AMPA receptors & synaptic plasticity

In my second coursework essay, I discuss a number of recent studies which demonstrate that synaptic strengthening in different regions of the mammalian brain requires the incorporation of Ca²⁺-permeable GluR1-lacking AMPA receptors into the postsynaptic membrane of active or newly-potentiated synapses.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are glutamate-gated cation channels which mediate fast excitatory neurotransmission in the brain. AMPARs are homo- or heteromeric protein complexes, consisting of different combinations of GluR1-4 subunits. Each subunit has three transmembrane domains (M1, M2 and M3), and a fourth domain (M2) which forms a loop that enters the membrane and lines the pore of the channel.

The changes in synaptic efficacy underlying plasticity are known to involve membrane trafficking of AMPARs. For example, during N-methyl-D-aspartate (NMDA) receptor-mediated long-term potentiation (LTP) in the hippocampus, "silent" synapses are converted into active ones by the incorporation of AMPARs into the postsynaptic membrane by a two-step process. The receptors are first inserted by exocytosis into the membrane at extrasynaptic sites in the dendritic shaft; this is known to be dependent upon activation of Ca²⁺-calmodulin- dependent protein kinase II-alpha (CaMKII-alpha). They then diffuse laterally within the membrane to the dendritic spine, so that they are closely apposed to presynaptic neurotransmitter release sites. Conversely, during long-term depression, AMPARs are removed from the postsynaptic membrane by clathrin-mediated endocytosis (Malinov & Malenka, 2002).

It is known, from early studies in which recombinant AMPA receptor subtypes were expressed in Xenopus oocytes, that subunit composition determines the functional properties of AMPARs. The presence of the GluR2 subunit has significant effects on the properties of the channel, as posttranscriptional editing of the RNA causes a glutamine to arginine switch at the 'Q-R' site, such that receptors containing this subunit are impermeable to Ca²⁺.

AMPARs lacking the GluR2 subunit have unique electrophysiological properties. They are permeable to Ca²⁺, have high single channel conductance and are inwardly rectifying due to voltage-dependent block by endogenous polyamines. That is, they allow inward current to pass at negative membrane potentials, but only allow reduced outward current at positive potentials, and so do not have a linear current-voltage (I-V) relationship.

GluR2-lacking AMPARs are believed to constitute approximately 8% of the total number of receptors in the brain are GluR1 homomers; in the hippocampus, AMPARs are believed to be composed predominantly of GluR1-GluR2 or GluR2-GluR3 heteromers (Wenthold, et al, 1996).

Here I discuss several recent studies which demonstrate that synaptic strengthening in different regions of the brain involves a change in the subunit composition of AMPARs. The studies show that Ca²⁺-permeable AMPARs lacking the GluR2 subunit are incorporated into the postsynaptic membrane of active or newly-potentiated synapses, and that this occurs both in vitro and in vivo.