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

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 3663 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 common continuous mode of variation modulated the expression of many genes, reflecting a range from metabolically highly active faster-spiking cells that proximally target pyramidal cells, to slower-spiking cells that target distal dendrites or interneurons. Within classes, cells showed further variability along the continuum and this correlated with their spiking phenotype. Surprisingly, several cell types previously described as discrete classes represented ranges along this continuum. 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.

Hippocampal hub neurons maintain unique functional properties throughout their lifetime

“…In line with this, a significant portion of ebGABAs project to the medial septum 12 . In the present study, we have found that ebGABAs express combinations of molecular markers typical of two extra classes of GABAergic projection cells: strong nNOS-expressing backprojection cells, likely innervating dentate gyrus and CA3 14,18 , and M2R-expressing retrohippocampal cells innervating subiculum and retrosplenial cortex 19 . Combined with the fact that biocytin-filled ebGABAs exhibited little local axonal arborization, these data indicate that ebGABAs could form several classes of projection cells innervating various target regions.…”

“…To estimate the cell types comprised in the ebGABA population, we examined the combinatorial expression of molecular markers in these cells. In the hippocampus, strong nNOS+ cells are GABAergic projection cells that also express SOM, NPY and M2R 14 and are likely to innervate the dentate gyrus and CA3 18 . We confirmed that strong nNOS+ ebGABAs belong to this cell type by finding that these cells often co-expressed SOM (94 ± 11%, n=4 brains), NPY (93 ± 13%, n=5 brains) and M2R (62 ± 27%, n=3 brains, Figure 2c and Supplementary Figure 3).…”

“…More generally, it is not known whether an early neuronal birth date leads to distinct functional properties in adult circuits. To fill this gap, we have examined ebGABAs in the CA1 region of the hippocampus, because this area is well understood in terms of cell types and connectivity 14 and is more accessible for in vivo calcium imaging.…”

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…While neurons and glial cells traditionally have been classified into sub-categories based on morphological and anatomical criteria or differences in neurotransmitter repertoire, a new and more fine-grained view of neurons and glial cell sub-types is now emerging as a result of recent transcriptomic analyses of the brain at the single-cell level. Thus, more than 500 molecularly distinct classes of neurons and glial cells have been identified in the mouse brain [1,2], and information about the cellular composition of specific brain regions is increasing rapidly [2][3][4][5][6][7][8]. Insights into the developmental trajectories for the different cell lineages-proceeding from immature progenitors to specialized cells -are generated by computational analyses of single-cell transcriptomes derived from different developmental stages [8][9][10].…”

Specific hippocampal interneurons shape consolidation of recognition memory

“…In particular, the hippocampus plays a key role in memory consolidation allowing the long-term storage of recently acquired events. Hippocampal circuits are regulated by a large variety of local inhibitory interneurons, whose identities and functions are under intense scrutiny (Harris et al, 2018, Pelkey et al, 2017, Parra et al, 1998. These interneurons are controlled by complex neuromodulatory systems ensuring their coordinated functions to shape behavioral responses (Klausberger and Somogyi, 2008).…”