The circuit and neuro-cellular mechanisms that underlie learning and memory have occupied the interest of scientists for many decades. The most compelling and widely accepted theories of learning and memory hold that memories are stored at synapses. More specifically, memories are formed and stored by persistent increases and/or decreases in the amplitude of postsynaptic potentials evoked during synaptic transmission across excitatory glutamatergic synapses. The most widely studied of these changes in synaptic efficacy are long-term potentiation (LTP) and long-term depression (LTD). LTP is the persistent increase in the amplitude of excitatory postsynaptic potentials (EPSPs) that follows high-intensity activation of a glutamatergic synapse. Conversely, LTD is the persistent decrease in EPSPs that follows low-intensity activation of a glutamatergic synapse. The mechanisms that trigger these changes in synaptic efficacy are relatively well-understood [1
], but the mechanisms that express efficacy changes are less so.
In recent years, it has become clear that the trafficking of glutamate receptors into and out of the postsynaptic membrane plays a central role in the modulation of synaptic strength. Synapses can be potentiated or depressed in an activity-dependent manner through the postsynaptic insertion or internalization of the subtype of glutamate receptor known as the AMPAR (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors) [2
]. In most cases, this insertion and retrieval of AMPA receptors is triggered by calcium influx through another glutamate receptor subtype, the N-methyl-D-aspartate receptor (NMDAR). This has led to the concept that AMPARs are the receptors responsible for the expression of synaptic plasticity, while NMDARs are responsible for its control.
With regard to AMPAR-trafficking-mediated plasticity, increases and decreases in efficacy do not occur in a manner where the synapse simply slides up and down a continuum of strength [5
]. Rather synapses change their efficacy by jumping between discrete mechanistic states such that, along with strength changes, come changes in the rules governing receptor trafficking [6
]. We have previously identified five such synaptic plasticity states (active, silent, recently-silent, potentiated and depressed [6
]. The plastic state in which a synapse resides determines its potential for undergoing further synaptic plasticity. Such states may form part of the underlying mechanism for metaplasticity [7
]. Silent synapses, whose postsynaptic membranes contain NMDARs but no functional AMPARs, can be converted via an intermediate state (see below) to 'active' synapses, i.e. those containing both AMPARs and NMDARs, by AMPAR insertion into the postsynaptic membrane [2
]. Active synapses can be potentiated by a high-intensity stimulus, or depressed by low-frequency stimulation (LFS) of presynaptic axons [6
]. Prolonged LFS can even result in the silencing of a synaptic connection [6
]. However, even when present in the synaptic membrane, AMPARs are not always available for down-regulation. For example, recently-unsilenced synapses (i.e. those into which AMPARs have recently been inserted) cannot undergo synaptic depression in response to LFS [6
]. Thus, AMPAR regulation appears to be linked to the state of the synapse.
With regard to NMDARs, previous studies have suggested that, unlike the AMPAR, NMDARs are not subject to activity-dependent down-regulation during LTD [14
], and data have shown that potentiation of NMDAR-mediated responses does not occur during LTP [10
]. Recently however, it has been demonstrated that synaptic currents mediated by NMDARs can be regulated by synaptic activity or other factors, particularly in the negative direction [6
]. During synaptic depression at active synapses, NMDAR-mediated responses are suppressed in an NMDAR-dependent manner [6
]. This depression is accompanied by a decrease in postsynaptic NMDA sensitivity [6
]. Evidence of NMDAR endocytosis following application of exogenous agonists has been shown in heterologous and neuronal systems [21
], but it is not known whether this endocytic process can be induced by synaptic activity or whether it underlies activity-dependent synaptic plasticity. In addition, whether NMDARs, like the AMPARs, are subject to plastic state-dependent regulation is unknown. Because currents carried by the NMDAR control and trigger synaptic plasticity, a state-dependence of this receptor would determine the ability of the synapse to undergo further plasticity.