Deep Survey of GABAergic Interneurons: Emerging Insights From Gene-Isoform Transcriptomics

Abstract

GABAergic interneuron diversity is a key feature in the brain that helps to create different brain activity patterns and behavioral states. Cell type classification schemes—based on anatomical, physiological and molecular features—have provided us with a detailed understanding of the distinct types that constitute this diversity and their contribution to brain function. Over recent years, the utility of single-cell RNAseq has majorly complemented this existing framework, vastly expanding our knowledge base, particularly regarding molecular features. Single-cell gene-expression profiles of tens of thousands of GABAergic cells from many different types are now available. The analysis of these data has shed new lights onto previous classification principles and illuminates a path towards a deeper understanding of molecular hallmarks behind interneuron diversity. A large part of such molecular features is synapse-related. These include ion channels and receptors, as well as key synaptic organizers and trans-synaptic signaling molecules. Increasing evidence suggests that transcriptional and post-transcriptional modifications further diversify these molecules and generate cell type-specific features. Thus, unraveling the cell type-specific nature of gene-isoform expression will be a key in cell type classification. This review article discusses progress in the transcriptomic survey of interneurons and insights that have begun to manifest from isoform-level analyses.

Transcriptional and morphological profiling of parvalbumin interneuron subpopulations in the mouse hippocampus

“…Nevertheless, our data do not exclude the hypothesis that input/output connectivity of these cells is defined by CAMs. First, it is possible that isoform level, non-mRNA, or translational information is instead more predictive of morphology and circuit connectivity 22 . Second, CAMs could specify connections exclusively during earlier development, after which key specification factors are downregulated 64 , and CAM function shifts toward the maintenance and modulation of synaptic transmission.…”

“…Recent single-cell RNA-seq assays have facilitated classification efforts 8 – 12 and increased expectations that transcriptomic information could explain the entirety of cell-type-specific features, a crucial step toward understanding the multimodal identity of neural cell types. While several studies have employed single-cell RNA-seq to characterize transcriptomic and physiological features 12 – 21 , the relationship between transcriptomic information and neuronal morphology is the subject of on-going research 14 , 20 – 22 .…”

Isoform cell type specificity in the mouse primary motor cortex

“…Transcriptional and post-transcriptional control of individual isoforms of genes is crucial for neuronal differentiation [1][2][3][4][5] , and isoforms of genes have been shown to be specific to cell-types in mouse and human brains [6][7][8][9][10][11] . It is therefore not surprising that dysregulation of splicing has been shown to be associated with several neurodevelopmental and neuropsychiatric diseases 3,12,13 .…”

A Diversity of Cell Types, Subtypes and Phenotypes in the Central Nervous System: The Importance of Studying Their Complex Relationships

“…In the CNS, the different types of neurons, which are identified by their neurotransmitters, neurotrophic or neuroprotective factors (Que et al, 2019 ; Sugino et al, 2019 ; Cizeron et al, 2020 ), are accompanied by non-neuronal cells showing similar, or greater levels of heterogeneity. This cellular diversity pertains to glial cells (microglia, astrocytes, cells of the oligodendrocytic lineage) and the peripheral immune cells that can infiltrate the CNS (Oberheim et al, 2012 ; Butt and Verkhratsky, 2018 ; Foerster et al, 2019 ; Stratoulias et al, 2019 ; Dumas and Prinz, 2020 ).…”