Limits...
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.

Show MeSH

Related in: MedlinePlus

Enhanced LTP and diminished LTD in the Tg-GluN2B2A(CT) mouse hippocampal slices.(A) A slight increase in LTP was seen in the 100 Hz stimulation protocol in the Tg-GluN2B2A(CT) mice. (B) When a 10 Hz stimulation was applied for 10 s a significant increase in LTP was seen in the Tg-GluN2B2A(CT) mice over their wild-type littermates. (C) LTD was diminished at 5 Hz stimulation in the Tg-GluN2B2A(CT) mice. (D) LTD was significantly diminished at the 3 Hz stimulation protocol. (E) At the 1 Hz stimulation, the Tg-GluN2B2A(CT) mice show significantly diminished LTD. (F) A summary plot of the % change in fEPSP slope versus the frequencies.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4216132&req=5

pone-0111865-g005: Enhanced LTP and diminished LTD in the Tg-GluN2B2A(CT) mouse hippocampal slices.(A) A slight increase in LTP was seen in the 100 Hz stimulation protocol in the Tg-GluN2B2A(CT) mice. (B) When a 10 Hz stimulation was applied for 10 s a significant increase in LTP was seen in the Tg-GluN2B2A(CT) mice over their wild-type littermates. (C) LTD was diminished at 5 Hz stimulation in the Tg-GluN2B2A(CT) mice. (D) LTD was significantly diminished at the 3 Hz stimulation protocol. (E) At the 1 Hz stimulation, the Tg-GluN2B2A(CT) mice show significantly diminished LTD. (F) A summary plot of the % change in fEPSP slope versus the frequencies.

Mentions: We then measured synaptic plasticity in the Tg-GluN2B2A(CT) CA1 slices. Overexpression of GluN2B2A(CT) significantly increased LTP versus their wild-type littermates at both 100 Hz (Figure 5B) (n = 13/6, 176.6±16.2%; Figure 5A) and 10 Hz (n = 5/3, 180.7±33.0%) frequencies. Interestingly, while 10 Hz response did not differ, LTD was also significantly impaired as compared to the wild-type hippocampal slices at 5 Hz (n = 4/2, 121.6±2.2%; Figure 5C), 3 Hz (n = 6/3, 103.6±13.8%; Figure 5D) and 1 Hz (n = 21/13, 114.2±6.6%; Figure 5E). This shows that although the Tg-GluN2B2A(CT) mice have significantly increased LTP, they also have significantly blocked 1 Hz and 3 Hz induced LTD (summarized in Figure 5F). This decrease in LTD in Tg-GluN2B2A(CT) slices was more similar to that seen in the Tg-GluN2A mice [23].


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 and diminished LTD in the Tg-GluN2B2A(CT) mouse hippocampal slices.(A) A slight increase in LTP was seen in the 100 Hz stimulation protocol in the Tg-GluN2B2A(CT) mice. (B) When a 10 Hz stimulation was applied for 10 s a significant increase in LTP was seen in the Tg-GluN2B2A(CT) mice over their wild-type littermates. (C) LTD was diminished at 5 Hz stimulation in the Tg-GluN2B2A(CT) mice. (D) LTD was significantly diminished at the 3 Hz stimulation protocol. (E) At the 1 Hz stimulation, the Tg-GluN2B2A(CT) mice show significantly diminished 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-g005: Enhanced LTP and diminished LTD in the Tg-GluN2B2A(CT) mouse hippocampal slices.(A) A slight increase in LTP was seen in the 100 Hz stimulation protocol in the Tg-GluN2B2A(CT) mice. (B) When a 10 Hz stimulation was applied for 10 s a significant increase in LTP was seen in the Tg-GluN2B2A(CT) mice over their wild-type littermates. (C) LTD was diminished at 5 Hz stimulation in the Tg-GluN2B2A(CT) mice. (D) LTD was significantly diminished at the 3 Hz stimulation protocol. (E) At the 1 Hz stimulation, the Tg-GluN2B2A(CT) mice show significantly diminished LTD. (F) A summary plot of the % change in fEPSP slope versus the frequencies.
Mentions: We then measured synaptic plasticity in the Tg-GluN2B2A(CT) CA1 slices. Overexpression of GluN2B2A(CT) significantly increased LTP versus their wild-type littermates at both 100 Hz (Figure 5B) (n = 13/6, 176.6±16.2%; Figure 5A) and 10 Hz (n = 5/3, 180.7±33.0%) frequencies. Interestingly, while 10 Hz response did not differ, LTD was also significantly impaired as compared to the wild-type hippocampal slices at 5 Hz (n = 4/2, 121.6±2.2%; Figure 5C), 3 Hz (n = 6/3, 103.6±13.8%; Figure 5D) and 1 Hz (n = 21/13, 114.2±6.6%; Figure 5E). This shows that although the Tg-GluN2B2A(CT) mice have significantly increased LTP, they also have significantly blocked 1 Hz and 3 Hz induced LTD (summarized in Figure 5F). This decrease in LTD in Tg-GluN2B2A(CT) slices was more similar to that seen in the Tg-GluN2A mice [23].

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