Extrasynaptic NMDA receptor dependent long-term potentiation of hippocampal CA1 pyramidal neurons

Qian Yang,Zhen-Hua Liao,Jian-Hong Luo,Sheng-Tian Li,Jiejie Wang,Dandan Liu,Weidong Li,Jue-Gang Ju,Geng Zhu,Naijian Chao,Yue Zhang,Yi-Xin Xiao

doi:10.1038/s41598-017-03287-7

Qian Yang, Zhen-Hua Liao + Show 10 more

Open Access

https://doi.org/10.1038/s41598-017-03287-7

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Abstract

In the adult mouse hippocampus, NMDA receptors (NMDARs) of CA1 neurons play an important role in the synaptic plasticity. The location of NMDARs can determine their roles in the induction of long-term potentiation (LTP). However, the extrasynaptic NMDARs (ES-NMDARs) dependent LTP haven’t been reported. Here, through the use of a 5-Hz stimulation and MK-801 (an irreversible antagonist of NMDARs) in the CA1 neurons of adult mice hippocampal slices, synaptic NMDARs were selectively inhibited and NMDAR-mediated excitatory postsynaptic currents were not recovered. We found that a robust LTP was induced by 3-train 100-Hz stimulation when the synaptic NMDARs and extrasynaptic NR2B containing NMDARs were blocked, but not in the any of the following conditions: blocking of all NMDARs (synaptic and extrasynaptic), blocking of the synaptic NMDARs, and blocking of the synaptic NMDARs and extrasynaptic NR2A-containing NMDARs. The results indicate that this LTP is ES-NMDARs dependent, and NR2B-containing ES-NMDARs modulates the threshold of LTP induction.

Highlights

The role of NMDA receptors (NMDARs) in the induction of long-term potentiation (LTP) in the hippocampus is well established[1,2,3,4]
After the MK-801 application and 5-Hz stimulation, the S-NMDARs were blocked and the amplitude of the NMDA-EPSCs recorded through whole-cell patch-clamp was almost zero
Voltage-clamp recordings demonstrated that the single test stimuli could not induce any NMDA-EPSCs in 30 min after the washout of MK-801, indicating that most of the active S-NMDARs in the same input pathway were irreversibly blocked (Fig. 1)

Summary

Introduction

The role of NMDA receptors (NMDARs) in the induction of long-term potentiation (LTP) in the hippocampus is well established[1,2,3,4]. The different subtypes of NMDARs play varied roles in LTP induction, and many studies have especially focused on the NR2A and NR2B subunits. The role of NR2B in LTP is unclear It reported that the inhibition of NR2B by Ro25-6981 or ifenprodil had no effect on LTP induction in the adult hippocampal CA1 synapse[11]. That the postsynaptic location of NMDARs is critical to synaptic plasticity[13,14,15] This makes the roles of NR2A and NR2B subunits in synaptic plasticity more complex, and additional studies are warranted. It has been demonstrated that S-NMDARs play an important role in LTP, but whether the activation or inhibition of ES-NMDARs influences LTP remains unknown. By combining a short train of 5-Hz stimulation and an irreversible use-dependent NMDAR antagonist (MK-801), we succeeded in selectively inhibiting S-NMDARs in mature hippocampal slices and found a new kind of LTP which was induced when S-NMDARs and NR2B-containing ES-NMDARs were inhibited

Methods

Results

Conclusion