Abstract
Cortical GABAergic interneurons constitute a highly diverse population of inhibitory neurons that are key regulators of cortical microcircuit function. An important and heterogeneous group of cortical interneurons specifically expresses the serotonin receptor 3A (5-HT3AR) but how this diversity emerges during development is poorly understood. Here we use single-cell transcriptomics to identify gene expression patterns operating in Htr3a-GFP+ interneurons during early steps of cortical circuit assembly. We identify three main molecular types of Htr3a-GFP+ interneurons, each displaying distinct developmental dynamics of gene expression. The transcription factor Meis2 is specifically enriched in a type of Htr3a-GFP+ interneurons largely confined to the cortical white matter. These MEIS2-expressing interneurons appear to originate from a restricted region located at the embryonic pallial–subpallial boundary. Overall, this study identifies MEIS2 as a subclass-specific marker for 5-HT3AR-containing interstitial interneurons and demonstrates that the transcriptional and anatomical parcellation of cortical interneurons is developmentally coupled.
Highlights
Cortical GABAergic interneurons constitute a highly diverse population of inhibitory neurons that are key regulators of cortical microcircuit function
We found that Meis[2], a transcription factor expressed in olfactory bulb INs45,46 was the most enriched transcription factor in Htr3a-GFP þ type 1 INs across postnatal development (Fig. 1g-i, Supplementary Table 13)
Type 1 INs were enriched in transcription factors expressed in lateral ganglionic eminence (LGE)-derived progenitors such as Etv[1], Pbx[1] and Sp8, which are found in olfactory bulb INs (Fig. 1i, Supplementary Fig. 5)
Summary
Cortical GABAergic interneurons constitute a highly diverse population of inhibitory neurons that are key regulators of cortical microcircuit function. The transcription factor Meis[2] is enriched in a type of Htr3a-GFP þ interneurons largely confined to the cortical white matter These MEIS2-expressing interneurons appear to originate from a restricted region located at the embryonic pallial– subpallial boundary. Using this approach we identified a distinct subclass of Htr3a-GFP þ INs largely confined to the cortical WM and characterized by the specific expression of the transcription factor Meis[2] These neurons appeared to originate from a restricted MEIS2 þ /PROX1- domain located outside of the CGE at the embryonic pallial-subpallial boundary (PSB). We found that the Nr2f2-enriched cortical IN type identified using singlecell RNAseq preferentially distributed in superficial cortical layer 1 and expressed the marker RELN These data provide evidence for a coupling between the transcriptional and anatomical parcellation of IN subtypes. They indicate that neural network assembly relies on circuit elements with distinct molecular identities that are spatially segregated
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