The diversity of GABAergic neurons and neural communication elements

Abstract

The phenotypic diversity of cortical GABAergic neurons is probably necessary for their functional versatility in shaping the spatiotemporal dynamics of neural circuit operations underlying cognition. Deciphering the logic of this diversity requires comprehensive analysis of multi-modal cell features and a framework of neuronal identity that reflects biological mechanisms and principles. Recent high-throughput single-cell analyses have generated unprecedented data sets characterizing the transcriptomes, morphology and electrophysiology of interneurons. We posit that cardinal interneuron types can be defined by their synaptic communication properties, which are encoded in key transcriptional signatures. This conceptual framework integrates multi-modal cell features, captures neuronal input-output properties fundamental to circuit operation and may advance understanding of the appropriate granularity of neuron types, towards a biologically grounded and operationally useful interneuron taxonomy.

Fig. 1:. A work draft taxonomy of transcriptomic neuron types of the cortical GABAergic system.

a | Major GABAergic subclasses and cell types recognized by classic anatomical, physiological, molecular and developmental studies. Schematics of the characteristic morphology of these cell types are also shown. Light grey lines represent dendrites; dark grey lines represent axons. b | Current taxonomy of transcriptomic types in the primary visual and anterolateral motor cortex. Note that the major types and branches are consistent with classic studies. Currently only a few of the 60 ‘atomic types’ are well correlated with the anatomically and physiologically defined types. ‘?’ denotes that the correlation between the transcriptomic type and the indicated morphological type is not yet firmly established. A major discrepancy is the Lamp5–Lhx6-type cells, which were clustered as caudal-ganglionic-eminence-derived neurogliaform cells but were recognized as medial-ganglionic-eminence-derived chandelier cells (CHCs). 5-HT_3AR, serotonin 3A receptor; CCK, cholecystokinin; CR, calretinin; NOS1, nitric oxide 1; PVALB, parvalbumin; SST, somatostatin; VIP, vasoactive intestinal peptide. Part b is adapted from ref., Springer Nature Limited.

Fig. 2:. Transcriptional signatures of synaptic communication delineate cardinal GABAergic neuron types.

a | Six cardinal types — long projection cells (LPCs), chandelier cells (CHCs), PV-basket cells (PVCs), cholecystokinin-expressing basket cells (CCK-BCs), interneuron selective cells (ISCs) and Martinotti cells (MNCs) — are distinguished by their characteristic innervation of cellular and subcellular targets. Where data are available, these cardinal types manifest distinct input–output connectivity patterns and further display distinct intrinsic, synaptic and network properties indicative of mediating specific forms of input–output transformation. b | Cell phenotypes and properties emerge from the workings of macromolecular machines (cellular modules) that consist of multi-protein complexes. As molecular components of these complexes, protein variants with different biochemical and biophysical properties encoded by members of a given gene family can customize cellular modules and cell-type-specific properties. c | Examples of cellular modules that shape neuronal connectivity, synaptic transmission, electrical signalling, intracellular signal transduction and gene transcription. d | Six categories of gene families shape a set of membrane-proximal molecular machines that customize the input–output connectivity and transformation properties of different GABAergic cardinal types. AC, adenylyl cyclase; AIS, axon initial segment; CaBP, calcium-binding protein; Cav, voltage-gated calcium channel; DCV, dense core vesicle; GluR, glutamate receptor; GPCR, G protein-coupled receptor; IN, interneuron; Kv, voltage-gated potassium channel; PDE, phosphodiesterase; PTP, protein tyrosine phosphatase; PyN, pyramidal neuron; RGS, regulator of G protein signalling; RHO-GEF, RHO guanine nucleotide exchange factor; RTK, receptor tyrosine kinase; SV, synaptic vesicle; Syt, synaptotagmin. Adapted with permission from ref., Elsevier.

Fig. 3:. A conceptual framework of neuronal identity.

A neuron type can be defined as a canonical neural communication element that mediates characteristic input–output transformations and that is encoded by key transcription signatures that customize a congruent set of cellular machines. This scheme integrates the anatomical, physiological, functional and developmental genetic features that together define neuronal cell types. It emphasizes cardinal neuron types that are reliably generated in each member of a species, build species-stereotyped circuit templates and are likely rooted in the genome. Not shown is the notion that these cardinal types are probably further diversified and customized (for example, by neuronal activity and experience) to shape circuit elements characteristic of individual organisms. Features in parentheses are commonly measured cell properties but are reflections of core features of cell types. See text for detailed description.