Figure 2. Hypothetical model of synaptic plasticity regulation by NMDAR subunits.

A) A model to explain why the LTD/LTP induction threshold may differ between synapses with low (upper) and high (lower) NR2A/NR2B ratios. In these two synapses, the same frequencies of stimulation will produce different outcomes in synaptic plasticity, because of the difference in the relative level of activated PP2B and CaMKII, which stimulate LTD and LTP pathways, respectively. In synapses with a low NR2A/NR2B ratio (upper panels), large amounts of Ca²⁺ can enter the spine through NMDARs in response to synaptic stimulation and/or the calcium is more likely to activate CaMKII that is brought to the site of calcium entry via an interaction with the NR2B subunit. Therefore, modest synaptic activity is more likely to activate CaMKII and stimulate LTP pathways. With a low NR2A/NR2B ratio (upper panels), only very weak stimulation would activate calcineurin (PP2B) without sufficiently activating CaMKII, allowing LTD to be induced. Conversely, when NR2A-containing NMDARs dominate the postsynaptic membrane (lower panels), Ca²⁺ entry through NMDARs is limited and/or there is less CaMKII brought to the site of calcium entry via NR2B. This increases the stimulation requirements needed to activate CaMKII more than PP2B. Note that, in this model, both NR2A and NR2B-containing NMDARs are activated during the stimulation to induce LTD or LTP. The ratio of the two subunits receptors controls Ca²⁺ entry to spines or CaMKII sequestration, and hence the plasticity thresholds for LTD and LTP. Not depicted in this schematic is the fact that there is a level of postsynaptic activation below which synaptic plasticity is not induced, due to insufficient calcium entry.

B) Shematic depicting how NMDAR subunit regulates the properties of synaptic modification. The x-axis represents the level of the integrated postsynaptic response (which is related to the frequency of synaptic activation), while the y-axis represents the lasting change in synaptic strength. The curves are schematized from the data of (Kirkwood et al., 1996; Philpot et al., 2007; Philpot et al., 2003). When the synaptic NR2A/NR2B ratio is high, the LTD-LTP crossover point (θ_m) shifts to the right, decreasing the likelihood that LTP will occur. Conversely, when the synaptic NR2A/B ratio is low, θ_m slides to the left, favoring LTP over LTD.