A novel mechanism of hippocampal LTD involving muscarinic receptor-triggered interactions between AMPARs, GRIP and liprin-α

Bryony A Dickinson,Morgan Sheng,Ceri H Davies,Jihoon Jo,Kwangwook Cho,Heon Seok,Gi Hoon Son,Graham L Collingridge,Daniel J Whitcomb

doi:10.1186/1756-6606-2-18

Abstract

BackgroundLong-term depression (LTD) in the hippocampus can be induced by activation of different types of G-protein coupled receptors, in particular metabotropic glutamate receptors (mGluRs) and muscarinic acethycholine receptors (mAChRs). Since mGluRs and mAChRs activate the same G-proteins and isoforms of phospholipase C (PLC), it would be expected that these two forms of LTD utilise the same molecular mechanisms. However, we find a distinct mechanism of LTD involving GRIP and liprin-α.ResultsWhilst both forms of LTD require activation of tyrosine phosphatases and involve internalisation of AMPARs, they use different molecular interactions. Specifically, mAChR-LTD, but not mGluR-LTD, is blocked by peptides that inhibit the binding of GRIP to the AMPA receptor subunit GluA2 and the binding of GRIP to liprin-α. Thus, different receptors that utilise the same G-proteins can regulate AMPAR trafficking and synaptic efficacy via distinct molecular mechanisms.ConclusionOur results suggest that mAChR-LTD selectively involves interactions between GRIP and liprin-α. These data indicate a novel mechanism of synaptic plasticity in which activation of M1 receptors results in AMPAR endocytosis, via a mechanism involving interactions between GluA2, GRIP and liprin-α.

Highlights

Long-term depression (LTD) in the hippocampus can be induced by activation of different types of G-protein coupled receptors, in particular metabotropic glutamate receptors and muscarinic acethycholine receptors
To our surprise, we found that muscarinic acethycholine receptors (mAChRs)-LTD, but not metabotropic glutamate receptors (mGluRs)-LTD, involves interactions between GRIP and the AMPAR subunit GluA2 (IUPHAR nomenclature for subunits previously known as GluR2 or GluRB; see [24])
MAChR-LTD selectively involves interactions between GRIP and liprin-α. These data indicate a novel mechanism of synaptic plasticity in which activation of M1 receptors results in AMPAR endocytosis, via a mechanism involving interactions between GluA2, GRIP

Summary

Introduction

Long-term depression (LTD) in the hippocampus can be induced by activation of different types of G-protein coupled receptors, in particular metabotropic glutamate receptors (mGluRs) and muscarinic acethycholine receptors (mAChRs). It is extremely important to understand how ACh regulates synaptic function, that which is relevant to learning and memory. In this context, activation of mAChRs using carbachol (CCh) induces LTD of excitatory synaptic transmission in various brain regions, including the visual cortex [13,14,15], perirhinal cortex [16,17] and hippocampus [13,18,19,20,21]

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Discussion

Conclusion