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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 long-term recognition memory of the Tg-GluN2A2B(CT) mice and impaired long-term memory on the Tg-GluN2D2B(CT) mice.(A) All groups of mice tested showed similar exploratory behavior in the training session. At the one hour retention session, the Tg-GluN2A, Tg-GluN2B and Tg-GluN2A2B(CT) mice showed similar interest in the novel object as the wild-type mice. Whereas the Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice show almost no preference for the novel object. At the 24 hour retention test, as expected the Tg-GluN2A and Tg-GluN2D2B(CT) mice showed no preference for the novel object. The Tg-GluN2B, The Tg-GluN2A2B(CT) and Tg-GluN2B2A(CT) mice all spent similar amounts of time with the novel object. *p = 0.003, **p = 7.7×10−5. (B) In addition to the enhancement seen in the Tg-GluN2A2B(CT) mice at the 24 hour recall session, these mice also showed enhanced recognition memory even at 3 days post-training over the wild-type mice. *p = 0.003. Whereas the GLUN2A2B(CT) mice show no preference for the novel object at 3 day or 7 days.
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pone-0111865-g002: Enhanced long-term recognition memory of the Tg-GluN2A2B(CT) mice and impaired long-term memory on the Tg-GluN2D2B(CT) mice.(A) All groups of mice tested showed similar exploratory behavior in the training session. At the one hour retention session, the Tg-GluN2A, Tg-GluN2B and Tg-GluN2A2B(CT) mice showed similar interest in the novel object as the wild-type mice. Whereas the Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice show almost no preference for the novel object. At the 24 hour retention test, as expected the Tg-GluN2A and Tg-GluN2D2B(CT) mice showed no preference for the novel object. The Tg-GluN2B, The Tg-GluN2A2B(CT) and Tg-GluN2B2A(CT) mice all spent similar amounts of time with the novel object. *p = 0.003, **p = 7.7×10−5. (B) In addition to the enhancement seen in the Tg-GluN2A2B(CT) mice at the 24 hour recall session, these mice also showed enhanced recognition memory even at 3 days post-training over the wild-type mice. *p = 0.003. Whereas the GLUN2A2B(CT) mice show no preference for the novel object at 3 day or 7 days.

Mentions: To investigate recognition memory functions in the transgenic mice, we tested the mice in a novel object recognition task for both short-term and long-term memory domains. During training, all transgenic mouse groups showed comparable exploratory behavior and motivation for the task, exploring each object to a similar degree (Figure 2A) (Wt: n = 10, 51.55±3.65%; Tg-GluN2A: n = 10, 50.15±0.932%; Tg-GluN2B: n = 9, 49.17±1.611%; Tg-GluN2A2B(CT): n  = 10, 51.85±3.192%; Tg-GluN2B2A(CT): n = 10, 49.85±0.932%; Tg-GluN2D2B(CT): n = 20, 52.52±2.097%).


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 long-term recognition memory of the Tg-GluN2A2B(CT) mice and impaired long-term memory on the Tg-GluN2D2B(CT) mice.(A) All groups of mice tested showed similar exploratory behavior in the training session. At the one hour retention session, the Tg-GluN2A, Tg-GluN2B and Tg-GluN2A2B(CT) mice showed similar interest in the novel object as the wild-type mice. Whereas the Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice show almost no preference for the novel object. At the 24 hour retention test, as expected the Tg-GluN2A and Tg-GluN2D2B(CT) mice showed no preference for the novel object. The Tg-GluN2B, The Tg-GluN2A2B(CT) and Tg-GluN2B2A(CT) mice all spent similar amounts of time with the novel object. *p = 0.003, **p = 7.7×10−5. (B) In addition to the enhancement seen in the Tg-GluN2A2B(CT) mice at the 24 hour recall session, these mice also showed enhanced recognition memory even at 3 days post-training over the wild-type mice. *p = 0.003. Whereas the GLUN2A2B(CT) mice show no preference for the novel object at 3 day or 7 days.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4216132&req=5

pone-0111865-g002: Enhanced long-term recognition memory of the Tg-GluN2A2B(CT) mice and impaired long-term memory on the Tg-GluN2D2B(CT) mice.(A) All groups of mice tested showed similar exploratory behavior in the training session. At the one hour retention session, the Tg-GluN2A, Tg-GluN2B and Tg-GluN2A2B(CT) mice showed similar interest in the novel object as the wild-type mice. Whereas the Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice show almost no preference for the novel object. At the 24 hour retention test, as expected the Tg-GluN2A and Tg-GluN2D2B(CT) mice showed no preference for the novel object. The Tg-GluN2B, The Tg-GluN2A2B(CT) and Tg-GluN2B2A(CT) mice all spent similar amounts of time with the novel object. *p = 0.003, **p = 7.7×10−5. (B) In addition to the enhancement seen in the Tg-GluN2A2B(CT) mice at the 24 hour recall session, these mice also showed enhanced recognition memory even at 3 days post-training over the wild-type mice. *p = 0.003. Whereas the GLUN2A2B(CT) mice show no preference for the novel object at 3 day or 7 days.
Mentions: To investigate recognition memory functions in the transgenic mice, we tested the mice in a novel object recognition task for both short-term and long-term memory domains. During training, all transgenic mouse groups showed comparable exploratory behavior and motivation for the task, exploring each object to a similar degree (Figure 2A) (Wt: n = 10, 51.55±3.65%; Tg-GluN2A: n = 10, 50.15±0.932%; Tg-GluN2B: n = 9, 49.17±1.611%; Tg-GluN2A2B(CT): n  = 10, 51.85±3.192%; Tg-GluN2B2A(CT): n = 10, 49.85±0.932%; Tg-GluN2D2B(CT): n = 20, 52.52±2.097%).

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