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

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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.

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Jake F Watson

Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

For correspondence
jwatson@mrc-lmb.cam.ac.uk

Competing interests
The authors declare that no competing interests exist.
Hinze Ho

Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Ingo H Greger

Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

For correspondence
ig@mrc-lmb.cam.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7291-2581

Funding

Medical Research Council (MC_U105174197)

Jake F Watson
Hinze Ho
Ingo H Greger

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures were carried out under PPL 70/8135 in accordance with UK Home Office regulations. Experiments conducted in the UK are licensed under the UK Animals (Scientific Procedures) Act of 1986 following local ethical approval.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.