Morpho-physiological Diversity of Cholecystokinin-expressing Interneurons in the Dentate Gyrus

The hippocampus plays a crucial role in learning, memory, and emotion, with the dentate gyrus (DG) serving as the primary gateway. The DG receives multimodal sensory inputs from outside the hippocampus and relays this integrated information to downstream regions for further processing. Within the DG, inhibitory GABAergic interneurons (INs) regulate information processing, thereby influencing the overall hippocampal function. Cholecystokinin (CCK)-expressing INs in the DG are particularly implicated in emotional behavior due to their expression of cannabinoid and serotonin receptors. However, studying the morpho-electrophysiological features and functions of these INs has been challenging due to the off-target labeling of granule cells (GCs), the primary excitatory neurons in the DG, when using the CCK recombinase driver line. To address this issue, we employed an intersectional strategy to selectively label CCK INs, allowing us to investigate their electrophysiological, morphological, and synaptic features, which were further confirmed by post hoc pro-CCK immunostaining. Our analysis identified nine distinct subtypes of CCK INs, each with unique projection patterns targeting specific domains along the axo-somato-dendritic axis of GCs. CCK INs also exhibited diverse passive intrinsic properties and firing patterns. In addition, we found that CCK INs generate action potentials before GCs in response to cortical input, suggesting that they play a role in modulating GC input-output transformation. In summary, our findings indicate that DG CCK INs are diverse subpopulations with distinct roles in network functions.