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

Summary of LTP, LTD and behavioral tasks results.The Tg-NRA2B(CT) mice had enhanced LTP, as well as enhanced long-term recognition memory and contextual fear conditioning. The Tg-GluN2B2A(CT) mice have significantly impaired LTD resulting in impaired short-term recognition memory and impaired long-term cued fear conditioning. The Tg-GluN2D2B(CT) mice have decreased LTD at 5 Hz and impaired long-term recognition memory and long-term cued fear memory.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111865-g007: Summary of LTP, LTD and behavioral tasks results.The Tg-NRA2B(CT) mice had enhanced LTP, as well as enhanced long-term recognition memory and contextual fear conditioning. The Tg-GluN2B2A(CT) mice have significantly impaired LTD resulting in impaired short-term recognition memory and impaired long-term cued fear conditioning. The Tg-GluN2D2B(CT) mice have decreased LTD at 5 Hz and impaired long-term recognition memory and long-term cued fear memory.

Mentions: Interestingly our present study has provided clear evidence supporting the second hypothesis that is known as the “GluN2B intracellular domain” hypothesis [4], [33]. Two separate pieces of evidence came from our behavioral analyses of the Tg-GluN2B2A(CT) and Tg-GluN2A2B(CT) transgenic mice. First, we found that the Tg-GluN2A2B(CT) mice had enhanced object recognition memory and emotional memory. These phenotypes are very similar to those of the Tg-GluN2B mice (and also Tg-GluN2B rats) (Figure 7). On the contrary, when the C-terminal domain of the GluN2B subunit was replaced by that of the GluN2A subunit, as we did in Tg-GluN2B2A(CT) mice, this swap led to profound memory deficits in novel object recognition test and long-term cued fear memories. These memory deficits mirrored those of Tg-GluN2A mice [23]. These subunits-swap experiments, by extending to learning and memory enhancement, are consistent with other reports that the intracellular domains of the GluN2 subunits play critical roles in mediating different functions, such as synaptic localization, clustering, signal transduction, and behaviors [22], [33]–[39]. Therefore, our studies suggest that both “synaptic coincidence-detection” hypotheses and “GluN2B intracellular signaling” hypothesis are mutually complementary in term of explaining the molecular determinants for memory enhancement.


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)

Summary of LTP, LTD and behavioral tasks results.The Tg-NRA2B(CT) mice had enhanced LTP, as well as enhanced long-term recognition memory and contextual fear conditioning. The Tg-GluN2B2A(CT) mice have significantly impaired LTD resulting in impaired short-term recognition memory and impaired long-term cued fear conditioning. The Tg-GluN2D2B(CT) mice have decreased LTD at 5 Hz and impaired long-term recognition memory and long-term cued fear memory.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111865-g007: Summary of LTP, LTD and behavioral tasks results.The Tg-NRA2B(CT) mice had enhanced LTP, as well as enhanced long-term recognition memory and contextual fear conditioning. The Tg-GluN2B2A(CT) mice have significantly impaired LTD resulting in impaired short-term recognition memory and impaired long-term cued fear conditioning. The Tg-GluN2D2B(CT) mice have decreased LTD at 5 Hz and impaired long-term recognition memory and long-term cued fear memory.
Mentions: Interestingly our present study has provided clear evidence supporting the second hypothesis that is known as the “GluN2B intracellular domain” hypothesis [4], [33]. Two separate pieces of evidence came from our behavioral analyses of the Tg-GluN2B2A(CT) and Tg-GluN2A2B(CT) transgenic mice. First, we found that the Tg-GluN2A2B(CT) mice had enhanced object recognition memory and emotional memory. These phenotypes are very similar to those of the Tg-GluN2B mice (and also Tg-GluN2B rats) (Figure 7). On the contrary, when the C-terminal domain of the GluN2B subunit was replaced by that of the GluN2A subunit, as we did in Tg-GluN2B2A(CT) mice, this swap led to profound memory deficits in novel object recognition test and long-term cued fear memories. These memory deficits mirrored those of Tg-GluN2A mice [23]. These subunits-swap experiments, by extending to learning and memory enhancement, are consistent with other reports that the intracellular domains of the GluN2 subunits play critical roles in mediating different functions, such as synaptic localization, clustering, signal transduction, and behaviors [22], [33]–[39]. Therefore, our studies suggest that both “synaptic coincidence-detection” hypotheses and “GluN2B intracellular signaling” hypothesis are mutually complementary in term of explaining the molecular determinants for memory enhancement.

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