Cholecystokinin from entorhinal cortex switches long-term potentiation in hippocampus

Our earlier studies showed that activation of cholecystokinin (CCK) neurons that originated from the entorhinal cortex (EC) induces long-term potentiation (LTP) and neuroplasticity in the auditory cortex. Lesions in EC or hippocampus will lead to memory deficits which have received intensive studies. In the present study, we found CCK peptide knockdown mice (CCK-CreER) showed severe deficits in spatial memory and hippocampal CA3-CA1 LTP formation induced by high-frequency (HF) electrical stimulation (ES) in vivo. We also found the same HF ES stimulation still induced CA3-CA1 LTP in CCK B-receptor knockout mice (CCKBR-KO), which exhibited normal spatial memory, while CCK A-receptor antagonist Devazepide totally blocked the LTP formation. We thus hypothesize that CCK released in respond to HF ES stimulation participates in LTP formation, the effect of which is mediated by CCKAR in hippocampus CA3-CA1 pathway. We further injected Cre-dependent ChR2-eYFP virus into either hippocampus or EC of CCK-Cre mice, and applied light stimulation in hippocampus. While HF light stimulation of CCK positive neuron in hippocampus, followed by low frequency (LF) ES stimulation of CA3, did not induce LTP, the same HF light manipulation of CCK positive projections from entorhinal cortex initiated LTP in CA3-CA1 pathway. Increased CCK concentration was also detected in hippocampus after HF light stimulation of these EC-originated terminals. We explain that HF stimulation of the EC originated CCK terminals induced CCK release in hippocampus, and LF ES stimulation of CA3 could induce LTP in the presence of CCK. The enhanced connectivity within hippocampus induced by this HF light-stimulation protocol was further supported in a spatial fear memory test, in which the CCK-Cre mice showed fear against both the footshock-given region and the HF light-paired region.