Memory, plasticity and sleep - A role for calcium permeable AMPA receptors?

Jason D Shepherd

doi:10.3389/fnmol.2012.00049

Abstract

Experience shapes and molds the brain throughout life.These changes in neuronal circuits are produced by a myriad of molecular and cellular processes. Simplistically, circuits are modified through changes in neurotransmitter release or through neurotransmitter detection at synapses. The predominant neurotransmitter receptor in excitatory transmission, the AMPA-type glutamate receptor (AMPAR), is exquisitely sensitive to changes in experience and synaptic activity. These ion channels are usually impermeable to calcium, a property conferred by the GluA2 subunit. However, GluA2-lacking AMPARs are permeable to calcium and have recently been shown to play a unique role in synaptic function. In this review, I will describe new findings on the role of calcium permeable AMPARs (CP-AMPARs) in experience-dependent and synaptic plasticity.These studies suggest that CP-AMPARs play a prominent role in maintaining circuits in a labile state where further plasticity can occur, thus promoting metaplasticity. Moreover, the abnormal expression of CP-AMPARs has been implicated in drug addiction and memory disorders and thus may be a novel therapeutic target.

Highlights

AMPA-type glutamate receptors (AMPARs) consist of heterotetrameric complexes composed of subunits GluA1–4 (Hollmann and Heinemann, 1994)
As follow-up studies show, an mGluR1/5 agonist could reverse the abnormal accumulation of CP-AMPARs in the nucleus accumbens (NAc) (McCutcheon et al, 2011) and depotentiation of cortical NAc inputs by optogenetic stimulation in vivo restored normal transmission and abolished cocaine-induced locomotor sensitization (Pascoli et al, 2012). These results suggest that mGluR1/5 activation in ventral tegmental area (VTA) DA neurons may be a novel therapeutic target for addiction by decreasing the abnormal levels of CP-AMPARs
Clem and Huganir (2010) find that reconsolidation is blocked by mGluR1 antagonists and results in a decrease in AMPAR transmission that was previously potentiated by fear conditioning. This reversal in potentiation is due to the selective removal of CP-AMPARs, and the long-term depression (LTD) induction was greatly reduced in mice receiving the retrieval–extinction protocol, compared with those receiving extinction alone. These findings suggest that the presence of CP-AMPARs renders the memory trace labile and allows full memory erasure or modification but only in a constrained time window

Summary

MOLECULAR NEUROSCIENCE

The predominant neurotransmitter receptor in excitatory transmission, the AMPA-type glutamate receptor (AMPAR), is exquisitely sensitive to changes in experience and synaptic activity. These ion channels are usually impermeable to calcium, a property conferred by the GluA2 subunit. I will describe new findings on the role of calcium permeable AMPARs (CP-AMPARs) in experience-dependent and synaptic plasticity. These studies suggest that CP-AMPARs play a prominent role in maintaining circuits in a labile state where further plasticity can occur, promoting metaplasticity.

INTRODUCTION

CONCLUSION