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Cholecystokinin release triggered by NMDA receptors produces LTP and sound–sound associative memory

Significance Neuropeptides represent the most diverse family of neurotransmitters with a wide distribution in the rodent brain. Cholecystokinin (CCK) is an octapeptide present in very high concentrations in the cortex, where it is expressed in several circuits. It has emerged as a useful marker, for example as an interneuron subpopulation, but its function is still unclear. Here we show that CCK, via its CCKB receptor, is essential for high-frequency stimulation-induced long-term potentiation, and that release of CCK is controlled by NMDA receptors. Thus, CCK may play an important role in memory formation. Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK−/− mice lacked neocortical LTP and showed deficits in a cue–cue associative learning paradigm; and administration of CCK rescued associative learning deficits. High-frequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after low-frequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue–cue associative memory.