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 G(q)-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.
