AMPA receptor anchoring at CA1 synapses is determined by an interplay of N-terminal domain and TARP γ8 interactions

Abstract

<jats:p>AMPA receptor (AMPAR) abundance and positioning at excitatory synapses regulates the strength of transmission. Changes in AMPAR localisation can enact synaptic plasticity, allowing long-term information storage, and is therefore tightly controlled. Multiple mechanisms regulating AMPAR synaptic anchoring have been described, but with limited coherence or comparison between reports, our understanding of this process is unclear. Here, combining synaptic recordings and super-resolution imaging, we compare the contributions of three AMPAR interaction domains controlling transmission at hippocampal CA1 synapses. We show that the AMPAR C-termini play only a modulatory role, whereas the extracellular N-terminal domain (NTD) and PDZ interactions of the auxiliary subunit TARP γ8 are both crucial, and each is sufficient to maintain transmission. Our data support a model in which γ8 accumulates AMPARs at the postsynaptic density, where the NTD further tunes their positioning. This interplay between cytosolic (γ8) and synaptic cleft (NTD) interactions provides versatility to regulate synaptic transmission and plasticity.</jats:p>

The amino-terminal domain of GluA1 mediates LTP maintenance via interaction with neuroplastin-65

“…In this study, we observed that overexpression of GluA1ΔATD fails to change the synaptic rectification index in CA1 neurons, suggesting that the ATD of GluA1 is necessary for synaptic targeting, in line with the results obtained in hippocampal slice cultures (20,21). More recently, a study presented on the bio-Rxiv shows that, although GluA1ΔATD fails to rescue synaptic function, it does target at the PSD, implying that it may have different nanocluster properties compared to GluA1 (32). We also observed that GluA1 A2-ATD can mediate synaptic transmission, consistent with a previous study in slice cultures (21), indicating that an ATD is required for GluA1 to efficiently localize at the postsynaptic membrane.…”

“…However, the domains of AMPARs that mediate the interactions with those proteins have not yet been determined. Our findings of the GluA1 ATD-interacting protein Np65 and the demonstration of this interaction in mediating LTP maintenance, together with recent works (20,21,32), highlight the importance of the ATDs in AMPARs' synaptic anchoring during LTP.…”

“…These observations suggest that AMPAR-mediated basal synaptic transmissions can be separated from LTP. The properties of nanoclusters formed by GluA1ΔATD but not GluA2ΔATD are changed compared to the full-length receptors at postsynaptic membrane (32). This observation implies that GluA2 ATD may not be involved in shaping the nanocluster property of the receptor; thus replacing with GluA2 ATD may fail to rescue the nanocluster properties of GluA1ΔATD assumably required for LTP.…”

Long-term potentiation is independent of the C-tail of the GluA1 AMPA receptor subunit

“…Based on recent findings from us and others ( Díaz-Alonso et al, 2017 ; Sheng et al, 2018 ; Watson et al, 2017 ; Watson et al, 2020 ; Zeng et al, 2019 ), we propose that constitutive and activity-dependent AMPAR trafficking has two essential requirements. On one hand, the multivalent interaction between transmembrane AMPAR regulatory proteins (TARPs) and PSD scaffolding proteins (the intracellular slot).…”

“…Based on recent findings from us and others (Diaz-Alonso et al, 2017;Sheng et al, 2018;Watson et al, 2017;Watson et al, 2020;Zeng et al, 2019), we propose that constitutive and activity-dependent AMPAR trafficking has two essential requirements.…”