Understanding neuronal firing patterns and long-term potentiation (LTP) induction in studying learning, memory, and neurological diseases is critical. However, recently, despite the rapid advancement in neuroscience, we are still constrained by the experimental design, detection tools for exploring the mechanisms and pathways involved in LTP induction, and detection ability of neuronal action potentiation signals. This review will reiterate LTP-related electrophysiological recordings in the mammalian brain for nearly 50 years and explain how excitatory and inhibitory neural LTP results have been detected and described by field- and single-cell potentials, respectively. Furthermore, we focus on describing the classic model of LTP of inhibition and discuss the inhibitory neuron activity when excitatory neurons are activated to induce LTP. Finally, we propose recording excitatory and inhibitory neurons under the same experimental conditions by combining various electrophysiological technologies and novel design suggestions for future research. We discussed different types of synaptic plasticity, and the potential of astrocytes to induce LTP also deserves to be explored in the future.

Studies have demonstrated that NMDA receptors (NMDARs) mediate multiple forms of synaptic plasticity, including the induction of long-term potentiation (LTP) and long-term depression (LTD) ^[1] . The NR2A subunit is closely associated with LTP generation, which in turn induces learning and memory-related behaviors. This is evidenced by the significant memory deficit behaviors observed in NR2A knockout (NR2A -/-) mice ^[2] . Consequently, NR2A-KO animals serve as a valuable model for exploring memory encoding-related pathways and mechanisms, as well as for providing insights into drug-based treatments for memory disorders. Previous research has shown that cholecystokinin (CCK)-expressing neurons are abundantly present in the cerebral cortex and hippocampus, and they are involved in memory engram functions across multiple brain regions ^[3–6] . However, it remains unclear whether CCK administration can ameliorate the memory deficits exhibited by NR2A knockout animals in certain learning and memory behaviors. In this study, the novel object recognition task and auditory paired conditioned fear learning paradigm were employed to evaluate the role of CCK in rescuing memory deficits in NR2A knockout (NR2A-KO) mice. Our results revealed that NR2A-KO mice displayed significant impairments in both the novel object recognition paradigm and the conditioned fear behavioral paradigm. Notably, CCK administration improved the performance of these mice in these behavioral tasks. Concurrently, in vitro multichannel electrophysiological recordings were used to investigate the effects of CCK administration on LTP induction in the cortex and hippocampus. The findings indicated that CCK restored the loss of LTP in the cortex and hippocampus of NR2A-KO mice. Furthermore, fiber photometry was utilized to monitor calcium (Ca²⁺) activity in the auditory cortex (AC) in response to the auditory cue of paired conditioned fear. The results showed that CCK administration significantly enhanced calcium signal changes in the auditory cortex in response to the sound, suggesting that CCK treatment restored the memory of auditory paired conditioned fear in NR2A-KO mice to the level of wild-type mice. To verify the hypothesis that NR2A deficiency may affect CCK release from CCK neurons, building on our previous studies which showed that the projection of CCK neurons from the lateral entorhinal cortex (LEC) to the auditory cortex is involved in sound - cued associative memory ^{[7, 8]} , we employed a specific CCKBR sensor system combined with optogenetic viruses. We examined CCK release from CCK axon terminals projecting from the LEC to the AC following high - frequency stimulation in the presence of an NR2A antagonist. The results demonstrated that the NR2A antagonist blocked CCK release. Anatomically, a large number of NMDARs composed of NR2A subunits were found to be clustered at the CCK axon terminals projecting from the LEC to the AC, which structurally verified the possibility that NR2A might affect CCK release. Collectively, these results indicate that CCK administration not only compensates for the loss of LTP in NR2A-KO mice but also ameliorates certain memory deficit - like behaviors exhibited by these animals. Overall, our study suggests that CCK is a potential target for the treatment of memory deficits and clarifies its therapeutic role in the memory deficit behaviors displayed by NR2A-KO animals.