Somatostatin interneurons function in laminar and cell-type specific circuits

Abstract

Pyramidal neurons receive, process, and store information in their apical and basal dendrites by integrating thousands of excitatory and inhibitory inputs. Dendritic inhibition is mediated by somatostatin-expressing (SST) GABAergic interneurons, which gate dendritic excitation with branch and spine-specific precision. While SST interneurons are often treated as a homogenous group with dense efferent connectivity, it has long been understood that SST interneurons have significant diversity. However, the functional significance of this diversity is unknown. Here, we describe genetic strategies for targeting SST subtypes based on transcriptomic, morphological, and electrophysiological parameters. These strategies revealed a surprising laminar organization of SST subtypes, which suggested that SST interneurons may engage in subtype-specific cortical circuits. Using slice electrophysiology and synaptic puncta analysis, we demonstrated that three SST subtypes expressing the marker genes Calretinin (Calb2), Chrna2, and Crhr2 differentially innervate pyramidal neurons across layers with both intralaminar and translaminar connectivity. Strikingly, within layer 5, each of these three types specifically innervates either intratelencephalic tract (IT) or pyramidal tract (PT) pyramidal neurons with non-overlapping subcellular targeting domains. Notably, of these three, only Calb2 interneurons strongly innervates Parvalbumin-expressing (PV) interneurons in a laminar-specific way. These results reveal that SST subtypes are organized in layerand cell-type specific circuits with local excitatory and inhibitory neurons and suggest that SST interneuron diversity modulates dendritic inhibition in compartmentalized parallel subnetworks.