A role for calcium-permeable AMPA receptors in synaptic plasticity and learning.

Brian J Wiltgen,Nate Jacobs,Andrea Abdipranoto,Gordon A Royle,Susumu Tonegawa,Stephen F Heinemann,Thomas J O'Dell,Erin E Gray,Michael S Fanselow,Bryce Vissel,Faysal Saab,Nopporn Thangthaeng

doi:10.1371/journal.pone.0012818

Abstract

A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca2+-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice). Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP) that was independent of NMDARs and mediated by GluR2-lacking Ca2+-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca2+-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs.

Highlights

N-methyl-D-aspartate receptors (NMDARs) are necessary for most forms of synaptic plasticity in the CA1 region of the hippocampus [1]
Tissue selective deletion of GluR2 in c-KO mice To study the effects of Ca2+-permeable AMPARs on plasticity and memory we generated a line of mice in which GluR2 was deleted from pyramidal cells of the CA1 region of the hippocampus as described in Text S1
When compared to control mice, the largest loss of GluR2 from the dorsal hippocampus of GluR2-cKO mice was seen in the CA1 region while minor loss of GluR2 was observed in CA3

Summary

Introduction

N-methyl-D-aspartate receptors (NMDARs) are necessary for most forms of synaptic plasticity in the CA1 region of the hippocampus [1] Activation of these receptors is essential for spatial and contextual learning [2,3,4]. This surprising discovery was first described in the now-classic ‘upstairs/downstairs’ watermaze studies [5,6] In these experiments, rats were trained in a maze located on the lower floor of a laboratory and were subsequently able to acquire spatial information about a second upstairs maze even in the presence of the NMDAR antagonist APV. The same effect has been observed using contextual fear conditioning [7,8] These results imply that the NMDAR is not required for all forms of hippocampusdependent learning and suggest that alternative plasticity mechanisms become available following recent behavioral experience

Methods

Results

Conclusion