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The effects of NR2 subunit-dependent NMDA receptor kinetics on synaptic transmission and CaMKII activation.

Santucci DM, Raghavachari S - PLoS Comput. Biol. (2008)

Bottom Line: Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation.They also support the conclusion that receptors containing either subtype can drive long-term potentiation.These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.

ABSTRACT
N-Methyl-D-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function.

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Effects of NR2 subtype on long-term potentiation.The synapse model was coupled to a model of postsynaptic potentiation, where CaMKII phosphorylation is the switch for LTP. (A–C) Sample traces of active CaMKII concentration for synapses with different numbers of each receptor type present (A,B) show that NR2A-containing receptors drove LTP more effectively, per receptor, than did NR2B-containing NMDARs (C). (D) The receptor open probability during the stimulation period was the main determinant of calcium influx. (E) The total time the receptors spent open during the stimulation was a good predictor of the probability a synapse would be potentiated. (F) Long-term potentiation via the triheteromeric receptors was also intermediate between NR2A- and NR2B-containing receptors but more similar to NR2A-containing NMDARs. (G) When glutamate release was paired with brief depolarizations of the postsynaptic cell at different temporal offsets, NR2A-containing receptors showed a much narrower temporal window for potentiation than did NR2B-containing receptors.
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pcbi-1000208-g007: Effects of NR2 subtype on long-term potentiation.The synapse model was coupled to a model of postsynaptic potentiation, where CaMKII phosphorylation is the switch for LTP. (A–C) Sample traces of active CaMKII concentration for synapses with different numbers of each receptor type present (A,B) show that NR2A-containing receptors drove LTP more effectively, per receptor, than did NR2B-containing NMDARs (C). (D) The receptor open probability during the stimulation period was the main determinant of calcium influx. (E) The total time the receptors spent open during the stimulation was a good predictor of the probability a synapse would be potentiated. (F) Long-term potentiation via the triheteromeric receptors was also intermediate between NR2A- and NR2B-containing receptors but more similar to NR2A-containing NMDARs. (G) When glutamate release was paired with brief depolarizations of the postsynaptic cell at different temporal offsets, NR2A-containing receptors showed a much narrower temporal window for potentiation than did NR2B-containing receptors.

Mentions: NR2A-containing NMDARs let in more calcium per receptor than NR2B-NMDARs (Figure 6C–F), and were more effective at driving LTP (Figure 7A–E). The probability of a synapse to potentiate after tetanic stimulation exceeded 99 percent with only 3 NR2A-NMDARs present, while the same required 9 NR2B-NMDARs (Figure 7C). Even if we set the number of receptors such that the total time open was the same, NR2A-NMDARs showed a greater rate of potentiation. This is because the time they spent open was mostly right after glutamate release, while the postsynaptic cell was depolarized. The total time open during the one second tetanic stimulation period, however, predicted the probability of potentiation well (Figure 7D and 7E). This quantity was about three times longer per receptor for NR2A-NMDARs than for NR2B-NMDARs (87.4 vs. 26.1 msec). We ran the simulation using our hypothetical kinetic scheme for triheteromeric receptors. Again, the behavior of the NR2A/B receptors was intermediate between the diheteromers but more similar to that of NR2A-NMDARs (Figure 7F). Reaching a 99 percent probability of potentiation required 4 receptors, and the time open during the tetanus also predicted the probability of potentiation well.


The effects of NR2 subunit-dependent NMDA receptor kinetics on synaptic transmission and CaMKII activation.

Santucci DM, Raghavachari S - PLoS Comput. Biol. (2008)

Effects of NR2 subtype on long-term potentiation.The synapse model was coupled to a model of postsynaptic potentiation, where CaMKII phosphorylation is the switch for LTP. (A–C) Sample traces of active CaMKII concentration for synapses with different numbers of each receptor type present (A,B) show that NR2A-containing receptors drove LTP more effectively, per receptor, than did NR2B-containing NMDARs (C). (D) The receptor open probability during the stimulation period was the main determinant of calcium influx. (E) The total time the receptors spent open during the stimulation was a good predictor of the probability a synapse would be potentiated. (F) Long-term potentiation via the triheteromeric receptors was also intermediate between NR2A- and NR2B-containing receptors but more similar to NR2A-containing NMDARs. (G) When glutamate release was paired with brief depolarizations of the postsynaptic cell at different temporal offsets, NR2A-containing receptors showed a much narrower temporal window for potentiation than did NR2B-containing receptors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2563690&req=5

pcbi-1000208-g007: Effects of NR2 subtype on long-term potentiation.The synapse model was coupled to a model of postsynaptic potentiation, where CaMKII phosphorylation is the switch for LTP. (A–C) Sample traces of active CaMKII concentration for synapses with different numbers of each receptor type present (A,B) show that NR2A-containing receptors drove LTP more effectively, per receptor, than did NR2B-containing NMDARs (C). (D) The receptor open probability during the stimulation period was the main determinant of calcium influx. (E) The total time the receptors spent open during the stimulation was a good predictor of the probability a synapse would be potentiated. (F) Long-term potentiation via the triheteromeric receptors was also intermediate between NR2A- and NR2B-containing receptors but more similar to NR2A-containing NMDARs. (G) When glutamate release was paired with brief depolarizations of the postsynaptic cell at different temporal offsets, NR2A-containing receptors showed a much narrower temporal window for potentiation than did NR2B-containing receptors.
Mentions: NR2A-containing NMDARs let in more calcium per receptor than NR2B-NMDARs (Figure 6C–F), and were more effective at driving LTP (Figure 7A–E). The probability of a synapse to potentiate after tetanic stimulation exceeded 99 percent with only 3 NR2A-NMDARs present, while the same required 9 NR2B-NMDARs (Figure 7C). Even if we set the number of receptors such that the total time open was the same, NR2A-NMDARs showed a greater rate of potentiation. This is because the time they spent open was mostly right after glutamate release, while the postsynaptic cell was depolarized. The total time open during the one second tetanic stimulation period, however, predicted the probability of potentiation well (Figure 7D and 7E). This quantity was about three times longer per receptor for NR2A-NMDARs than for NR2B-NMDARs (87.4 vs. 26.1 msec). We ran the simulation using our hypothetical kinetic scheme for triheteromeric receptors. Again, the behavior of the NR2A/B receptors was intermediate between the diheteromers but more similar to that of NR2A-NMDARs (Figure 7F). Reaching a 99 percent probability of potentiation required 4 receptors, and the time open during the tetanus also predicted the probability of potentiation well.

Bottom Line: Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation.They also support the conclusion that receptors containing either subtype can drive long-term potentiation.These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.

ABSTRACT
N-Methyl-D-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function.

Show MeSH
Related in: MedlinePlus