Id2 GABAergic interneurons: a neglected fourth major group of cortical inhibitory cells

Abstract

Cortical GABAergic interneurons (INs) represent a diverse population of locally projecting cells that provide specialized forms of inhibition to pyramidal neurons and other INs. Most recent work on INs has focused on subtypes distinguished by expression of Parvalbumin (PV), Somatostatin (SST), or Vasoactive Intestinal Peptide (VIP), but a fourth group that includes neurogliaform cells (NGFCs) has remained largely enigmatic due to a lack of genetic tools. Here, we show that these INs can be accessed experimentally using intersectional genetics with the gene Id2. We find that outside of layer 1 (L1), the vast majority of Id2 INs are NGFCs that express high levels of neuropeptide Y (NPY) and exhibit a late-spiking firing pattern, with extensive local connectivity. While much sparser, non-NGFC Id2 IN had more variable properties, with most corresponding to a diverse group of INs that strongly express the neuropeptide CCK. In vivo, using silicon probe recordings, we observed several intriguing aspects of NGFC activity, including a strong rebound in activity immediately following the cortical down state during NREM sleep. Our study provides insights into IN diversity and NGFC distribution and properties, and outlines an intersectional genetics approach for further study of this neglected group of INs.

Functional diversities within neurons and astrocytes in the adult rat auditory cortex revealed by single-nucleus RNA sequencing

“…2A ). In accord with previous reports, these subtypes are defined by prominent or combinatorial expression of marker genes Sox5 for Pv 38 ; Grin3a for Sst 35 ; Vip and Adarb2 6,43,44 for Vip inhibitory neurons, along with pan and putative interneuron markers Gad1 5,43,45 and Erbb4 37,38,43,46 ( Fig. 2C, left ).…”

Cell-type-specific inhibitory circuitry from a connectomic census of mouse visual cortex

“…both PV and CCK+ basket cells) 21,28,60 and DistTCs could include any molecular class that targets apical dendrites, not only SST neurons. The SparTC subclass included both neurogliaform cells and all layer 1 interneurons, suggesting it largely contained cells from the lamp5 and sncg transcriptomic classes 13 or the collective Id2 class 23 . Some cell types, such as chandelier cells 61 , had no examples in the column (although were found elsewhere in the EM volume 62 ), and other cells in the column either did not fall cleanly into classical categories.…”

“…both PV and CCK+ basket cells) 21, 28, 60 and DistTCs could include any molecular class that targets apical dendrites, not only SST neurons. The SparTC subclass included both neurogliaform cells and all layer 1 interneurons, suggesting it largely contained cells from the lamp5 and sncg transcriptomic classes 13 or the collective Id2 class 23 .…”

“…Inhibitory neurons, despite making up little more than 1 in 10 cortical neurons 18 , have at least as much cell type diversity as the vastly more numerous excitatory neurons 11,13,19 , offering the potential for highly selective control of cortical activity. However, most of our understanding of inhibitory connectivity is based not on individual cell types, but on a few coarse molecular subclasses [20][21][22] with certain shared developmental, functional, and synaptic properties. Parvalbumin (PV)-expressing neurons target the perisomatic region of excitatory cells, including basket cells that target the soma and proximal dendrites of excitatory neurons and chandelier cells that target the axon initial segment.…”

“…The connectivity of vasoactive intestinal peptide (VIP)-expressing neurons is heterogeneous, including not only a subclass of disinhibitory specialists that preferentially target SST cells 25, 27 , but also excitatory-targeting small basket cells that coexpress cholecystokinin (CCK) 28–30 . A fourth subclass expresses Id2 23 , spanning lamp5 and sncg transcriptomic groups 20, 22 , and includes neurogliaform cells with diffuse synaptic outputs as well as a variety of cell types in layer 1. Within these cardinal subclasses, individual cell types are highly diverse 12, 13, 31 and functionally distinct 18 but in most cases little is known about connectivity at that level.…”