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Cholecystokinin release triggered by NMDA receptors produces LTP and sound-sound associative memory.

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. High-frequency 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 low-frequency 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.

SUBMITTER: Chen X

PROVIDER: S-EPMC6442640 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Cholecystokinin release triggered by NMDA receptors produces LTP and sound-sound associative memory.

Chen Xi X Li Xiao X Wong Yin Ting YT Zheng Xuejiao X Wang Haitao H Peng Yujie Y Feng Hemin H Feng Jingyu J Baibado Joewel T JT Jesky Robert R Wang Zhedi Z Xie Hui H Sun Wenjian W Zhang Zicong Z Zhang Xu X He Ling L Zhang Nan N Zhang Zhijian Z Tang Peng P Su Junfeng J Hu Ling-Li LL Liu Qing Q He Xiaobin X Tan Ailian A Sun Xia X Li Min M Wong Kelvin K Wang Xiaoyu X Cheung Hon-Yeung HY Shum Daisy Kwok-Yan DK Yung Ken K L KKL Chan Ying-Shing YS Tortorella Micky M Guo Yiping Y Xu Fuqiang F He Jufang J

Proceedings of the National Academy of Sciences of the United States of America 20190308 13

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<sup>-/-</sup> mice lacked neocortical LTP and showed deficits in a cue-cue associative learning paradigm; and administration of CCK rescued associative learning deficits. ...[more]

PMID: 30850520

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Project description:It is well established that selective activation of group I metabotropic glutamate (mGlu) receptors induces LTD of synaptic transmission at Schaffer collateral-CA1 synapses. In contrast, application of 1S,3R-ACPD, a mixed agonist at group I and group II mGlu receptors, induces LTP. Using whole-cell recordings from CA1 pyramidal cells and field recordings in the hippocampal CA1 region, we investigated the specific contribution of group II mGlu receptors to synaptic plasticity at Schaffer collateral-CA1 synapses in acute slices of adult mice. Pharmacological activation of group II mGlu receptors (mGlu2 and mGlu3 receptors) with the specific agonist LY354740 in conjunction with electrical stimulation induced postsynaptic LTP. This form of plasticity requires coactivation of NMDA receptors (NMDARs). Group II mGlu receptor activation led to PKC-dependent phosphorylation of the GluN1 subunit. We found that both synaptic and extrasynaptic NMDARs, which are differentially modulated by mGlu2 and mGlu3 receptors, contribute to LTP induction. Furthermore, LTP initiated by activation of group II mGlu receptors was not occluded by LTP induced with high-frequency trains of stimuli. However, the phosphorylation of NMDARs mediated by group II mGlu receptor activation led to a priming effect that enhanced subsequent high-frequency stimulation-induced LTP. These findings reveal a novel metaplastic mechanism through which group II mGlu receptors modulate synaptic function at the Schaffer collateral input to CA1 pyramidal cells, thereby lowering the threshold to induce plasticity.Significance statementThe group II metabotropic glutamate (mGlu II) receptors exert a well characterized action on presynaptic neuron terminals to modulate neurotransmitter release. Here, we show that these receptors also have postsynaptic effects in promoting the induction of synaptic plasticity. Using an electrophysiological approach including field and whole-cell patch recording in hippocampi from wild-type and transgenic mice, we show that activation of group II mGlu receptors enhances NMDA receptor (NMDAR)-mediated currents through PKC-dependent phosphorylation. This priming of NMDARs lowers the threshold for the induction of LTP of synaptic transmission. These findings may also provide new insights into the mechanisms through which drugs targeting mGlu II receptors alleviate hypoglutamatergic conditions such as those occurring in certain brain disorders such as schizophrenia.

Dataset Information

Cholecystokinin release triggered by NMDA receptors produces LTP and sound-sound associative memory.

Publications

Cholecystokinin release triggered by NMDA receptors produces LTP and sound-sound associative memory.

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