AMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP \u03b38 interactions

Jake F Watson,Hinze Ho,Ingo H Greger,Alexandra Pinggera

doi:10.1038/s41467-021-25281-4

Abstract

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 from mouse hippocampal slices and super-resolution imaging in dissociated cultures, 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 (TARP γ8) and synaptic cleft (NTD) interactions provides versatility to regulate synaptic transmission and plasticity.

Highlights

AMPA receptor (AMPAR) abundance and positioning at excitatory synapses regulates the strength of transmission
We first set out to clarify the role of the GluA1 and GuA2 C-terminal domains (CTDs), using single-cell electroporation to express exogenous AMPAR subunits in hippocampal organotypic slices, and dual recordings from transfected and untransfected CA1 pyramidal neurons (Fig. 1c; see Supplementary Figure 1a for experimental details)[28]
We previously demonstrated that N-terminal domain (NTD) deletion from either GluA1 or GluA2 causes substantial deficits in synaptic transmission using this assay

Summary

Introduction

AMPA receptor (AMPAR) abundance and positioning at excitatory synapses regulates the strength of 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 (TARP γ8) and synaptic cleft (NTD) interactions provides versatility to regulate synaptic transmission and plasticity. These glutamate-gated cation channels are concentrated at the postsynaptic density (PSD) to mediate fast neuronal communication This receptor is central to synaptic plasticity: activity-dependent changes in the abundance of synaptic AMPARs can bi-directionally modify the strength of transmission, leading to either long-term potentiation (LTP) or long-term depression (LTD). TARPs bind to the major PSD components PSD-93/95, through PDZ (PSD-95, Dlg, ZO-1) interactions of their extreme C-terminus[17,18,19,20] This interaction is currently the best-characterised mechanism of AMPAR synaptic localisation

Methods

Results

Conclusion