AMPA receptor trafficking and learning

Abstract

In the last few years it has become clear that AMPA-type glutamate neurotransmitter receptors are rapidly transported into and out of synapses to strengthen or weaken their function. The remarkable dynamics of AMPA receptor (AMPAR) synaptic localization provides a compelling mechanism for understanding the cellular basis of learning and memory, as well as disease states involving cognitive dysfunction. Here, we summarize the evidence for AMPAR trafficking as a mechanism underlying a variety of learned responses derived from both behavioral and cellular studies. Evidence is also reviewed supporting synaptic dysfunction related to impaired AMPAR trafficking as a mechanism underlying learning and memory deficits in Alzheimer's disease. We conclude that emerging data support the concept of multistage AMPAR trafficking during learning and that a broad approach to include examination of all of the AMPAR subunits will provide a more complete view of the mechanisms underlying multiple forms of learning.

Figure 1

Primary findings of spatial learning studies on GluR1^−/− mice. Spatial working memory deficits in GluR1^−/− mice can be demonstrated using a T-maze (left) in which mice are forced to run down one arm (sample run) and are subsequently required to choose the alternate arm to obtain a reward (choice run). This short-term memory task requires the subject to remember the previously unsampled arm, which changes unpredictably, on a trial-by-trial basis. GluR1^−/− mice show profound performance deficits in this task indicating it is GluR1-dependent. In these mice, GluR1 AMPAR subunits are not available to be inserted into synaptic sites. In contrast, the same mice perform a spatial reference memory task (right) as well as wildtypes. This form of long-term memory can be examined using the Morris water maze in which mice gradually learn to find a submerged platform in an opaque pool of water based on spatial cues. The high level of performance of GluR1^−/− mice on these types of tasks indicates they are likely mediated, at least in part, by synaptic trafficking of AMPARs containing GluR2-4 subunits. Both forms of learning require the hippocampus and are NMDAR-dependent. N, NMDARs; A, AMPARs.

Figure 2

Summary of in vitro eyeblink classical conditioning. (A) Abducens nerve recordings showing burst discharge characteristic of a UR alone (top record) taken at the beginning of paired stimulation and an example of a CR (lower record, arrow) followed by a UR taken later in conditioning. (B) A typical acquisition curve for in vitro conditioning (Cond) showing few CRs during the first pairing session and significant acquisition of CRs by the second session. This phase of rapid acquisition is followed by an asymptotic phase of CR expression during subsequent pairing sessions. Unpaired stimuli during pseudoconditioning (Ps) results in no CRs. (C) Summary of the signaling pathways and AMPAR trafficking proposed for in vitro eyeblink classical conditioning. The early NMDAR-independent phase of conditioning is thought to occur during the first pairing session, before CRs are expressed, and involves synaptic incorporation of existing GluR1 AMPAR subunits to unsilence auditory nerve synapses. The later NMDAR-dependent phase occurs during the second pairing session and involves NMDAR-mediated synthesis and synaptic insertion of GluR4-containing AMPARs that are hypothesized to underlie the CRs. See text for details. GluR1, yellow ovals; GluR4, green ovals; pink rectangles, NMDARs.