Entorhinohippocampal cholecystokinin modulates spatial learning by facilitating neuroplasticity of hippocampal CA3-CA1 synapses.

Junfeng Su, Fengwen Huang, Yu Tian, Ran Tian, Gao Qianqian, Stephen Temitayo Bello, Dingxaun Zeng, Peter Jendrichovsky, C Geoffrey Lau, Wenjun Xiong, Daiguan Yu, Micky Tortorella, Xi Chen, Jufang He

Cell reports 2023 Dec 26

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The hippocampus is broadly impacted by neuromodulations. However, how neuropeptides shape the function of the hippocampus and the related spatial learning and memory remains unclear. Here, we discover the crucial role of cholecystokinin (CCK) in heterosynaptic neuromodulation from the medial entorhinal cortex (MEC) to the hippocampus. Systematic knockout of the CCK gene impairs CA3-CA1 LTP and space-related performance. The MEC provides most of the CCK-positive neurons projecting to the hippocampal region, which potentiates CA3-CA1 long-term plasticity heterosynaptically in a frequency- and NMDA receptor (NMDAR)-dependent manner. Selective inhibition of MEC CCKergic neurons or downregulation of their CCK mRNA levels also impairs CA3-CA1 LTP formation and animals' performance in the water maze. This excitatory extrahippocampal projection releases CCK upon high-frequency excitation and is active during animal exploration. Our results reveal the critical role of entorhinal CCKergic projections in bridging intra- and extrahippocampal circuitry at electrophysiological and behavioral levels. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Junfeng Su, Fengwen Huang, Yu Tian, Ran Tian, Gao Qianqian, Stephen Temitayo Bello, Dingxaun Zeng, Peter Jendrichovsky, C Geoffrey Lau, Wenjun Xiong, Daiguan Yu, Micky Tortorella, Xi Chen, Jufang He. Entorhinohippocampal cholecystokinin modulates spatial learning by facilitating neuroplasticity of hippocampal CA3-CA1 synapses. Cell reports. 2023 Dec 26;42(12):113467