AMPA Receptors and Synaptic Plasticity

AMPA receptors are responsible for the bulk of fast excitatory synaptic transmission throughout the CNS and their modulation is the ultimate mechanism that underlies much of the plasticity of excitatory transmission that is expressed in the brain.

Long -Term Potentiation (LTP)

LTP is expressed as an increase in the synaptic response to a baseline stimulus. This increase is usually seen following tetanic stimulation (a burst of high frequency stimuli, usually at 100 Hz). As AMPA receptors are the main driver of excitatory transmission, this usually equates to an increase in the functional response of AMPA receptors in the synapse, though pre-synaptic mechanisms involve increased release of glutamate.

Mechanisms of LTPFour different mechanisms of LTP can be found in juvenile rodents demonstrating that LTP can be expressed by either increased neurotransmitter release, increased receptor number, increased coductance or any combination
Increasing the post-synaptic response to a stimulus can be achieved either through increasing the number of AMPA receptors at the post-synaptic surface or by increasing the single channel conductance of the receptors expressed. Using non-stationary fluctuation analysis, we showed that LTP in the CA1 region of the hippocampus could be accounted for by these two mechanisms ( Benke et al 1998). However, it has become clear that the situation is somewhat more complex. Indeed, these two apparently different mechanisms to increase AMPA receptor response can be combined, with the insertion of Ca 2+ permeable AMPA receptors (those lacking the GluA2 subunit) that have a high conductance. Thus the overall conductance of a synapse may be increased by receptor insertion rather than modification of existing receptors ( Terashima et al 2004), and that this insertion is under the control of PICK1. During LTP, this form of synaptic modification is transient, with the GluA2-lacking receptors being replaced over time ( Plant et al 2006) with those incorporating the GluA2 subunit.

Long-term Depression (LTD)

pHluorin-GluA2Visualisation of AMPA receptor internalisation in 'LTD'.The N-terminus GluR2 subunit was tagged with ecliptic-pHluorin and used to visualise cell surface expression in cultured hippocampal neurones. Blue circles represent diffuse fluorescence indicative of extra-synaptic AMPA receptors; red circles represent punctate fluorescence, indicative of synaptic AMPA receptors. On NMDA application, there is a transient loss of extra-synaptic receptors followed by a loss of synaptic receptors. Mounted on the internet with permission of Ashby et al, 2004 J. Neurosci. 24; 5172-5176 © Society for Neuroscience
While there are many different processes that give rise to LTD of glutamatergic transmission, all seem to converge on a single mechanism of expression, namely the removal of AMPA receptors from the post-synaptic membrane.  Work at the MRC Centre has previously shown that such removal occurs outside of the dendritic spine. The loss of surface-expressed GluA2-containing receptors was visualised directly using a pHluorin-tagged GluA2 subunit during a form of LTD induced by exposure to NMDA in cultured hippocampal neurones ( Ashby et al, 2004). There is a transient loss of extra-synaptic receptors that precedes the loss of synaptically localised receptors, suggesting that AMPA receptors are not internalised directly from the synapse, but from the surrounding membrane. Synaptic receptors could then be translocated out from the synapse. These two processes could combine to produce the long-lasting loss of synaptic AMPA receptors that is thought to be the molecular basis of LTD.

AMPAR Trafficking

AMPA receptor C-termini contain binding sites for a large number of interacting proteins that play crucial roles in AMPA receptor trafficking and targeting to the correct location. This in turn is critical for the modulation of AMP receptor function in synaptic plasticity. For instance, the PDZ binding site on the GluA2 receptor subunit binds PICK1 and GRIP. GRIP is involved in holding GluA2-containing receptor complexes in place, while PICK1 is more involved in the movement of such receptors into and out of the plasma membrane. The equilibrium in the interaction of the GluA2 C-terminus with these two proteins is critical in determining how GluA2-containing AMPA receptors are handled.

Two further critical binding sites on the GluA2 subunit C-terminus are those for NSF and AP2, which overlap with each other. NSF is involved in the delivery of GluA2 containing AMPA receptors to the cell surface while AP2 is well known as part of the complex responsible for clathrin-mediated internalisation. Thus these two proteins are also involved in opposite processes; activation of NMDA receptors results in the activation of a Ca2+ sensing protein, hippocalcin, which in turn binds to AP2. This protein is thus targeted to GluA2 subunit and, competing with NSF for the binding domain and resulting in AMPA receptor internalisation. Indeed, the hippocalcin/AP2/GluA2 interaction sequence was shown to be involved in NMDAR-mediated LTD in the hippocampus (Palmer et al 2005). More recently, another Ca2+ sensing protein, NCS-1, was shown to be involved in mGlu receptor-mediated LTD in the perirhinal cortex, again via AMPA receptor internalisation (Jo et al 2008).