Abstract
Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK-/- mice lacked neocortical LTP and showed deficits in a cue-cue associative learning paradigm; and administration of CCK rescued associative learning deficits. Highfrequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after lowfrequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue-cue associative memory.
Original language | English |
---|---|
Pages (from-to) | 6397-6406 |
Number of pages | 10 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 116 |
Issue number | 13 |
Early online date | 8 Mar 2019 |
DOIs | |
Publication status | Published - 26 Mar 2019 |
Scopus Subject Areas
- General
User-Defined Keywords
- Cholecystokinin
- Entorhinal cortex
- Long-term potentiation
- Memory
- NMDA receptor
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In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 13, 26.03.2019, p. 6397-6406.
Research output: Contribution to journal › Journal article › peer-review
TY - JOUR
T1 - Cholecystokinin release triggered by NMDA receptors produces LTP and sound-sound associative memory
AU - Chen, Xi
AU - Li, Xiao
AU - Wong, Yin Ting
AU - Zheng, Xuejiao
AU - Wang, Haitao
AU - Peng, Yujie
AU - Feng, Hemin
AU - Feng, Jingyu
AU - Baibado, Joewel T.
AU - Jesky, Robert
AU - Wang, Zhedi
AU - Xie, Hui
AU - Sun, Wenjian
AU - Zhang, Zicong
AU - Zhang, Xu
AU - He, Ling
AU - Zhang, Nan
AU - Zhang, Zhijian
AU - Tang, Peng
AU - Su, Junfeng
AU - Hu, Ling Li
AU - Liu, Qing
AU - He, Xiaobin
AU - Tan, Ailian
AU - Sun, Xia
AU - Li, Min
AU - Wong, Kelvin
AU - Wang, Xiaoyu
AU - Cheung, Hon Yeung
AU - Shum, Daisy Kwok Yan
AU - YUNG, Kin Lam
AU - Chan, Ying Shing
AU - Tortorella, Micky
AU - Guo, Yiping
AU - Xu, Fuqiang
AU - He, Jufang
N1 - Funding Information: 21. Hefft S, Jonas P (2005) Asynchronous GABA release generates long-lasting inhibition at a hippocampal interneuron-principal neuron synapse. Nat Neurosci 8:1319–1328. Materials and Methods Sprague-Dawley rats (only male, 8–12 wk) and C57/BL/6 (C57), Thy1-ChR2-eYFP (C57 background), CCK-Cre [Ccktm1.1(Cre)Zjh/J, C57 background; Jackson Laboratory], CCK-CreER [Ccktm2.1(Cre/ERT2)Zjh/J, C57 background, Jackson Laboratory] mice (both male and female, 8–12 wk) were used for in vivo extracellular recordings, in vitro cultured cell recordings, in vitro brain slice recordings, behavioral experiments, and immunohistochemistry. All experimental procedures were approved by the Animal Subjects Ethics SubCommittees of the City University of Hong Kong. Full methods can be found in SI Appendix, Materials and Methods. ACKNOWLEDGMENTS. We thank Guoping Feng (Massachusetts Institute of Technology) and Minmin Luo (Chinese Institute for Brain Research, Beijing) for sharing of some transgenic mouse lines for our preliminary study; Eduardo Lau for administrative and technical assistance; Tomas Hökfelt (Karolinska Institutet), Richard Salvi (New York University at Buffalo), Kuanhong Wang (NIH), Robert Oswald (Cornell University), Bin Hu (University of Calgary), and Jun Xia (Hong Kong University of Science and Technology) for critical comments; and Colin Blakemore (University of London), and Longnian Lin (East China Normal University) for insightful discussion. This work was supported by Hong Kong Research Grants Council, Guangdong Science and Technology Foundation, Natural Science Foundation of China, and Health and Medical Research Fund, Innovation and Technology Fund (Grants C1014-15G, MRP/ 101/17X, 31571096, 31371114, 31671102, 31200852, 31171060, 03141196, 01121906, 561313M, 11101215M, 11166316M, 11102417M, 11101818M, 2014B050505016). We also thank the following charitable foundations for their generous support: the Charlie Lee Charitable Foundation, the Fong Shu Fook Tong Foundation, and the Croucher Foundation. 22. Melzer S, et al. (2012) Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex. Science 335:1506–1510. 23. Whissell PD, Cajanding JD, Fogel N, Kim JC (2015) Comparative density of CCK-and PV-GABA cells within the cortex and hippocampus. Front Neuroanat 9:124. 24. Basu J, et al. (2016) Gating of hippocampal activity, plasticity, and memory by en-torhinal cortex long-range inhibition. Science 351:aaa5694. 25. Watakabe A, et al. (2012) Area-specific substratification of deep layer neurons in the rat cortex. J Comp Neurol 520:3553–3573. 26. Morino P, et al. (1994) Cholecystokinin in cortico-striatal neurons in the rat: Immu-nohistochemical studies at the light and electron microscopical level. Eur J Neurosci 6: 681–692. 27. Shakiryanova D, Tully A, Hewes RS, Deitcher DL, Levitan ES (2005) Activity-dependent liberation of synaptic neuropeptide vesicles. Nat Neurosci 8:173–178. 28. Verhage M, et al. (1991) Differential release of amino acids, neuropeptides, and catecholamines from isolated nerve terminals. Neuron 6:517–524. 29. Liu L, et al. (2004) Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304:1021–1024. 30. Lüscher C, Malenka RC (2012) NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Harb Perspect Biol 4:a005710. 31. Zamanillo D, et al. (1999) Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284:1805–1811. 32. Liu X, et al. (2012) Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484:381–385. 33. Ramirez S, et al. (2013) Creating a false memory in the hippocampus. Science 341: 387–391. 34. Andersen P, Sundberg SH, Sveen O, Wigström H (1977) Specific long-lasting poten-tiation of synaptic transmission in hippocampal slices. Nature 266:736–737. 35. Redondo RL, Morris RG (2011) Making memories last: The synaptic tagging and capture hypothesis. Nat Rev Neurosci 12:17–30. 36. Horinouchi Y, et al. (2004) Reduced anxious behavior in mice lacking the CCK2 re-ceptor gene. Eur Neuropsychopharmacol 14:157–161. 37. Frankland PW, Josselyn SA, Bradwejn J, Vaccarino FJ, Yeomans JS (1997) Activation of amygdala cholecystokininB receptors potentiates the acoustic startle response in the rat. J Neurosci 17:1838–1847. 38. Josselyn SA, et al. (1995) The CCKB antagonist, L-365,260, attenuates fear-potentiated startle. Peptides 16:1313–1315. 39. Chen X, et al. (2013) Encoding and retrieval of artificial visuoauditory memory traces in the auditory cortex requires the entorhinal cortex. J Neurosci 33:9963–9974. 40. Higuchi S, Miyashita Y (1996) Formation of mnemonic neuronal responses to visual paired associates in inferotemporal cortex is impaired by perirhinal and entorhinal lesions. Proc Natl Acad Sci USA 93:739–743. 41. Suthana N, et al. (2012) Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med 366:502–510. 42. Zhao C, Kao JP, Kanold PO (2009) Functional excitatory microcircuits in neonatal cortex connect thalamus and layer 4. J Neurosci 29:15479–15488. 43. Lee HK, Kameyama K, Huganir RL, Bear MF (1998) NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21:1151–1162. Funding Information: ACKNOWLEDGMENTS. We thank Guoping Feng (Massachusetts Institute of Technology) and Minmin Luo (Chinese Institute for Brain Research, Beijing) for sharing of some transgenic mouse lines for our preliminary study; Eduardo Lau for administrative and technical assistance; Tomas Hökfelt (Karolinska Institutet), Richard Salvi (New York University at Buffalo), Kuanhong Wang (NIH), Robert Oswald (Cornell University), Bin Hu (University of Calgary), and Jun Xia (Hong Kong University of Science and Technology) for critical comments; and Colin Blakemore (University of London), and Longnian Lin (East China Normal University) for insightful discussion. This work was supported by Hong Kong Research Grants Council, Guangdong Science and Technology Foundation, Natural Science Foundation of China, and Health and Medical Research Fund, Innovation and Technology Fund (Grants C1014-15G, MRP/ 101/17X, 31571096, 31371114, 31671102, 31200852, 31171060, 03141196, 01121906, 561313M, 11101215M, 11166316M, 11102417M, 11101818M, 2014B050505016). We also thank the following charitable foundations for their generous support: the Charlie Lee Charitable Foundation, the Fong Shu Fook Tong Foundation, and the Croucher Foundation.
PY - 2019/3/26
Y1 - 2019/3/26
N2 - Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK-/- mice lacked neocortical LTP and showed deficits in a cue-cue associative learning paradigm; and administration of CCK rescued associative learning deficits. Highfrequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after lowfrequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue-cue associative memory.
AB - Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK-/- mice lacked neocortical LTP and showed deficits in a cue-cue associative learning paradigm; and administration of CCK rescued associative learning deficits. Highfrequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after lowfrequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue-cue associative memory.
KW - Cholecystokinin
KW - Entorhinal cortex
KW - Long-term potentiation
KW - Memory
KW - NMDA receptor
UR - http://www.scopus.com/inward/record.url?scp=85063962818&partnerID=8YFLogxK
U2 - 10.1073/pnas.1816833116
DO - 10.1073/pnas.1816833116
M3 - Journal article
C2 - 30850520
AN - SCOPUS:85063962818
SN - 0027-8424
VL - 116
SP - 6397
EP - 6406
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 13
ER -