AMPA receptor trafficking and learning

Abstract

In the last several 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 the AMPAR subunits will provide a more complete view of the mechanisms underlying multiple forms of learning.

Plexin-A4-dependent retrograde semaphorin 3A signalling regulates the dendritic localization of GluA2-containing AMPA receptors

“…The diversity in regulation of AMPA receptor subunit expression suggests that changes in the properties of AMPA receptors serve specific functions in a variety of brain areas. Altering the level of AMPA receptor activity has also been shown to play an important role in dendritic patterning and synapse maturation and formation 2,3 , and disturbance of AMPA receptor localization has been implicated in many psychiatric and neurological disorders 4 . The dendritic targeting of AMPA receptors is therefore a crucial part of dendritic development and function.…”

Two-stage AMPA receptor trafficking in classical conditioning and selective role for glutamate receptor subunit 4 (tGluA4) flop splice variant

“…Analysis of the expression pattern of tGluA4 mRNA and its alternatively spliced isoforms showed that tGluA4 flip and flop were the most abundantly expressed variants in the adult turtle brain, followed by tGluA4c flip and flop and a novel variant that is truncated at the C-terminal end, tGluA4trc1. Here, we were interested in determining whether these alternatively spliced isoforms of tGluA4 were differentially regulated in an in vitro model of classical conditioning (Keifer and Zheng 2010).…”

“…It is widely accepted that trafficking of AMPARs mediates rapid synaptic modifications underlying long-term potentiation (LTP), long-term depression, and learning (Derkach et al 2007;Keifer and Zheng 2010). Previously, we developed an in vitro brain stem preparation from the turtle, which generates a neural analog of eyeblink classical conditioning in which to study the cellular and molecular mechanisms of this form of learning [see Keifer et al (1995), Keifer and Houk (2011), and Keifer and Zheng (2010) for reviews].…”

“…Previously, we developed an in vitro brain stem preparation from the turtle, which generates a neural analog of eyeblink classical conditioning in which to study the cellular and molecular mechanisms of this form of learning [see Keifer et al (1995), Keifer and Houk (2011), and Keifer and Zheng (2010) for reviews]. Brain tissue from turtles is remarkably resistant to hypoxia, thereby allowing preservation of neural circuits in a dish for extensive periods, which can be subjected to pharmacological agents or incubation procedures.…”

“…In place of using a tone or airpuff for behaving animals, stimulation of the auditory nerve [the "tone" conditioned stimulus (CS)] is paired with the trigeminal nerve [the "airpuff" unconditioned stimulus (US)], which results in the gradual acquisition of burst discharge in the abducens nerve (controlling blinking in this species) in response to the CS that is representative of a neural correlate or "fictive" blink conditioned response (CR). Our previous studies of in vitro eyeblink classical conditioning suggested that acquisition of CRs is initiated by synaptic insertion of AMPARs containing tGluA1 subunits followed by the synthesis and synaptic incorporation of tGluA4 subunits (Keifer and Houk 2011;Keifer and Zheng 2010;Mokin et al 2007;Zheng and Keifer 2009). Since the sequence and domain structure of tGluA4 and its splice variants have now been characterized (Sabirzhanov and Keifer 2011), we developed a small-interfering RNA (siRNA) to selectively suppress expression of tGluA4 AMPAR subunits to directly test our two-stage model of AMPAR trafficking during in vitro classical conditioning.…”