Transcriptomic and anatomic parcellation of 5-HT3AR expressing cortical interneuron subtypes revealed by single-cell RNA sequencing

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.

The distribution, number, and certain neurochemical identities of infracortical white matter neurons in a lar gibbon (Hylobates lar) brain

“…Moreover, the number of WMIC in the lar gibbon is three times the number of neurons found in the entire cerebral cortex of one of the smallest primates, Microcebus murinus (Herculano‐Houzel, Catania, Manger, & Kaas, ). Finally, given the location and widespread connectivity of at least some of these neurons, they are well positioned to exert a wide‐ranging effect over normal cortical function and dysfunction in illness, as well as homeostasis of the cortex (Clancy et al, ; Colombo, ; Frazer et al, ; Hoerder‐Suabedissen & Molnár, ; Kilduff et al, ; Mortazavi et al, ; Suárez‐Solá et al, ; Tomioka & Rockland, ; von Engelhardt et al, ).…”

“…WMICs could be considered a distinct neural system in their own right (Colombo, ; Suárez‐Solá et al, ), or alternatively, as closely affiliated with the cerebral cortex, and/or as a distinct deep cortical layer (distinct and deep to cortical layer VII as discussed by Reep, ). in vitro studies in rodents have shown that WMICs have action potentials and are interconnected with the overlying gray matter (Case et al, ; Clancy et al, ; Frazer et al, ; von Engelhardt et al, ). Among other issues, further work might address how these neurons are developmentally related to specific cortical layers, for example, through the use of specific cortical layer markers (Bakken et al, ; Hevner, ; Hoerder‐Suabedissen et al, , ).…”

“…in vitro studies in rodents have shown that WMICs have action potentials and are interconnected with the overlying gray matter (Case et al, 2017;Clancy et al, 2001;Frazer et al, 2017;von Engelhardt et al, 2011). Among other issues, further work might address how these neurons are developmentally related to specific cortical layers, for example, through the use of specific cortical layer markers (Bakken et al, 2016;Hevner, 2007;Hoerder-Suabedissen et al, 2009.…”

“…The density of WMICs decreases during ontogeny from the prenatal to the adult brain (Duque, Krsnik, Kostovic, & Rakic, 2016;Kanold & Luhmann, 2010), but this change varies depending on the cortical region examined, brain size and the extent of cortical gyrencephaly (García-Marin et al, 2010;Kostovic & Rakic, 1980Suárez-Solá et al, 2009). Hodological studies of WMICs indicate that they are integrated into the circuitry of the overlying region of cortical gray matter (Clancy et al, 2001;Frazer et al, 2017;Shering & Lowenstein, 1994;Tomioka et al, 2005;Tomioka & Rockland, 2007;von Engelhardt et al, 2011), while functionally, subpopulations have been linked to vasodilation (Suárez-Solá et al, 2009), homeostatic sleep regulation (Kilduff, Cauli, & Gerashchenko, 2011), the regulation of information transfer (Colombo, 2018), and the regulation of arousal and transthalamic cortico-cortical communication (Hoerder-Suabedissen et al, 2018;Molnár, 2018). These characteristics of WMICs indicate that they are not just a remnant of the subplate, and form a distinct functional neural system (Colombo, 2018;Hoerder-Suabedissen et al, 2018;Hoerder-Suabedissen & Molnár, 2015;Molnár, 2018;Suárez-Solá et al, 2009).…”

Early emergence of cortical interneuron diversity in the mouse embryo

“…For example, clusters primarily populated by MGE-derived cells can be further segregated into those with features of SST+ interneurons (N3 and N4) and those without (N1, N2 and N9), which presumably include neurons that will differentiate into PV+ interneurons. The profile of emerging CGE-specific interneuron classes, such as those characterized by the expression of Meis2 (21), is also delineated at this stage. This analysis also revealed that the CGE gives rise to neurons with molecular profile of SST+ interneurons (N13), which reinforces the view that this anatomical region contains a molecularly heterogeneous pool of progenitor cells (15).…”