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Molecular and genetic determinants of the NMDA receptor for superior learning and memory functions.

Jacobs S, Cui Z, Feng R, Wang H, Wang D, Tsien JZ - PLoS ONE (2014)

Bottom Line: The opening-duration of the NMDA receptors implements Hebb's synaptic coincidence-detection and is long thought to be the rate-limiting factor underlying superior memory.Surprisingly, we found that the voltage-gated channel opening-durations through either GluN2A or GluN2B are sufficient and their temporal differences are marginal.In contrast, the C-terminal intracellular domain of the GluN2B subunit is necessary and sufficient for superior performances in long-term novel object recognition and cued fear memories and superior flexibility in fear extinction.

View Article: PubMed Central - PubMed

Affiliation: Brain and Behavior Discovery Institute and Department of Neurology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, United States of America.

ABSTRACT
The opening-duration of the NMDA receptors implements Hebb's synaptic coincidence-detection and is long thought to be the rate-limiting factor underlying superior memory. Here, we investigate the molecular and genetic determinants of the NMDA receptors by testing the "synaptic coincidence-detection time-duration" hypothesis vs. "GluN2B intracellular signaling domain" hypothesis. Accordingly, we generated a series of GluN2A, GluN2B, and GluN2D chimeric subunit transgenic mice in which C-terminal intracellular domains were systematically swapped and overexpressed in the forebrain excitatory neurons. The data presented in the present study supports the second hypothesis, the "GluN2B intracellular signaling domain" hypothesis. Surprisingly, we found that the voltage-gated channel opening-durations through either GluN2A or GluN2B are sufficient and their temporal differences are marginal. In contrast, the C-terminal intracellular domain of the GluN2B subunit is necessary and sufficient for superior performances in long-term novel object recognition and cued fear memories and superior flexibility in fear extinction. Intriguingly, memory enhancement correlates with enhanced long-term potentiation in the 10-100 Hz range while requiring intact long-term depression capacity at the 1-5 Hz range.

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Related in: MedlinePlus

Enhanced LTP in the Tg-GluN2A2B(CT) mouse hippocampal slices.A. Slightly enhanced LTP seen in the Tg-GluN2A2B(CT) mice with a 1 s 100 Hz stimulation. B. Significantly enhanced LTP was seen in the Tg-GluN2A2B(CT) mice when a 10 Hz stimulation was applied from 10 s. C–E. No changes in LTD were seen in the 5 Hz, 3 Hz, or 1 Hz stimulation protocols. F. A summary plot of the % change in fEPSP slope versus the frequencies.
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pone-0111865-g004: Enhanced LTP in the Tg-GluN2A2B(CT) mouse hippocampal slices.A. Slightly enhanced LTP seen in the Tg-GluN2A2B(CT) mice with a 1 s 100 Hz stimulation. B. Significantly enhanced LTP was seen in the Tg-GluN2A2B(CT) mice when a 10 Hz stimulation was applied from 10 s. C–E. No changes in LTD were seen in the 5 Hz, 3 Hz, or 1 Hz stimulation protocols. F. A summary plot of the % change in fEPSP slope versus the frequencies.

Mentions: We first performed LTP and LTD studies on the Tg-GluN2A2B(CT) mice. In the Tg-GluN2A2B(CT) mice, LTP can be readily induced by 100 Hz stimulation (Figure 4A) (Wt: n = 6/3(# of slices/# of animals), 135.2±7.6%; Tg-GluN2A2B(CT): n = 7/4, 146.5±8.7%). Interestingly, a significant increase in LTP was observed in the transgenic mice, compared to that of wild-type slices, in response to the 10 Hz frequency stimulation (Figure 4B) (Wt: n = 7/4, 103.2±13.0%; Tg-GluN2A2B(CT): n = 5/3, 150.1±17.0%). Additionally, a significant difference was further observed at 5 Hz stimulation (Figure 4C) (Wt: n = 4/3, 94.4±1.8%; Tg-GluN2A2B(CT): n = 6/4, 115.5±3.9%). There is no statistical difference at the 3 Hz stimulation (Figure 4D) (Wt: n = 7/3, 70.3±11.3%; Tg-GluN2A2B(CT): n = 5/3, 79.2±13.3%) or 1 Hz stimulation (Figure 4E) (Wt: n = 7/5, 82.4±1.6%; Tg-GluN2A2B(CT): n = 6/3, 95.4±15.6%). Overall, we found that the Tg-GluN2A2B(CT) mice show little difference in the LTD, except at 5 Hz, but show significantly enhanced LTP around at 10 Hz frequency (Figure 4F). These data indicate that the GluN2A2B(CT) overexpression produced synaptic changes that were more similar to that of GluN2B overexpression in the transgenic mice and rats [14], [16], [18].


Molecular and genetic determinants of the NMDA receptor for superior learning and memory functions.

Jacobs S, Cui Z, Feng R, Wang H, Wang D, Tsien JZ - PLoS ONE (2014)

Enhanced LTP in the Tg-GluN2A2B(CT) mouse hippocampal slices.A. Slightly enhanced LTP seen in the Tg-GluN2A2B(CT) mice with a 1 s 100 Hz stimulation. B. Significantly enhanced LTP was seen in the Tg-GluN2A2B(CT) mice when a 10 Hz stimulation was applied from 10 s. C–E. No changes in LTD were seen in the 5 Hz, 3 Hz, or 1 Hz stimulation protocols. F. A summary plot of the % change in fEPSP slope versus the frequencies.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216132&req=5

pone-0111865-g004: Enhanced LTP in the Tg-GluN2A2B(CT) mouse hippocampal slices.A. Slightly enhanced LTP seen in the Tg-GluN2A2B(CT) mice with a 1 s 100 Hz stimulation. B. Significantly enhanced LTP was seen in the Tg-GluN2A2B(CT) mice when a 10 Hz stimulation was applied from 10 s. C–E. No changes in LTD were seen in the 5 Hz, 3 Hz, or 1 Hz stimulation protocols. F. A summary plot of the % change in fEPSP slope versus the frequencies.
Mentions: We first performed LTP and LTD studies on the Tg-GluN2A2B(CT) mice. In the Tg-GluN2A2B(CT) mice, LTP can be readily induced by 100 Hz stimulation (Figure 4A) (Wt: n = 6/3(# of slices/# of animals), 135.2±7.6%; Tg-GluN2A2B(CT): n = 7/4, 146.5±8.7%). Interestingly, a significant increase in LTP was observed in the transgenic mice, compared to that of wild-type slices, in response to the 10 Hz frequency stimulation (Figure 4B) (Wt: n = 7/4, 103.2±13.0%; Tg-GluN2A2B(CT): n = 5/3, 150.1±17.0%). Additionally, a significant difference was further observed at 5 Hz stimulation (Figure 4C) (Wt: n = 4/3, 94.4±1.8%; Tg-GluN2A2B(CT): n = 6/4, 115.5±3.9%). There is no statistical difference at the 3 Hz stimulation (Figure 4D) (Wt: n = 7/3, 70.3±11.3%; Tg-GluN2A2B(CT): n = 5/3, 79.2±13.3%) or 1 Hz stimulation (Figure 4E) (Wt: n = 7/5, 82.4±1.6%; Tg-GluN2A2B(CT): n = 6/3, 95.4±15.6%). Overall, we found that the Tg-GluN2A2B(CT) mice show little difference in the LTD, except at 5 Hz, but show significantly enhanced LTP around at 10 Hz frequency (Figure 4F). These data indicate that the GluN2A2B(CT) overexpression produced synaptic changes that were more similar to that of GluN2B overexpression in the transgenic mice and rats [14], [16], [18].

Bottom Line: The opening-duration of the NMDA receptors implements Hebb's synaptic coincidence-detection and is long thought to be the rate-limiting factor underlying superior memory.Surprisingly, we found that the voltage-gated channel opening-durations through either GluN2A or GluN2B are sufficient and their temporal differences are marginal.In contrast, the C-terminal intracellular domain of the GluN2B subunit is necessary and sufficient for superior performances in long-term novel object recognition and cued fear memories and superior flexibility in fear extinction.

View Article: PubMed Central - PubMed

Affiliation: Brain and Behavior Discovery Institute and Department of Neurology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, United States of America.

ABSTRACT
The opening-duration of the NMDA receptors implements Hebb's synaptic coincidence-detection and is long thought to be the rate-limiting factor underlying superior memory. Here, we investigate the molecular and genetic determinants of the NMDA receptors by testing the "synaptic coincidence-detection time-duration" hypothesis vs. "GluN2B intracellular signaling domain" hypothesis. Accordingly, we generated a series of GluN2A, GluN2B, and GluN2D chimeric subunit transgenic mice in which C-terminal intracellular domains were systematically swapped and overexpressed in the forebrain excitatory neurons. The data presented in the present study supports the second hypothesis, the "GluN2B intracellular signaling domain" hypothesis. Surprisingly, we found that the voltage-gated channel opening-durations through either GluN2A or GluN2B are sufficient and their temporal differences are marginal. In contrast, the C-terminal intracellular domain of the GluN2B subunit is necessary and sufficient for superior performances in long-term novel object recognition and cued fear memories and superior flexibility in fear extinction. Intriguingly, memory enhancement correlates with enhanced long-term potentiation in the 10-100 Hz range while requiring intact long-term depression capacity at the 1-5 Hz range.

Show MeSH
Related in: MedlinePlus