Glutamate-Induced AMPA Receptor Desensitization Increases Their Mobility and Modulates Short-Term Plasticity through Unbinding from Stargazin

Abstract

Short-term plasticity of AMPAR currents during high-frequency stimulation depends not only on presynaptic transmitter release and postsynaptic AMPAR recovery from desensitization, but also on fast AMPAR diffusion. How AMPAR diffusion within the synapse regulates synaptic transmission on the millisecond scale remains mysterious. Using single-molecule tracking, we found that, upon glutamate binding, synaptic AMPAR diffuse faster. Using AMPAR stabilized in different conformational states by point mutations and pharmacology, we show that desensitized receptors bind less stargazin and are less stabilized at the synapse than receptors in opened or closed-resting states. AMPAR mobility-mediated regulation of short-term plasticity is abrogated when the glutamate-dependent loss in AMPAR-stargazin interaction is prevented. We propose that transition from the activated to the desensitized state leads to partial loss in AMPAR-stargazin interaction that increases AMPAR mobility and allows faster recovery from desensitization-mediated synaptic depression, without affecting the overall nano-organization of AMPAR in synapses.

Structural rearrangement of the intracellular domains during AMPA receptor activation

“…Therefore, potential activity-dependent structural rearrangement of the CTD may be of importance for regulation of AMPAR function. Furthermore, it is interesting to note that recent work has shown that pushing synaptic AMPARs into different conformational states influences their mobility (50). Activity-dependent interaction with the membrane or other proteins through the CTD could alter lateral diffusion, consistent with observed effects related to receptor desensitization.…”

“…1D). The positive allosteric modulator cyclothiazide (CTZ) and the competitive antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) were characterized independently at the functional GluA2-CFP/YFP constructs expressed in oocytes, along with determination of glutamate EC 50 (Fig. S2 and Table S2).…”

Synaptic AMPA receptor composition in development, plasticity and disease

“…Furthermore, dynamic AMPAR-TARP interactions have also been recently demonstrated to underlie by ability of AMAPRs to support high-frequency stimulation despite undergoing desentisiation 117 . A general consensus is that agonist binding reduces AMPAR affinity for Stargazin 98,117,118 (but see 119,120 ) allowing AMPARs to diffuse away from the synaptically-anchored Stargazin. This loss of desensitised AMPARs from the postsynaptic density frees up 'slots' for non-desensitised AMPARs, which maintains synaptic transmission 117 .…”

“…A large body of work has demonstrated that Stargazin, and other Type I TARPs (γ3, γ4 and γ8), can promote synaptic trapping of AMPARs through binding to PSD95 and, as discussed above, this interaction offers an attractive mechanism for how AMPARs are recruited and accumulated at the postsynapse during LTP 33, 98 . Furthermore, dynamic AMPAR-TARP interactions have also been recently demonstrated to underlie by ability of AMAPRs to support high-frequency stimulation despite undergoing desentisiation 117 . A general consensus is that agonist binding reduces AMPAR affinity for Stargazin 98,117,118 (but see 119,120 ) allowing AMPARs to diffuse away from the synaptically-anchored Stargazin.…”

“…A general consensus is that agonist binding reduces AMPAR affinity for Stargazin 98,117,118 (but see 119,120 ) allowing AMPARs to diffuse away from the synaptically-anchored Stargazin. This loss of desensitised AMPARs from the postsynaptic density frees up 'slots' for non-desensitised AMPARs, which maintains synaptic transmission 117 . Thus, in addition to their well-characterised role in determining the biophysical properties of AMPARs, TARPs also play a key role in synaptic AMPAR retention under basal and activity-dependent conditions.…”