AMPA-Type Glutamate Receptor Conductance Changes and Plasticity: Still a Lot of Noise

Abstract

Twenty years ago, we reported from the Collingridge Lab that a single-channel conductance increase through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (AMPARs) could mediate one form of plasticity associated with long-term potentiation (LTP) in the hippocampus (Benke et al., Nature 395:793-797, 1998). Revealed through peak-scaled non-stationary fluctuation analysis (PS-NSFA, also known as noise analysis), this component of LTP could be exclusively mediated by direct increases in channel conductance or by increases in the number of high conductance synaptic AMPARs. Re-evaluation of our original data in the light of the molecular details regarding AMPARs, conductance changes and plasticity suggests that insertion of high-conductance GluA1 homomers can account for our initial findings. Any potential cost associated with manufacture or trafficking of new receptors could be mitigated if pre-existing synaptic AMPARs also undergo a modest conductance change. The literature suggests that the presence of high conductance AMPARs and/or GluA1 homomers confers an unstable synaptic state, suggesting state transitions. An experimental paradigm is proposed to differentiate these possibilities. Validation of this state diagram could provide insight into development, disease pathogenesis and treatment.

Keywords: AMPA receptor; Conductance; Glutamate; LTP; Phosphorylation; Rectification.

Figure 1.

A) Increases in AMPAR conductance and LTP. Conductance change (% increase) is plotted versus LTP (% increase in peak synaptic amplitude). Original data from[1] is plotted (circles) versus simulated data for multiple scenarios as described in the text. If conductance gradually increased, it would follow the red solid line (not biophysically plausible); if the number of GluA1/2 heteromers gradually increased, it would follow the black line. If the proportion of high conductance GluA1/2 heteromers increased from 0 to 100%, it would follow the short-dashed red line (supra-linear). If this increased more physiologically from 15% to 100%, it would follow the long-dashed red line (sub-linear). For Scenarios 3 (increased GluA1 homomers only, green) and 4/6 (increased GluA1 homomers and increased GluA1/2 conductance, blue or blue/cyan lines), greater percentage increases in GluA1 homomers are indicated at the points noted by the arrows. For Scenario 5 (increased GluA1/2 conductance and increased GluA1/2 heteromers, red/cyan) increased percentage of GluA1/2 heteromers are noted by the arrow. In scenarios 4 and 5 involving increased GluA1/2 conductance, the initial percentage of high conductance GluA1/2 was 15%. (B) Scenarios involving the insertion of calcium permeable AMPARs can be distinguished based on the rectification observed. Specifically, with increased plasticity, greater rectification will be observed depending on the relative insertion of GluA1 homomers.

Figure 2.

Proposed state diagram for hippocampal excitatory synapses. Each synapse may exist in one of these states at a given time; State 2 is the stable state and all states return to this state after plasticity inducing stimuli. States 1, 3 and 4 are potentially unstable, intermediate states that form after plasticity inducing stimuli. LTP stimuli eventually result in larger or more numerous synapses, while LTD stimuli eventually result in smaller or fewer synapses.