Cholecystokinin Increases GABA Release by Inhibiting a Resting K⁺Conductance in Hippocampal Interneurons

Abstract

Cholecystokinin (CCK) is found co-localized with the inhibitory neurotransmitter GABA in interneurons of the hippocampus. Also, CCK receptors are found in abundance in this brain region. The possibility that CCK alters interneuron activity was examined using whole-cell current-and voltage-clamp recordings from visualized interneurons in the stratum radiatum of area CA1 in rat hippocampal slices. The effect of CCK on GABA-mediated IPSCs was also determined in pyramidal neurons. The sulfated octapeptide CCK-8S increased action potential frequency or generated 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 inhibited a conductance that was linear across command potentials and reversed near the equilibrium potential for K ϩ ions. The K ϩ channel blocker tetraethylammonium (10 mM) generated inward currents similar to those initiated by CCK, and it occluded the effect of the peptide. BaCl 2 (1 mM) and 4-aminopyridine (2 mM) did not alter the effect of CCK. The CCK B receptor antagonist PD-135,158 completely blocked the inward currents generated by CCK-8S. CCK also resulted in an increase in spontaneous action potential-dependent IPSC frequency, but no changes in action potential-independent miniature IPSCs or evoked IPSCs in pyramidal neurons. These results provide evidence that CCK can depolarize hippocampal interneurons through the inhibition of a resting K ϩ conductance, leading to increased tonic inhibition of pyramidal neurons. This action of CCK may contribute to its anticonvulsant properties, as observed in limbic seizure models.

Cholecystokinin inhibits endocannabinoid-sensitive hippocampal IPSPs and stimulates others

“…This finding is similar to observations by Miller et al (1997), who observed no effect of CCK on passive membrane properties of pyramidal cells. However, Miller et al, (1997) did not observe an effect of CCK on the AHP, while others (e.g. Dodd and Kelly, 1979;Shinohara and Kawasaki, 1997) reported the AHP reduction that we see.…”

“…Hence, although the agonist does reduce the AHP, the pyramidal cell passive properties are insensitive to CCK8-S. This finding is similar to observations by Miller et al (1997), who observed no effect of CCK on passive membrane properties of pyramidal cells. However, Miller et al, (1997) did not observe an effect of CCK on the AHP, while others (e.g.…”

“…Reports of CCK's physiological actions are inconsistent, with both excitation (Dodd & Kelly, 1979;Boden & Hill, 1988;Bohme et al, 1988;Shinohara & Kawasaki, 1997), and inhibition (MacVicar et al, 1987;Perez de la Mora et al, 1993) of pyramidal cells having been demonstrated. CCK may inhibit pyramidal cells indirectly (Perez de la Mora et al, 1993) by increasing GABA release from interneurons (Miller & Lupica, 1994;Miller et al, 1997;Ferraro et al, 1999;Deng & Lei, 2006). Some discrepancies have been ascribed to dosage and application method, or to different effects of CCK on interneurons and pyramidal cells (Miller et al, 1997).…”

“…CCK may inhibit pyramidal cells indirectly (Perez de la Mora et al, 1993) by increasing GABA release from interneurons (Miller & Lupica, 1994;Miller et al, 1997;Ferraro et al, 1999;Deng & Lei, 2006). Some discrepancies have been ascribed to dosage and application method, or to different effects of CCK on interneurons and pyramidal cells (Miller et al, 1997). The close association of CCK only with certain interneurons suggests that some of the reported discrepancies in CCK effects might reflect its actions on distinct classes of interneurons (Freund & Buzsaki, 1996).…”

Long-Term Repetitive Transcranial Magnetic Stimulation Increases the Expression of Brain-Derived Neurotrophic Factor and Cholecystokinin mRNA, but not Neuropeptide Tyrosine mRNA in Specific Areas of Rat Brain

“…The anatomical distribution of CCK-containing neurons in the hippocampus suggests that CCK is involved in both afferent and main efferent hippocampal pathways (Greenwood et al 1981), and a recent electrophysiological study has shown that CCK increases GABA release by inhibiting a resting K ϩ conductance in hippocampal interneurons, thus leading to an increased tonic inhibition of pyramidal neurons (Miller et al 1997).…”