Parvalbumin-positive (PV+) fast-spiking basket cells are thought to play key roles in network functions related to precise time keeping during behaviorally relevant hippocampal synchronous oscillations. Although they express relatively few receptors for neuromodulators, the highly abundant and functionally important neuropeptide cholecystokinin (CCK) is able to selectively depolarize PV+ basket cells, making these cells sensitive biosensors for CCK. However, the molecular mechanisms underlying the CCK-induced selective and powerful excitation of PV+ basket cells are not understood. We used single and paired patch-clamp recordings in acute rat hippocampal slices, in combination with post hoc identification of the recorded interneurons, to demonstrate that CCK acts via G-protein-coupled CCK2 receptors to engage sharply divergent intracellular pathways to exert its cell-type-selective effects. In contrast to CCK2 receptors on pyramidal cells that signal through the canonical Gq-PLC pathway to trigger endocannabinoid-mediated signaling events, CCK2 receptors on neighboring PV+ basket cells couple to an unusual, pertussis-toxin-sensitive pathway. The latter pathway involves ryanodine receptors on intracellular calcium stores that ultimately activate a nonselective cationic conductance to depolarize PV+ basket cells. CCK has highly cell-type-selective effects even within the PV+ cell population, as the PV+ dendrite-targeting bistratified cells do not respond to CCK. Together, these results demonstrate that an abundant ligand such as CCK can signal through the same receptor in different neurons to use cell-type-selective signaling pathways to provide divergence and specificity to its effects.
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