Transcriptomic and anatomic parcellation of 5-HT3AR expressing cortical interneuron subtypes revealed by single-cell RNA sequencing
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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.
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NPY+ multipolar interneurons and Meis2+ interstitial GABAergic neurons express 5HT3aR; NPY+ multipolar cells have irregular spiking and are abundant at the layer 1/2 boundary, while Meis2+ neurons reside in white matter and extend axons to deep cortex and striatum.
“Two additional types of interneuron express 5HT3aR: NPY+ multipolar cells and Meis2+ interstitial GABAergic neurons. NPY+ multipolar interneurons exhibit irregular spiking properties and are particularly abundant at the boundary between layers 1 and 2”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Frazer et al., 2017
The remaining Dlx6a-Cre fate mapped cortical population mapped to precursor states 2 and 3, likely including the Meis2-expressing CGE-derived GABAergic population.
“The remaining Dlx6a-Cre fate mapped cortical population mapped to precursor states 2 and 3 (Fig. 3I, Extended Data Fig. 5), likely including the Meis2-expressing CGE-derived GABAergic population that has been recently described21”
From Developmental diversification of cortical inhibitory interneurons (2018) · cites this paper as [21]
Gad1/Meis2 double-positive cells are probably CGE projection neuron precursors described previously, and their descendants were not found in the mouse visual cortex dataset.
“Cells expressing both genes are likely projection neuron precursors that have recently been described in the CGE21, but whose progeny is not captured in the mouse visual cortex dataset.”
From Developmental diversification of cortical inhibitory interneurons (2018) · cites this paper as [21]
Prior work has described these cells in cortical white matter and suggested they are projection neuron precursors.
“These cells have been recently described as being present in the cortical white matter and likely represent projection neuron precursors21.”
From Developmental diversification of cortical inhibitory interneurons (2018) · cites this paper as [21]
Meis2 neurons were identified as related to olfactory bulb interneurons.
“Meis2 neurons were identified as related to olfactory bulb interneurons (Frazer et al., 2017).”
From A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation (2021) · cites this paper as Frazer et al., 2017
The profile of emerging caudal ganglionic eminence-specific interneuron classes, such as those characterized by Meis2 expression, is delineated at this stage.
“The profile of emerging CGE-specific interneuron classes, such as those characterized by the expression of Meis2 (21), is also delineated at this stage.”
From Early emergence of cortical interneuron diversity in the mouse embryo (2018) · cites this paper as [21]
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“By contrast, this gene was previously reported to be mainly expressed in olfactory bulb interneurons of mice ( 49 ).”
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The total number of white matter interstitial neurons in the human brain
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“…that © 2019 Anatomical Society WMIN are remnants of subplate neurons (Kostovi c & Rakic, 1980, 1990; Valverde & Facal-Valverde, 1988; Chun & Shatz, 1989a,b; Hoerder-Suabedissen et al. 2009; Juda s et al. 2011; Kostovi c et al. 2011; Hoerder-Suabedissen & Molnar, 2012, 2013; Frazer et al. 2017).”
BackgroundOrigin, Development, and Synaptogenesis of Cortical Interneurons
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“Finally, a small population of Meis2 expressing inhibitory projection neurons reside in the white matter behind the cortex, and innervate deep layers of distant cortical areas (von Engelhardt et al., 2011; Frazer et al., 2017).”
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“This group corresponds to a previously identified population of interneurons that derives from the caudal ganglionic eminence and is primarily confined to deep cortical layers and the white matter.”
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“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).”
BackgroundInfluentialElucidating the developmental trajectories of GABAergic cortical interneuron subtypes
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Transcriptomic and spatial organization of telencephalic GABAergic neurons
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“Thus, GABAergic progenitors accumulate in the early postnatal white matter and give rise to a subpopulation of cortical interstitial interneurons (Frazer et al., 2017).”
BackgroundMolecular Logic of Cellular Diversification in the Mammalian Cerebral Cortex
Di Bella, D. J., Habibi, E., Yang, S.-M., Stickels, R. R., Brown, J., Yadollahpour, P., Chen, F., Macosko, E. Z., Regev, A., & Arlotta, P. (2020) · doi:10.1101/2020.07.02.185439 · Cited by 20 · see citing works
Being superficial: a developmental viewpoint on cortical layer 1 wiring
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A ‘Marginal’ tale: the development of the neocortical layer 1
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Rostro-Caudal and Caudo-Rostral Migrations in the Telencephalon: Going Forward or Backward?
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“The LMS cross the PSB at the level of where dLGE interneurons are generated and destined to the olfactory bulbs and cortical white matter (Stenman et al., 2003; Inta et al., 2008; Frazer et al., 2017; blue arrows in Figures 1A,B).”
BackgroundUnderstanding and modeling regional specification of the human ganglionic eminence
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“Although strong sonic hedgehog (SHH)/GLI3 signaling is known to be sufficient to induce the ventral GE fate of theMGE, the requirements of ventralizing cues within the LGE and CGE appear to be highly context dependent (Ahn et al., 2016; Arber et al., 2015).”
InfluentialGenetic approaches to elucidating cortical and hippocampal GABAergic interneuron diversity
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A single-cell mass cytometry-based atlas of the developing mouse brain
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Projections to the putamen from neurons located in the white matter and the claustrum in the macaque
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“This confirms and extends, for the in vivo condition in NHP, previous in vitro experiments in mice reporting 5HTr3 WMNs having collaterals to both overlying cortex and striatum (Frazer et al., 2017; von Engelhardt et al., 2011), and provides new data about the looped architecture interconnecting the striatum, cortex,…”
BackgroundMethodResultInfluentialThe neuronal transcription factor MEIS2 is a calpain-2 protease target
Müller, T., Reichlmeir, M., Hau, A., Wittig, I., & Schulte, D. (2024) · Journal of Cell Science · doi:10.1242/jcs.261482 · Cited by 9 · see citing works
A transposase-derived gene required for human brain development
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Hidden in the white matter: Current views on interstitial white matter neurons
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“A subpopulation of IWMNs expressing the 5HT 3A receptors coexpresses the transcription factor MEIS2 (Table 1), which could be considered a subclass-specific marker of these cells (Frazer and others 2017).”
InfluentialDesiderio, S., Schwaller, F., Tartour, K., Padmanabhan, K., Lewin, G. R., Carroll, P., & Marmigère, F. (2023) · eLife · doi:10.7554/elife.89287 · Cited by 7 · see citing works
A developmental atlas of the mouse brain by single-cell mass cytometryPreprint
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The transcriptomic and spatial organization of telencephalic GABAergic neuronal typesPreprint
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Cell type specification and diversity in subpallial organoids
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Somatic mutations reveal hypermutable brains and are associated with neuropsychiatric disordersPreprint
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“…and the 5HT3A receptor (Luzzati et al., 2011a; Luzzati et al., 2014; Liu et al., 2009; Garcı´a-Gonza´lez et al., 2020), typical of multiple LGE-and caudal GE (CGE)-class interneurons (Ma et al., 2012; Frazer et al., 2017) which were not reported to contribute to the striatum (Marin et al., 2000).”
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Transcriptomic Correlates of State Modulation in GABAergic Interneurons: A Cross-Species Analysis
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“…example, Cbln1 (precerebellin) and Meis2+ neurons [a cell type defined by expression of the homeo-box transcription factor Meis2 (Tasic et al. 2016, Frazer et al. 2017)] showed a strong spatial association, but also non-overlapping spatial distribution, indicating possible paracrine compositional…”
Etude du rôle de la kinésine KIF21B au cours du développement cortical
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“…diversification—have been described previously in other neuronal types 46 —the predetermined (invariant) mode has been reported for pyramidal neurons 17 , chandelier neurons 47 and Meis2 + /CGE-derived interneurons 48 , whereas expanding trajectories were observed in retinal ganglion cells 46 .”
He, F., Jiang, R., Huang, Q., Shi, Y., Wang, Y., Liu, J., Zhao, G., 赵载华, Dong, X., Zhou, Y., et al. (2026) · Environmental Science & Technology · doi:10.1021/acs.est.6c00855
- Authors
- Frazer, S., Prados, J., Niquille, M., Cadilhac, C., Markopoulos, F., Gomez, L., Tomasello, U., Telley, L., Holtmaat, A., Jabaudon, D., & Dayer, A.
- Affiliations
- University of Geneva (CH)
- Corresponding author
- Dayer, Alexandre
- ORCID
- Venue
- Nature Communications
- Published
- 2017-01-30
- Volume
- 8
- Issue
- 1
- Pages
- 14219-14219
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5290279
- OpenAlex
- W2581498631
- Cited by
- 72
- References
- 59
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 14 · 2023: 6 · 2022: 9 · 2021: 4 · 2020: 11 · 2019: 4 · 2018: 13 · 2017: 2
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- ARBOR - Bern University of Applied Sciences Repository (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- BFH: ARBOR
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (155896)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- 5-HT3A receptor, cortical interneurons, GABAergic interneurons, MEIS2, cortical white matter, interneuron development, embryonic brain development, gene expression dynamics
- MeSH terms
- Reelin Protein, Animals, Cerebral Cortex, Embryo, Mammalian, Female, Interneurons, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Nerve Tissue Proteins, Serine Endopeptidases, Biomarkers, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Sequence Analysis, RNA, Homeodomain Proteins, Gene Expression Regulation, Developmental, Gene Expression Profiling, Microfluidics, Receptors, Serotonin, 5-HT3, Green Fluorescent Proteins, Mice, COUP Transcription Factor II, Single-Cell Analysis, GABAergic Neurons
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