CHOLECYSTOKININ INCREASES GABA RELEASE BY INHIBITING A RESTING K+ CONDUCTANCE IN HIPPOCAMPAL INTERNEURONS

Cholecystokinin (CCK) is found co-localized with the inhibitory neurot ransmitter GABA in interneurons of the hippocampus. Also, CCK receptor s are found in abundance in this brain region. The possibility that CC K alters interneuron activity was examined using whole-cell current- a nd voltage-clamp recordings from visualized interneurons in the stratu m radiatum of area CAI in rat hippocampal slices. The effect of CCK on GABA-mediated IPSCs was also determined in pyramidal neurons. The sul fated octapeptide CCK-8S increased action potential frequency or gener ated inward currents in the majority of interneurons. These effects of CCK persisted in the presence of tetrodotoxin and cadmium, suggesting that they were direct. Current-voltage plots revealed that CCK-8S inh ibited a conductance that was linear across command potentials and rev ersed near the equilibrium potential for K+ ions. The K+ channel block er tetraethylammonium (10 mM) generated inward currents similar to tho se initiated by CCK, and it occluded the effect oi the peptide. BaCl2, (1 mM) and 4-aminopyridine (2 mM) did not alter the effect of CCK. Th e CCKB receptor antagonist PD-135,158 completely blocked the inward cu rrents generated by CCK-8S. CCK also resulted in an increase in sponta neous action potential-dependent IPSC frequency, but no changes in act ion potential-independent miniature IPSCs or evoked IPSCs in pyramidal neurons. These results provide evidence that CCK can depolarize hippo campal interneurons through the inhibition of a resting K+ conductance , leading to increased tonic inhibition of pyramidal neurons. This act ion of CCK may contribute to its anticonvulsant properties, as observe d in limbic seizure models.