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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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The Role of NR2B Subunit in Enhanced Prefrontal-LTP in Transgenic Slices.A: NR2A-selectice antagonist (NVP-AAM077) reduced prefrontal cortex l LTP in Wt slices. B: NR2B-selectice antagonist (Ro25-6981) also reduced prefrontal cortex LTP in Wt slices. C: Effect of NVP-AAM077 on prefrontal cortex LTP in Tg slices. D: Ro25-6981 had much larger effect on prefrontal cortex LTP in Tg slices. E: Statistical analysis shows the effects of NVP-AAM077 on prefrontal cortical LTP in both Tg and Wt slice, it indicates a significant involvement of NR2A subunits in prefrontal cortex LTP of both Tg and Wt slices. F: Statistical analysis shows the effects of Ro25-6981 on prefrontal cortex LTP in both Tg and Wt slice, suggesting a significant involvement of NR2B subunits in prefrontal cortex LTP of both Tg and Wt slices. All values are mean ± SEM. Statistical differences were evaluated with Student's t –test (A, B, C, D) and Tukey's HSD post-hoc test (E, F)(*denotes p<0.05, **denotes P<0.01).
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pone-0020312-g004: The Role of NR2B Subunit in Enhanced Prefrontal-LTP in Transgenic Slices.A: NR2A-selectice antagonist (NVP-AAM077) reduced prefrontal cortex l LTP in Wt slices. B: NR2B-selectice antagonist (Ro25-6981) also reduced prefrontal cortex LTP in Wt slices. C: Effect of NVP-AAM077 on prefrontal cortex LTP in Tg slices. D: Ro25-6981 had much larger effect on prefrontal cortex LTP in Tg slices. E: Statistical analysis shows the effects of NVP-AAM077 on prefrontal cortical LTP in both Tg and Wt slice, it indicates a significant involvement of NR2A subunits in prefrontal cortex LTP of both Tg and Wt slices. F: Statistical analysis shows the effects of Ro25-6981 on prefrontal cortex LTP in both Tg and Wt slice, suggesting a significant involvement of NR2B subunits in prefrontal cortex LTP of both Tg and Wt slices. All values are mean ± SEM. Statistical differences were evaluated with Student's t –test (A, B, C, D) and Tukey's HSD post-hoc test (E, F)(*denotes p<0.05, **denotes P<0.01).

Mentions: To evaluate the contribution of NR2A and NR2B subunits to prefrontal cortex LTP, the selective antagonists of NMDA receptor subunits were applied to the prefrontal slices. NVP-AAM077 and Ro25-6981 are selective antagonists for NR2A-containing NMDARs and NR2B-containing NMDARs, respectively [16]. In Wt slices, LTP was significantly reduced but not completely blocked by 0.4 µM NVP-AAM077 (Figure 4A, 118.8±1.2%; n = 6 slices/2 mice, Student's t-test, p<0.01) or 0.3 µM Ro 25–6981 (Figure 4B, 120.6±1.9%; n = 8slices/3mice, Student's t-test, p<0.05), respectively. Similarly, NVP-AAM077 or Ro 25–6981 also reduced LTP in the transgenic slices (Figure 4C, Tg with NVP: 133.6±5.6%, n = 6 slices/2 mice, p<0.05; Figure 4D, Tg with Ro25: 119.7±1.4%, n = 7 slices/3 mice, p<0.01). These results suggest that both NR2B and NR2A subunits contribute to the induction of prefrontal LTP in both Wt and Tg slice. Especially, under the NVP-AAM077 treatment, LTP in Tg slices was significantly larger than that of Wt slices (Figure 4E, Tg: 133.6±5.6%; n = 6 slices/2 mice; Wt: 118.8±1.2%; n = 6 slices/2 mice, Tukey's HSD post-hock test, p<0.05). In addition, under the Ro 25–6981 treatment, LTP of Wt slices was comparable with that of Tg slices (Figure 4F, Wt: 120.6±1.9%, n = 8 slices/3mice; Tg: 119.7±1.4%, n = 7 slices/3 mice; Tukey's HSD post-hock test, p>0.05). These results suggest that overexpression of NR2B subunit is responsible for enhanced prefrontal cortex LTP in Tg slices.


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)

The Role of NR2B Subunit in Enhanced Prefrontal-LTP in Transgenic Slices.A: NR2A-selectice antagonist (NVP-AAM077) reduced prefrontal cortex l LTP in Wt slices. B: NR2B-selectice antagonist (Ro25-6981) also reduced prefrontal cortex LTP in Wt slices. C: Effect of NVP-AAM077 on prefrontal cortex LTP in Tg slices. D: Ro25-6981 had much larger effect on prefrontal cortex LTP in Tg slices. E: Statistical analysis shows the effects of NVP-AAM077 on prefrontal cortical LTP in both Tg and Wt slice, it indicates a significant involvement of NR2A subunits in prefrontal cortex LTP of both Tg and Wt slices. F: Statistical analysis shows the effects of Ro25-6981 on prefrontal cortex LTP in both Tg and Wt slice, suggesting a significant involvement of NR2B subunits in prefrontal cortex LTP of both Tg and Wt slices. All values are mean ± SEM. Statistical differences were evaluated with Student's t –test (A, B, C, D) and Tukey's HSD post-hoc test (E, F)(*denotes p<0.05, **denotes P<0.01).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105019&req=5

pone-0020312-g004: The Role of NR2B Subunit in Enhanced Prefrontal-LTP in Transgenic Slices.A: NR2A-selectice antagonist (NVP-AAM077) reduced prefrontal cortex l LTP in Wt slices. B: NR2B-selectice antagonist (Ro25-6981) also reduced prefrontal cortex LTP in Wt slices. C: Effect of NVP-AAM077 on prefrontal cortex LTP in Tg slices. D: Ro25-6981 had much larger effect on prefrontal cortex LTP in Tg slices. E: Statistical analysis shows the effects of NVP-AAM077 on prefrontal cortical LTP in both Tg and Wt slice, it indicates a significant involvement of NR2A subunits in prefrontal cortex LTP of both Tg and Wt slices. F: Statistical analysis shows the effects of Ro25-6981 on prefrontal cortex LTP in both Tg and Wt slice, suggesting a significant involvement of NR2B subunits in prefrontal cortex LTP of both Tg and Wt slices. All values are mean ± SEM. Statistical differences were evaluated with Student's t –test (A, B, C, D) and Tukey's HSD post-hoc test (E, F)(*denotes p<0.05, **denotes P<0.01).
Mentions: To evaluate the contribution of NR2A and NR2B subunits to prefrontal cortex LTP, the selective antagonists of NMDA receptor subunits were applied to the prefrontal slices. NVP-AAM077 and Ro25-6981 are selective antagonists for NR2A-containing NMDARs and NR2B-containing NMDARs, respectively [16]. In Wt slices, LTP was significantly reduced but not completely blocked by 0.4 µM NVP-AAM077 (Figure 4A, 118.8±1.2%; n = 6 slices/2 mice, Student's t-test, p<0.01) or 0.3 µM Ro 25–6981 (Figure 4B, 120.6±1.9%; n = 8slices/3mice, Student's t-test, p<0.05), respectively. Similarly, NVP-AAM077 or Ro 25–6981 also reduced LTP in the transgenic slices (Figure 4C, Tg with NVP: 133.6±5.6%, n = 6 slices/2 mice, p<0.05; Figure 4D, Tg with Ro25: 119.7±1.4%, n = 7 slices/3 mice, p<0.01). These results suggest that both NR2B and NR2A subunits contribute to the induction of prefrontal LTP in both Wt and Tg slice. Especially, under the NVP-AAM077 treatment, LTP in Tg slices was significantly larger than that of Wt slices (Figure 4E, Tg: 133.6±5.6%; n = 6 slices/2 mice; Wt: 118.8±1.2%; n = 6 slices/2 mice, Tukey's HSD post-hock test, p<0.05). In addition, under the Ro 25–6981 treatment, LTP of Wt slices was comparable with that of Tg slices (Figure 4F, Wt: 120.6±1.9%, n = 8 slices/3mice; Tg: 119.7±1.4%, n = 7 slices/3 mice; Tukey's HSD post-hock test, p>0.05). These results suggest that overexpression of NR2B subunit is responsible for enhanced prefrontal cortex LTP in Tg slices.

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