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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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Diminished LTD at the 5 Hz range in the Tg-GluN2D2B(CT) mouse hippocampal slices.(A) No changes from the wild-type hippocampal slices were seen in the LTP of the Tg-GluN2D2B(CT) mouse hippocampal slices when a 100 Hz stimulation was applied. (B) When a 10 Hz stimulation was applied for 10 s there, again was no significant change in LTP observed in the Tg-GluN2D2B(CT) mice over their wild-type littermates. (C) LTD was diminished at 5 Hz stimulation in the Tg-GluN2D2B(CT) mice. (D) LTD was not significantly diminished at the 3 Hz stimulation protocol. (E) At the 1 Hz stimulation, the Tg-GluN2D2B(CT) mice showed no significant differences in LTD. (F) A summary plot of the % change in fEPSP slope versus the frequencies.
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pone-0111865-g006: Diminished LTD at the 5 Hz range in the Tg-GluN2D2B(CT) mouse hippocampal slices.(A) No changes from the wild-type hippocampal slices were seen in the LTP of the Tg-GluN2D2B(CT) mouse hippocampal slices when a 100 Hz stimulation was applied. (B) When a 10 Hz stimulation was applied for 10 s there, again was no significant change in LTP observed in the Tg-GluN2D2B(CT) mice over their wild-type littermates. (C) LTD was diminished at 5 Hz stimulation in the Tg-GluN2D2B(CT) mice. (D) LTD was not significantly diminished at the 3 Hz stimulation protocol. (E) At the 1 Hz stimulation, the Tg-GluN2D2B(CT) mice showed no significant differences in LTD. (F) A summary plot of the % change in fEPSP slope versus the frequencies.

Mentions: Finally, we examined the effects of GluN2D2B(CT) overexpression on CA1 plasticity. Since GluN2D has very weak magnesium dependency but much greater opening duration, it would lead to significantly more Ca2+ influx into the postsynaptic sites. We performed LTP and LTD measurements on the Tg-GluN2D2B(CT) hippocampal slices. Interestingly, we found no differences at either the 100 Hz (Figure 6A) (n = 8/6, 128±8.6%) or the 10 Hz frequency between the transgenic and control littermates (Figure 6B) (n = 6/3, 125.5±12.6%). However, at the 5 Hz frequency, a small, but significant LTP was observed in the transgenic slices, in comparison to the LTD induced in the slices from the control littermates (Figure 6C) (n = 5/4, 123.5±3.6%). However, there were no significant differences observed in LTD at 1 Hz stimulation (Figure 6E) (n = 8/4, 88.6±7.6%), 3 Hz (Figure 6D) (n = 7/5, 87.6±12.4%). The summary graphs show the overall similarities between the Tg-GluN2D2B(CT) mice and their wild-type counterparts, except in its 5 Hz frequency response (Figure 6F).


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)

Diminished LTD at the 5 Hz range in the Tg-GluN2D2B(CT) mouse hippocampal slices.(A) No changes from the wild-type hippocampal slices were seen in the LTP of the Tg-GluN2D2B(CT) mouse hippocampal slices when a 100 Hz stimulation was applied. (B) When a 10 Hz stimulation was applied for 10 s there, again was no significant change in LTP observed in the Tg-GluN2D2B(CT) mice over their wild-type littermates. (C) LTD was diminished at 5 Hz stimulation in the Tg-GluN2D2B(CT) mice. (D) LTD was not significantly diminished at the 3 Hz stimulation protocol. (E) At the 1 Hz stimulation, the Tg-GluN2D2B(CT) mice showed no significant differences in LTD. (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-g006: Diminished LTD at the 5 Hz range in the Tg-GluN2D2B(CT) mouse hippocampal slices.(A) No changes from the wild-type hippocampal slices were seen in the LTP of the Tg-GluN2D2B(CT) mouse hippocampal slices when a 100 Hz stimulation was applied. (B) When a 10 Hz stimulation was applied for 10 s there, again was no significant change in LTP observed in the Tg-GluN2D2B(CT) mice over their wild-type littermates. (C) LTD was diminished at 5 Hz stimulation in the Tg-GluN2D2B(CT) mice. (D) LTD was not significantly diminished at the 3 Hz stimulation protocol. (E) At the 1 Hz stimulation, the Tg-GluN2D2B(CT) mice showed no significant differences in LTD. (F) A summary plot of the % change in fEPSP slope versus the frequencies.
Mentions: Finally, we examined the effects of GluN2D2B(CT) overexpression on CA1 plasticity. Since GluN2D has very weak magnesium dependency but much greater opening duration, it would lead to significantly more Ca2+ influx into the postsynaptic sites. We performed LTP and LTD measurements on the Tg-GluN2D2B(CT) hippocampal slices. Interestingly, we found no differences at either the 100 Hz (Figure 6A) (n = 8/6, 128±8.6%) or the 10 Hz frequency between the transgenic and control littermates (Figure 6B) (n = 6/3, 125.5±12.6%). However, at the 5 Hz frequency, a small, but significant LTP was observed in the transgenic slices, in comparison to the LTD induced in the slices from the control littermates (Figure 6C) (n = 5/4, 123.5±3.6%). However, there were no significant differences observed in LTD at 1 Hz stimulation (Figure 6E) (n = 8/4, 88.6±7.6%), 3 Hz (Figure 6D) (n = 7/5, 87.6±12.4%). The summary graphs show the overall similarities between the Tg-GluN2D2B(CT) mice and their wild-type counterparts, except in its 5 Hz frequency response (Figure 6F).

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