Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics.

Kenneth D Harris,Lorenza Magno,Sten Linnarsson,Hannah Hochgerner,Nathan G Skene,Nicoletta Kessaris,Carolina Bengtsson Gonzales,Linda Katona,Peter Somogyi,Jens Hjerling-Leffler,Peter Jonas

doi:10.1371/journal.pbio.2006387

Kenneth D Harris, Lorenza Magno + Show 9 more

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https://doi.org/10.1371/journal.pbio.2006387

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Abstract

Understanding any brain circuit will require a categorization of its constituent neurons. In hippocampal area CA1, at least 23 classes of GABAergic neuron have been proposed to date. However, this list may be incomplete; additionally, it is unclear whether discrete classes are sufficient to describe the diversity of cortical inhibitory neurons or whether continuous modes of variability are also required. We studied the transcriptomes of 3,663 CA1 inhibitory cells, revealing 10 major GABAergic groups that divided into 49 fine-scale clusters. All previously described and several novel cell classes were identified, with three previously described classes unexpectedly found to be identical. A division into discrete classes, however, was not sufficient to describe the diversity of these cells, as continuous variation also occurred between and within classes. Latent factor analysis revealed that a single continuous variable could predict the expression levels of several genes, which correlated similarly with it across multiple cell types. Analysis of the genes correlating with this variable suggested it reflects a range from metabolically highly active faster-spiking cells that proximally target pyramidal cells to slower-spiking cells targeting distal dendrites or interneurons. These results elucidate the complexity of inhibitory neurons in one of the simplest cortical structures and show that characterizing these cells requires continuous modes of variation as well as discrete cell classes.

Highlights

Cortical circuits are composed of highly diverse neurons, and a clear definition of cortical cell types is essential for the explanation of their contribution to network activity patterns and behavior
Because different cell types express genes in different amounts, “clusters” of cells with similar expression patterns are likely to correspond to different cell types
Because we observed no major difference in interneuron classes between ages, data were pooled between them (S1 Fig)

Summary

Introduction

Cortical circuits are composed of highly diverse neurons, and a clear definition of cortical cell types is essential for the explanation of their contribution to network activity patterns and behavior. In hippocampal area CA1—one of the architecturally simplest cortical structures—GABAergic neurons have been divided so far into at least 23 classes of distinct connectivity, firing patterns, and molecular content [1,2,3,4,5,6]. CA1 GABAergic neurons have been divided into six major groups based on connectivity and expression patterns of currently used molecular markers. Somatostatin (SST)-positive oriens/lacunosum-moleculare (O-LM) cells target pyramidal cell distal dendrites and exhibit slower firing patterns [9]. Cholecystokinin (CCK)-positive interneurons are a diverse class characterized by asynchronous neurotransmitter release [15,16] that have been divided into at least five subtypes targeting different points along the somadendritic axis of pyramidal cells [17,18,19,20,21]. Additional rare types, such as large SST/NOS1 cells [27], have been described at a molecular level, but their axonal targets and relationship to other subtypes is unclear

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