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Forebrain NR2B overexpression facilitating the prefrontal cortex long-term potentiation and enhancing working memory function in mice.

Cui Y, Jin J, Zhang X, Xu H, Yang L, Du D, Zeng Q, Tsien JZ, Yu H, Cao X - PLoS ONE (2011)

Bottom Line: Its functions are associated with NMDA receptors.The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP.Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Brain Functional Genomics, The Key Laboratory of MOE, East China Normal University, Shanghai, China.

ABSTRACT
Prefrontal cortex plays an important role in working memory, attention regulation and behavioral inhibition. Its functions are associated with NMDA receptors. However, there is little information regarding the roles of NMDA receptor NR2B subunit in prefrontal cortical synaptic plasticity and prefrontal cortex-related working memory. Whether the up-regulation of NR2B subunit influences prefrontal cortical synaptic plasticity and working memory is not yet clear. In the present study, we measured prefrontal cortical synaptic plasticity and working memory function in NR2B overexpressing transgenic mice. In vitro electrophysiological data showed that overexpression of NR2B specifically in the forebrain region resulted in enhancement of prefrontal cortical long-term potentiation (LTP) but did not alter long-term depression (LTD). The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP. In addition, NR2B transgenic mice exhibited better performance in a set of working memory paradigms including delay no-match-to-place T-maze, working memory version of water maze and odor span task. Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.

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Enhancement of Non-spatial Working Memory in NR2B Transgenic Mice.A: Performance of the odor span task by transgenic mice and their control littlemate was compared over successive training 16 days. The Tg mice showed significantly improved performance on training days 7,10,11,12 (*p<0.05). B–E: the effect of genotype on stable performance (sessions 13–16) was assessed after Wt and Tg mice reached to a stable performance at sessions 13–16, a significant difference between the two groups was observed in span length (B), % accuracy (C) and error (D), but not in mean span length (E). F: In the no reward probe, the mean span length of each group was comparable with the mean span length of each group across across 11 sessions after the acquisition period (sessions 6–16). All values are mean ± SEM (*denotes p<0.05 when compared to Wt controls).
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pone-0020312-g006: Enhancement of Non-spatial Working Memory in NR2B Transgenic Mice.A: Performance of the odor span task by transgenic mice and their control littlemate was compared over successive training 16 days. The Tg mice showed significantly improved performance on training days 7,10,11,12 (*p<0.05). B–E: the effect of genotype on stable performance (sessions 13–16) was assessed after Wt and Tg mice reached to a stable performance at sessions 13–16, a significant difference between the two groups was observed in span length (B), % accuracy (C) and error (D), but not in mean span length (E). F: In the no reward probe, the mean span length of each group was comparable with the mean span length of each group across across 11 sessions after the acquisition period (sessions 6–16). All values are mean ± SEM (*denotes p<0.05 when compared to Wt controls).

Mentions: To further make sure that NR2B overexpression in prefrontal cortex certainly contributes to enhanced spatial working memory, the olfactory working memory of mice was assessed in the non-spatial cue dependent odor span task, which is hippocampus independent. The performance of the two groups in the odor span task across 16 sessions was compared using a two-way ANOVA. Significant main effects of both training day (F(15,287) = 5.781, p<0.001, Figure 6A) and genotype (F(1,287) = 29.965, p<0.001, Figure 6A) were observed, but there was no group-by-span length interaction (F(15,287) = 0.86, p>0.05). Sidak-Holm post-hoc test analysis revealed that the performance of NR2B transgenic mice was significantly better than their wild type mice on sessions 7, 10, 11, 12, 15 (p<0.05). When both the Tg and Wt mice reached a span length ≥4.3, they performed significantly better than their performance on session 1 (p<0.05). This took 5 sessions for both Tg and Wt mice to reach this acquisition criterion (span length ≥4.3 for 2 consecutive sessions). Following attainment of acquisition criteria, all mice was continually trained to a stable level of performance with span length fluctuating within a maximum of 3 spans over 4 consecutive days. Since mice reached to a stable performance at sessions 13-16, the effect of genotype on stable performance was assessed by measuring simple 2-odor discrimination, span length, % accuracy, total errors and mean span latency of two groups across these sessions. Compared to the Wt mice, the Tg mice exhibited significantly higher span length (T = 456.5, p<0.01, Figure 6B), higher % accuracy (T = 405, p<0.001, Figure 6C) and fewer total errors (T = 418.5, p<0.001, Figure 6D). As there was no significant effect of genotype on mean span latency (F(1,74) = 0.134, p>0.05 0.715, Figure 6E) and 2-odor discrimination (T = 702, p>0.05 0.343), the difference in span length between groups was not a consequence of the Tg mice being faster or more sensitive to odor.


Forebrain NR2B overexpression facilitating the prefrontal cortex long-term potentiation and enhancing working memory function in mice.

Cui Y, Jin J, Zhang X, Xu H, Yang L, Du D, Zeng Q, Tsien JZ, Yu H, Cao X - PLoS ONE (2011)

Enhancement of Non-spatial Working Memory in NR2B Transgenic Mice.A: Performance of the odor span task by transgenic mice and their control littlemate was compared over successive training 16 days. The Tg mice showed significantly improved performance on training days 7,10,11,12 (*p<0.05). B–E: the effect of genotype on stable performance (sessions 13–16) was assessed after Wt and Tg mice reached to a stable performance at sessions 13–16, a significant difference between the two groups was observed in span length (B), % accuracy (C) and error (D), but not in mean span length (E). F: In the no reward probe, the mean span length of each group was comparable with the mean span length of each group across across 11 sessions after the acquisition period (sessions 6–16). All values are mean ± SEM (*denotes p<0.05 when compared to Wt controls).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105019&req=5

pone-0020312-g006: Enhancement of Non-spatial Working Memory in NR2B Transgenic Mice.A: Performance of the odor span task by transgenic mice and their control littlemate was compared over successive training 16 days. The Tg mice showed significantly improved performance on training days 7,10,11,12 (*p<0.05). B–E: the effect of genotype on stable performance (sessions 13–16) was assessed after Wt and Tg mice reached to a stable performance at sessions 13–16, a significant difference between the two groups was observed in span length (B), % accuracy (C) and error (D), but not in mean span length (E). F: In the no reward probe, the mean span length of each group was comparable with the mean span length of each group across across 11 sessions after the acquisition period (sessions 6–16). All values are mean ± SEM (*denotes p<0.05 when compared to Wt controls).
Mentions: To further make sure that NR2B overexpression in prefrontal cortex certainly contributes to enhanced spatial working memory, the olfactory working memory of mice was assessed in the non-spatial cue dependent odor span task, which is hippocampus independent. The performance of the two groups in the odor span task across 16 sessions was compared using a two-way ANOVA. Significant main effects of both training day (F(15,287) = 5.781, p<0.001, Figure 6A) and genotype (F(1,287) = 29.965, p<0.001, Figure 6A) were observed, but there was no group-by-span length interaction (F(15,287) = 0.86, p>0.05). Sidak-Holm post-hoc test analysis revealed that the performance of NR2B transgenic mice was significantly better than their wild type mice on sessions 7, 10, 11, 12, 15 (p<0.05). When both the Tg and Wt mice reached a span length ≥4.3, they performed significantly better than their performance on session 1 (p<0.05). This took 5 sessions for both Tg and Wt mice to reach this acquisition criterion (span length ≥4.3 for 2 consecutive sessions). Following attainment of acquisition criteria, all mice was continually trained to a stable level of performance with span length fluctuating within a maximum of 3 spans over 4 consecutive days. Since mice reached to a stable performance at sessions 13-16, the effect of genotype on stable performance was assessed by measuring simple 2-odor discrimination, span length, % accuracy, total errors and mean span latency of two groups across these sessions. Compared to the Wt mice, the Tg mice exhibited significantly higher span length (T = 456.5, p<0.01, Figure 6B), higher % accuracy (T = 405, p<0.001, Figure 6C) and fewer total errors (T = 418.5, p<0.001, Figure 6D). As there was no significant effect of genotype on mean span latency (F(1,74) = 0.134, p>0.05 0.715, Figure 6E) and 2-odor discrimination (T = 702, p>0.05 0.343), the difference in span length between groups was not a consequence of the Tg mice being faster or more sensitive to odor.

Bottom Line: Its functions are associated with NMDA receptors.The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP.Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Brain Functional Genomics, The Key Laboratory of MOE, East China Normal University, Shanghai, China.

ABSTRACT
Prefrontal cortex plays an important role in working memory, attention regulation and behavioral inhibition. Its functions are associated with NMDA receptors. However, there is little information regarding the roles of NMDA receptor NR2B subunit in prefrontal cortical synaptic plasticity and prefrontal cortex-related working memory. Whether the up-regulation of NR2B subunit influences prefrontal cortical synaptic plasticity and working memory is not yet clear. In the present study, we measured prefrontal cortical synaptic plasticity and working memory function in NR2B overexpressing transgenic mice. In vitro electrophysiological data showed that overexpression of NR2B specifically in the forebrain region resulted in enhancement of prefrontal cortical long-term potentiation (LTP) but did not alter long-term depression (LTD). The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP. In addition, NR2B transgenic mice exhibited better performance in a set of working memory paradigms including delay no-match-to-place T-maze, working memory version of water maze and odor span task. Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.

Show MeSH
Related in: MedlinePlus