what maintains distinct functional features later on. This is a compilation of my overview on a vibrant, fast-paced research field that still holds several unresolved questions. In Paper I, we used large-scale single-cell RNA sequencing to dissect the cellular com- position of the mouse somatosensory cortex and hippocampal CA1 region by identifying the distinct molecular subclasses of cells forming these brain regions. In particular, we unveiled a previously undescribed inhibitory interneuron labeled by transcription factor Pax6, which was further confirmed with immunohistochemistry, electrophysiology and morphological recon- structions. In Paper II, we characterized all striatal neuronal populations and compared them to their cortical counterparts using single-cell RNA sequencing. An important finding was that the typical parvalbumin-expressing neurons are part of a larger group of neurons expressing a novel marker, Pthlh, and that they exhibit a continuum of electrophysiological properties cor- related with the expression of parvalbumin. Furthermore, cortical and striatal parvalbumin- expressing neurons show significant transcriptomic and electrophysiological differences. In Paper III, we show that cortical somatostatin-expressing interneurons need the tran- scription factor Sox6 to maintain their subtype identity, specifically during migration. Using a combination of mouse genetics, single-cell RNA-sequencing, and electrophysiology we show that, while in controls the somatostatin-expressing class comprises nine molecularly distinct neuronal subtypes, the Sox6-mutant cortex contained only three molecular subtypes, without any significant somatostatin-cell loss. In Paper IV, we utilized conditional knockout strategies to remove Sox6 in parvalbu- min-expressing interneurons at different postnatal stages. Our data revealed that class of inter- neurons relies on postnatal expression of Sox6 for the growth and maintenance of their axonal boutons and synaptic function until adulthood. Altogether, the studies included in this thesis shine light on what GABAergic interneu- ron diversity encompasses, highlighting the particular role a transcription factor in maintenance of subtype identity (in somatostatin neurons) or particular functional features (in parvalbumin neurons).