Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain

Abstract

AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and are selectively recruited during activity-dependent plasticity to increase synaptic strength. A prerequisite for faithful signal transmission is the positioning and clustering of AMPARs at postsynaptic sites. The mechanisms underlying this positioning have largely been ascribed to the receptor cytoplasmic C-termini and to AMPAR-associated auxiliary subunits, both interacting with the postsynaptic scaffold. Here, using mouse organotypic hippocampal slices, we show that the extracellular AMPAR N-terminal domain (NTD), which projects midway into the synaptic cleft, plays a fundamental role in this process. This highly sequence-diverse domain mediates synaptic anchoring in a subunit-selective manner. Receptors lacking the NTD exhibit increased mobility in synapses, depress synaptic transmission and are unable to sustain long-term potentiation (LTP). Thus, synaptic transmission and the expression of LTP are dependent upon an AMPAR anchoring mechanism that is driven by the NTD.DOI: http://dx.doi.org/10.7554/eLife.23024.001

L-Type Voltage-Gated Ca2+ Channels Regulate Synaptic Activity-Triggered Recycling Endosome Fusion in Neuronal Dendrites

“…The discrepancy between our antibody feeding approach and expressed SEP-GluA1 could be the result of a trafficking defect of the expressed receptor. Indeed, recent reports demonstrated that fusion of fluorescent proteins to the N terminus of GluA1 impairs its synaptic localization (Díaz-Alonso et al, 2017; Watson et al, 2017). Alternatively, the discrepancy could be the result of the greatly enhanced signal amplification obtained using antibody-based detection.…”

Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation

“…Direct trapping of the receptor through its N-terminal domain, which protrudes into the synaptic cleft ( Fig. 1), has been described as an additional synaptic anchoring mechanism (13,14). Here, we discuss such new mechanistic insights into AMPAR synaptic traffic and anchorage.…”

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca 2+ /CaMKII signaling

“…However, LTP is normal in S845A knock‐in mice (Lee et al, ). The discrepancy between these two papers can be explained by recent findings that implicate the N‐terminal domain of GluA1 as important for its postsynaptic targeting and show that adding a tag such as GFP as in Esteban et al () impairs this targeting (Diaz‐Alonso et al, ; Watson et al, ). Accordingly, GFP‐GluA1 requires S845 to augment postsynaptic targeting when this targeting is impaired, while S845 is less important for postsynaptic targeting of endogenous untagged GluA1.…”