Cholecystokinin from the entorhinal cortex switches high-frequency-induced long-term potentiation in the hippocampus

Our earlier studies showed that activation of cholecystokinin (CCK) neurons that originated from the entorhinal cortex induce long-term potentiation and neuroplasticity in the auditory cortex. Lesions in the entorhinal cortex or the hippocampus will lead to memory deficits which have received intensive studies, including temporal, spatial, episodic memory, as well as associative fear conditioning. After AAV-DIO-ChR2-eYFP injected into the entorhinal cortex of the CCK-Cre mouse, we discovered that entorhinal CCK neurons project to hippocampus regions. We hypothesized that CCK is involved in the high-frequency stimulation induced long-term potentiation (LTP). High-frequency electrical stimulation (in Theta Burst format) in Schaffer collateral induced CA3-CA1 LTP on the wild-type mouse and CCK B-receptor knockout (CCK-BR KO) mouse, but not on the CCK peptide knockout mouse (CCK-KO). It was interesting to note that the hippocampus has many CCK A-receptors (ref. Allen Brain Atlas), which might be the reason of why CCK-BR-KO still has High-frequency stimulation induced LTP. The CCK-KO mouse exhibited severe fear memory and spatial memory deficit. On the CCK-Cre mouse with injection of AAV-DIO-ChR2-eYFP in the entorhinal cortex, we induced CA3-CA1 LTP with Low-frequency electrical stimulation on Schaffer collateral after High-frequency laser stimulation of the projection terminals originated from the entorhinal cortex. We explain that High-frequency stimulation of the CCK terminals induced CCK release in hippocampus, and LF stimulation could induce LTP in the presence of CCK.