Functional specialization of hippocampal somatostatin-expressing interneurons

Abstract

AbstractHippocampal somatostatin-expressing (Sst) GABAergic interneurons (INs) exhibit considerable anatomical and functional heterogeneity. Recent single cell transcriptome analyses have provided a comprehensiveSst-IN subtype census, a plausible molecular ground truth of neuronal identity whose links to specific functionality remain incomplete. Here, we designed an approach to identify and access subpopulations ofSst-INs based on transcriptomic features. Four mouse models based on single or combinatorial Cre- and Flp- expression differentiated functionally distinct subpopulations of CA1 hippocampalSst-INs that largely tiled the morpho-functional parameter space of theSst-INs superfamily. Notably, theSst;;Tac1intersection revealed a population of bistratified INs that preferentially synapsed onto fast-spiking interneurons (FS-INs) and were both necessary and sufficient to interrupt their firing. In contrast, theNdnf;;Nkx2-1intersection identified a population of oriens lacunosum-moleculare (OLM) INs that predominantly targeted CA1 pyramidal neurons, avoiding FS-INs. Overall, our results provide a framework to translate neuronal transcriptomic identity into discrete functional subtypes that capture the diverse specializations of hippocampalSst-INs.Significance statementGABAergic interneurons are important regulators of neuronal activity. Recent transcriptome analyses have provided a comprehensive classification of interneuron subtypes, but the connections between molecular identities and specific functions are not yet fully understood. Here, we developed an approach to identify and access subpopulations of interneurons based on features predicted by transcriptomic analysis. Functional investigation in transgenic animals revealed that hippocampal somatostatin-expressing interneurons (Sst-INs) can be divided into at least four subfamilies, each with distinct functions. Most importantly, theSst;;Tac1intersection targeted a population of bistratified cells that overwhelmingly targeted fast-spiking interneurons. In contrast, theNdnf;;Nkx2-1intersection revealed a population of oriens lacunosum-moleculare interneurons that selectively targeted CA1 pyramidal cells. Overall, this study reveals that genetically distinct subfamilies ofSst-INs form specialized circuits in the hippocampus with differing functional impact.