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; Dingxuan Zeng; Peter Jendrichovsky; C. Geoffrey Lau; Wenjun Xiong; Daiguan Yu; Micky Tortorella; Xi Chen; Jufang He

doi:10.1016/j.celrep.2023.113467

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, Dingxuan Zeng, Peter Jendrichovsky, C. Geoffrey Lau, Wenjun Xiong, Daiguan Yu, Micky Tortorella, Xi Chen^*, Jufang He^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

10 Citations (Scopus)

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Abstract

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. © 2023 The Author(s).

Original language	English
Article number	113467
Journal	Cell Reports
Volume	42
Issue number	12
Online published	17 Nov 2023
DOIs	https://doi.org/10.1016/j.celrep.2023.113467
Publication status	Published - 26 Dec 2023

Funding

We have received critical reviews of the manuscript from Dr. Jack Feldman, Bin Hu, Sungchil Yang, Yuanyuan Liu, Yingxi Lin, Wing Ho Yung, and Jan Schnupp and critical feedback from Dr. Guoping Feng, Tomas Ho¨ kfelt, and Zhen-Ge Luo on the earlier versions of results. We also thank the following charitable foundations for their generous support (to J.H. and X.C.): the Wong Chun Hong Endowed Chair Professorship, the Charlie Lee Charitable Foundation, and the Fong Shu Fook Tong Foundation. This work was supported by the Hong Kong Research Grants Council, General Research Fund (GRF; 11103220to J.H., 11101521to J.H., 11103922to J.H., and 11101818to J.H.); the Hong Kong Research Grants Council, Collaborative Research Fund CRF; C1043-21Gto J.H.); the Hong Kong Research Grants Council, Theme-Based Research Scheme (TBRS; T13-605/18-W to J.H.); the Innovation and Technology Fund (ITF; GHP_075_19GD to J.H.); the Health and Medical Research Fund (HMRF; 09203656 to J.H. and 06172456 to X.C.); and the Guangdong Province Science and Technology Program (2020A0505140007)

Research Keywords

cholecystokinin
CP: Neuroscience
heterosynaptic plasticity
long-term potentiation
neuromodulation
spatial memory

Publisher's Copyright Statement

This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

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10.1016/j.celrep.2023.113467

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Su, J., Huang, F., Tian, Y., Tian, R., Qianqian, G., Bello, S. T., Zeng, D., Jendrichovsky, P., Lau, C. G., Xiong, W., Yu, D., Tortorella, M., Chen, X., & He, J. (2023). Entorhinohippocampal cholecystokinin modulates spatial learning by facilitating neuroplasticity of hippocampal CA3-CA1 synapses. Cell Reports, 42(12), Article 113467. https://doi.org/10.1016/j.celrep.2023.113467

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title = "Entorhinohippocampal cholecystokinin modulates spatial learning by facilitating neuroplasticity of hippocampal CA3-CA1 synapses",

abstract = "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{\textquoteright} 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. {\textcopyright} 2023 The Author(s).",

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author = "Junfeng Su and Fengwen Huang and Yu Tian and Ran Tian and Gao Qianqian and Bello, {Stephen Temitayo} and Dingxuan Zeng and Peter Jendrichovsky and Lau, {C. Geoffrey} and Wenjun Xiong and Daiguan Yu and Micky Tortorella and Xi Chen and Jufang He",

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T1 - Entorhinohippocampal cholecystokinin modulates spatial learning by facilitating neuroplasticity of hippocampal CA3-CA1 synapses

AU - Su, Junfeng

AU - Huang, Fengwen

AU - Tian, Yu

AU - Tian, Ran

AU - Qianqian, Gao

AU - Bello, Stephen Temitayo

AU - Zeng, Dingxuan

AU - Jendrichovsky, Peter

AU - Lau, C. Geoffrey

AU - Xiong, Wenjun

AU - Yu, Daiguan

AU - Tortorella, Micky

AU - Chen, Xi

AU - He, Jufang

PY - 2023/12/26

Y1 - 2023/12/26

N2 - 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. © 2023 The Author(s).

AB - 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. © 2023 The Author(s).

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KW - CP: Neuroscience

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ER -

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

Abstract

Funding

Research Keywords

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GRF: Heterosynaptic Neuroplasticity of the Ascending Inputs in the Auditory Thalamus by Corticothalamic Modulation

HMRF: CCK-B Receptor Antagonist for the Treatment of Depression in the Mouse Model

CRF: Synthesized CCK-B Receptor Agonists to Alleviate Anterograde Amnesia in Animal Models

Cite this

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

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

Access Output

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Permanent Link

Other Files and Links

Fingerprint

Projects

GRF: Heterosynaptic Neuroplasticity of the Ascending Inputs in the Auditory Thalamus by Corticothalamic Modulation

HMRF: CCK-B Receptor Antagonist for the Treatment of Depression in the Mouse Model

CRF: Synthesized CCK-B Receptor Agonists to Alleviate Anterograde Amnesia in Animal Models

Cite this