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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

Selectively impaired emotional memory in the Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice.(A) The mice showed similar freezing responses immediately following the US. At the one hour retention session, the wild-type mice, the Tg-GluN2A, Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice all displayed similar freezing responses. Interestingly, both the Tg-GluN2B and the Tg-GluN2A2B(CT) mice spent significantly more time freezing. At the 24 hour recall session only the Tg-GluN2A mice demonstrated a diminished freezing response to the context in which the shock was delivered. *p = 0.005, **p = 0.0007. (B) The mice tested also showed similar pre-tone freezing responses and similar freezing at the one hour contextual recall. At the 24 hour recall session the Tg-GluN2A mice, the Tg-GluN2B2A(CT) mice and the Tg-GluN2D2B(CT) mice demonstrated significantly less freezing than the wild-type mice, whereas the Tg-GluN2A2B(CT) mice and Tg-GluN2B froze significantly more than the wild-type mice. *p<0.05, **p<1.0×10−6, *** p = 0.0007. (C) The Tg-GluN2A2B(CT) mice showed quicker fear extinction than the wild-type mice in the contextual fear extinction paradigm *p<0.05, **p<0.01. (D) The Tg-GluN2A2B(CT) mice showed quicker fear extinction to the CS than the wild-type mice in the contextual fear extinction paradigm *p<0.05, **p<0.01, ***p<0.001.
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pone-0111865-g003: Selectively impaired emotional memory in the Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice.(A) The mice showed similar freezing responses immediately following the US. At the one hour retention session, the wild-type mice, the Tg-GluN2A, Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice all displayed similar freezing responses. Interestingly, both the Tg-GluN2B and the Tg-GluN2A2B(CT) mice spent significantly more time freezing. At the 24 hour recall session only the Tg-GluN2A mice demonstrated a diminished freezing response to the context in which the shock was delivered. *p = 0.005, **p = 0.0007. (B) The mice tested also showed similar pre-tone freezing responses and similar freezing at the one hour contextual recall. At the 24 hour recall session the Tg-GluN2A mice, the Tg-GluN2B2A(CT) mice and the Tg-GluN2D2B(CT) mice demonstrated significantly less freezing than the wild-type mice, whereas the Tg-GluN2A2B(CT) mice and Tg-GluN2B froze significantly more than the wild-type mice. *p<0.05, **p<1.0×10−6, *** p = 0.0007. (C) The Tg-GluN2A2B(CT) mice showed quicker fear extinction than the wild-type mice in the contextual fear extinction paradigm *p<0.05, **p<0.01. (D) The Tg-GluN2A2B(CT) mice showed quicker fear extinction to the CS than the wild-type mice in the contextual fear extinction paradigm *p<0.05, **p<0.01, ***p<0.001.

Mentions: To investigate the emotional memory in the chimeric transgenic mice, we tested the mice in a contextual fear conditioning task. This type of fear conditioning is hippocampal-dependent and is often used to test short-term (one-hour) and long-term (one-day) time points. In the training session, all of the mice displayed similar freezing responses immediately after the shock was delivered (Figure 3A) (Wt: n = 13, 26.92±6.126%; Tg-GluN2A: n = 15, 25.75±3.146%; Tg-GluN2B: n = 30.00±3.637%; Tg-GluN2A2B(CT): n = 13, 34.61±5.155%; Tg-GluN2B2A(CT): n = 12, 25.00±7.812%; Tg-GluN2D2B(CT): n = 13, 23.18±7.045%). At the one-hour retention session, the wild-type mice, the Tg-GluN2A, Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice all displayed similar freezing responses when they were returned to the shock chamber in the absence of footshock (Wt: n = 13, 26.28±4.444%; Tg-GluN2A: n = 11, 32.22±4.789%; Tg-GluN2B2A(CT): n = 10, 25.28±6.286%; Tg-GluN2D2B(CT): n = 13, 37.51±5.415%). Interestingly, both the Tg-GluN2B and the Tg-GluN2A2B(CT) mice spent significantly more time freezing than the wild-type mice (Tg-GluN2B: n = 7, 45.06±2.823%; Tg-GluN2A2B(CTR): n = 13, 52.56±3.672%; F(6, 61)  = 4.98, p = 0.0007). This suggests that Tg- GluN2A2B(CT) mice, similar to Tg-GluN2B, exhibited enhanced 1-hr contextual fear memory.


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)

Selectively impaired emotional memory in the Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice.(A) The mice showed similar freezing responses immediately following the US. At the one hour retention session, the wild-type mice, the Tg-GluN2A, Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice all displayed similar freezing responses. Interestingly, both the Tg-GluN2B and the Tg-GluN2A2B(CT) mice spent significantly more time freezing. At the 24 hour recall session only the Tg-GluN2A mice demonstrated a diminished freezing response to the context in which the shock was delivered. *p = 0.005, **p = 0.0007. (B) The mice tested also showed similar pre-tone freezing responses and similar freezing at the one hour contextual recall. At the 24 hour recall session the Tg-GluN2A mice, the Tg-GluN2B2A(CT) mice and the Tg-GluN2D2B(CT) mice demonstrated significantly less freezing than the wild-type mice, whereas the Tg-GluN2A2B(CT) mice and Tg-GluN2B froze significantly more than the wild-type mice. *p<0.05, **p<1.0×10−6, *** p = 0.0007. (C) The Tg-GluN2A2B(CT) mice showed quicker fear extinction than the wild-type mice in the contextual fear extinction paradigm *p<0.05, **p<0.01. (D) The Tg-GluN2A2B(CT) mice showed quicker fear extinction to the CS than the wild-type mice in the contextual fear extinction paradigm *p<0.05, **p<0.01, ***p<0.001.
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pone-0111865-g003: Selectively impaired emotional memory in the Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice.(A) The mice showed similar freezing responses immediately following the US. At the one hour retention session, the wild-type mice, the Tg-GluN2A, Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice all displayed similar freezing responses. Interestingly, both the Tg-GluN2B and the Tg-GluN2A2B(CT) mice spent significantly more time freezing. At the 24 hour recall session only the Tg-GluN2A mice demonstrated a diminished freezing response to the context in which the shock was delivered. *p = 0.005, **p = 0.0007. (B) The mice tested also showed similar pre-tone freezing responses and similar freezing at the one hour contextual recall. At the 24 hour recall session the Tg-GluN2A mice, the Tg-GluN2B2A(CT) mice and the Tg-GluN2D2B(CT) mice demonstrated significantly less freezing than the wild-type mice, whereas the Tg-GluN2A2B(CT) mice and Tg-GluN2B froze significantly more than the wild-type mice. *p<0.05, **p<1.0×10−6, *** p = 0.0007. (C) The Tg-GluN2A2B(CT) mice showed quicker fear extinction than the wild-type mice in the contextual fear extinction paradigm *p<0.05, **p<0.01. (D) The Tg-GluN2A2B(CT) mice showed quicker fear extinction to the CS than the wild-type mice in the contextual fear extinction paradigm *p<0.05, **p<0.01, ***p<0.001.
Mentions: To investigate the emotional memory in the chimeric transgenic mice, we tested the mice in a contextual fear conditioning task. This type of fear conditioning is hippocampal-dependent and is often used to test short-term (one-hour) and long-term (one-day) time points. In the training session, all of the mice displayed similar freezing responses immediately after the shock was delivered (Figure 3A) (Wt: n = 13, 26.92±6.126%; Tg-GluN2A: n = 15, 25.75±3.146%; Tg-GluN2B: n = 30.00±3.637%; Tg-GluN2A2B(CT): n = 13, 34.61±5.155%; Tg-GluN2B2A(CT): n = 12, 25.00±7.812%; Tg-GluN2D2B(CT): n = 13, 23.18±7.045%). At the one-hour retention session, the wild-type mice, the Tg-GluN2A, Tg-GluN2B2A(CT) and Tg-GluN2D2B(CT) mice all displayed similar freezing responses when they were returned to the shock chamber in the absence of footshock (Wt: n = 13, 26.28±4.444%; Tg-GluN2A: n = 11, 32.22±4.789%; Tg-GluN2B2A(CT): n = 10, 25.28±6.286%; Tg-GluN2D2B(CT): n = 13, 37.51±5.415%). Interestingly, both the Tg-GluN2B and the Tg-GluN2A2B(CT) mice spent significantly more time freezing than the wild-type mice (Tg-GluN2B: n = 7, 45.06±2.823%; Tg-GluN2A2B(CTR): n = 13, 52.56±3.672%; F(6, 61)  = 4.98, p = 0.0007). This suggests that Tg- GluN2A2B(CT) mice, similar to Tg-GluN2B, exhibited enhanced 1-hr contextual fear memory.

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