Possible Role Of NMDA Receptor Lateral Diffusion On Change Of Synaptic Plasticity

NMDA(N-methyl-D-aspartate)ionotropic glutamate receptors are ligand-activated cation channels concentrated in the postsynaptic density (PSD),which play critical roles in excitatory synaptic transmission and synaptic plasticity in the central nervous system.In the previous study, NMDA receptors(NMDARs)are not simply anchored in the PSD.In fact, NMDARs-mediated synaptic expression could change in a short time. Such as inserting or evacuating into synaptic membrane according to different neuronal activity.It was proposed a new mechanism for regulating synaptic function.Recent work suggests that the distributions of NMDARs are quite different.NR2A-containing NMDARs are targeted to synaptic sites,whereas NR2B-containing NMDARs may be targeted to extrasynaptic sites.The surface mobility of NMDARs depends on the NR2 subunit,with NR2B-containing NMDARs being more active than NR2A-containing ones.Moreover,the exchange of NMDARs between synaptic and extrasynaptic sites(lateral diffusion)is bidirectional and keeps a dynamic equilibrium under the normal condition.Lateral diffusion of glutamate receptors was proposed as a mechanism for regulating receptor numbers at synapses and affecting the synaptic functions,especially the efficiency of synaptic transmission. Howerver,a direct link between receptor lateral diffusion and change in synaptic function has not yet been established.In our study,we investigated how lateral diffusion affecting the synaptic transmission. Firstly,we demonstrated NMDA receptor lateral diffusion in CA1 neurons in hippocampal slices by using the open-channel blockers (+)-MK-801.As MK-801 is a use-dependent antagonist,we used it as a high-affinity label to tag synaptic NMDA receptors that opened in response to synaptically released glutamate.We found that spontaneous EPSCs or evoked EPSCs could gradually recovery after MK-801 completely block.After ruling out presynaptic and postsynaptic possibilities,we approved that the anomalous recovery is consistent with lateral diffusion of extrasynaptic receptors into synapse.Secondly,when using whole cell perforted-patch recordings,we found the decay kinetics of NMDARs-mediated EPSCs delayed.So it suggested that both the numbers and the compositions of synaptic NMDARs were changed after the recovery.We believe that extrasynaptic NMDARs,mostyly NR1/NR2B receptors,move laterally into synaptic sites.Finally,we studied the direct link between synaptic plasticity and receptors lateral diffusion.And we surprised to see the chang of the polarity of synaptic plasticity.After sEPSC complete recovery from MK-801 block,long-term potentiation(LTP)-producing protocol induced only long-term depression (LTD)instead of LTP.In contrast,when we used the competitive NMDAR blocker D,L-AP-5 after the complete recovery,no subsequent change on synaptic plasticity was observed.And also when using MK-801 to block NMDARs-mediated field excitatory postsynaptic potential(fEPSP),after using LTP-producing protocol(high frequency stimulate),we also observed the similar reverse phenomenon in fEPSP.To sum up,our data suggest a revised model of NMDAR trafficking wherein extrasynaptic NMDARs,mostly NR1/NR2B receptors,move laterally into synaptic sites when only synaptic NMDARs were blocked by MK-801,resulting in altered rule of synaptic modification.Thus,CA1 synaptic exhibit a novel form of metaplasticity in which the direction of synaptic modification can be reverted through subtype-special lateral diffusion of NMDA receptors. 属性不符...