2. Academic Validation
  3. Entorhinohippocampal cholecystokinin modulates spatial learning by facilitating neuroplasticity of hippocampal CA3-CA1 synapses

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

  • Cell Rep. 2023 Nov 17;42(12):113467. doi: 10.1016/j.celrep.2023.113467.
Junfeng Su 1,  Fengwen Huang 2,  Yu Tian 3,  Ran Tian 3,  Gao Qianqian 3,  Stephen Temitayo Bello 4,  Dingxaun Zeng 3,  Peter Jendrichovsky 1,  C Geoffrey Lau 3,  Wenjun Xiong 5,  Daiguan Yu 6,  Micky Tortorella 7,  Xi Chen 8,  Jufang He 9
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, P.R. China.
  • 2 Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, P.R. China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, P.R. China. Electronic address: fwhuang2-c@my.cityu.edu.hk.
  • 3 Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, P.R. China.
  • 4 Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, P.R. China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, P.R. China.
  • 5 Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, P.R. China; City University of Hong Kong Shenzhen Research Institute, Shenzhen, P.R. China.
  • 6 Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China.
  • 7 Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, P.R. China; Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China.
  • 8 Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, P.R. China; City University of Hong Kong Shenzhen Research Institute, Shenzhen, P.R. China. Electronic address: xi.chen@cityu.edu.hk.
  • 9 Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, P.R. China; Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, P.R. China; City University of Hong Kong Shenzhen Research Institute, Shenzhen, P.R. China. Electronic address: jufanghe@cityu.edu.hk.
PMID: 37979171 DOI: 10.1016/j.celrep.2023.113467
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.

Keywords

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

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