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Induction- and conditioning-protocol dependent involvement of NR2B-containing NMDA receptors in synaptic potentiation and contextual fear memory in the hippocampal CA1 region of rats.

Zhang XH, Wu LJ, Gong B, Ren M, Li BM, Zhuo M - Mol Brain (2008)

Bottom Line: Studies using genetic and pharmacological approaches have reported inconsistent results of the requirement of NR2B-containing NMDARs in LTP in the CA1 region.Inhibition of NR2B-NMDARs did not affect the late phase LTP induced by four-train HFS.Pre-training intra-CA1 infusion of ifenprodil or Ro25-6981 impaired the contextual fear memory induced by five CS-US pairings, with no effect on the memory induced by one CS-US pairing.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institutes of Brain Science, Fudan University, Shanghai, PR China. xuehan.zhang@utoronto.ca

ABSTRACT
Long-term potentiation (LTP) in the hippocampal CA1 region requires the activation of N-methyl-D-aspartate receptors (NMDARs). Studies using genetic and pharmacological approaches have reported inconsistent results of the requirement of NR2B-containing NMDARs in LTP in the CA1 region. Pharmacological studies showed that NR2B-containing NMDARs are not required for LTP, while genetic studies reported that over-expression of NR2B-NMDARs enhances LTP and hippocampus-dependent memory. Here, we provide evidence showing that the functional role of NR2B-NMDARs in hippocampal LTP and memory depends on LTP-inducing and behavior-conditioning protocols. Inhibition of NR2B-NMDARs with the NR2B selective antagonist ifenprodil or Ro25-6981 suppressed LTP induced by spike-timing protocol, with no impact on LTP induced by pairing protocol or two-train high-frequency stimulation (HFS) protocol. Inhibition of NR2B-NMDARs did not affect the late phase LTP induced by four-train HFS. Ca²(+) imaging showed that there was difference in kinetics of intracellular Ca²(+) signals induced by spiking-timing and pairing protocols. Pre-training intra-CA1 infusion of ifenprodil or Ro25-6981 impaired the contextual fear memory induced by five CS-US pairings, with no effect on the memory induced by one CS-US pairing.

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NR2B-NMDARs are required for LTP induced by spike-timing protocol in area CA1. A. Schematic diagram of the spike-timing protocol. B. Spike-timing protocol, as indicated by the arrow, induced a significant LTP in CA1 pyramidal neurons (n = 8). Sample traces of EPSC are the averages of 7 consecutive responses recorded during 5–10 min and 25–30 min, respectively. C. Bath application of ifenprodil partially blocked the LTP. n = 8 neurons D. Bath application of Ro25-6981 partially blocked the LTP. n = 7 neurons for 0.3 μM Ro25-6981; n = 8 neurons for 3 μM Ro25-6981. E. Histograms showing the effects of ifenprodil and Ro25-6981 on the LTP. *p < 0.05 vs. control. F. NR2A-NMDARs are required for LTP induced by spike-timing protocol in area CA1. Bath application of NVP-AAM077 blocked the LTP. n = 7 neurons. inset: Histogram showing the effect of NVP-AAM077 on the LTP. *p < 0.05 vs. control.
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Figure 1: NR2B-NMDARs are required for LTP induced by spike-timing protocol in area CA1. A. Schematic diagram of the spike-timing protocol. B. Spike-timing protocol, as indicated by the arrow, induced a significant LTP in CA1 pyramidal neurons (n = 8). Sample traces of EPSC are the averages of 7 consecutive responses recorded during 5–10 min and 25–30 min, respectively. C. Bath application of ifenprodil partially blocked the LTP. n = 8 neurons D. Bath application of Ro25-6981 partially blocked the LTP. n = 7 neurons for 0.3 μM Ro25-6981; n = 8 neurons for 3 μM Ro25-6981. E. Histograms showing the effects of ifenprodil and Ro25-6981 on the LTP. *p < 0.05 vs. control. F. NR2A-NMDARs are required for LTP induced by spike-timing protocol in area CA1. Bath application of NVP-AAM077 blocked the LTP. n = 7 neurons. inset: Histogram showing the effect of NVP-AAM077 on the LTP. *p < 0.05 vs. control.

Mentions: To test whether the involvement of NR2B-NMDARs is dependent on specific LTP induction paradigm, we first examined the role of NR2B- and NR2A-NMDARs in LTP induced by spike-timing protocol (also named EPSPs-APs protocol) (Figure 1A). To be consistent with the experimental conditions used by Wang's Group [9], we first performed whole-cell patch clamp recordings in CA1 pyramidal neurons from rat hippocampus. Spike-timing protocol caused a significant potentiation of synaptic responses (Figure 1B: 190.8 ± 12.2% of baseline at 25–30 min post-induction, n = 8 slices; p < 0.05 vs. baseline). We then tested the possible contribution of NR2B-NMDARs. The non-competitive, selective NR2B-NMDAR antagonist ifenprodil (3 μM) was perfused throughout the experiments. As shown in Figure 1C and 1E, ifenprodil significantly reduced the potentiation (121.4 ± 10.7% of baseline, n = 8 slices, p < 0.05 vs. control). Similar inhibitory effects were found with another NR2B-NMDAR antagonist Ro25-6981 (Figure 1D and 1E: For 0.3 μM Ro25-6981, 130.6 ± 13.1% of baseline, n = 7 slices, p < 0.05 vs. control; For 0.3 μM Ro25-6981, 116.1 ± 13.4% of baseline, n = 8 slices, p < 0.05 vs. control).


Induction- and conditioning-protocol dependent involvement of NR2B-containing NMDA receptors in synaptic potentiation and contextual fear memory in the hippocampal CA1 region of rats.

Zhang XH, Wu LJ, Gong B, Ren M, Li BM, Zhuo M - Mol Brain (2008)

NR2B-NMDARs are required for LTP induced by spike-timing protocol in area CA1. A. Schematic diagram of the spike-timing protocol. B. Spike-timing protocol, as indicated by the arrow, induced a significant LTP in CA1 pyramidal neurons (n = 8). Sample traces of EPSC are the averages of 7 consecutive responses recorded during 5–10 min and 25–30 min, respectively. C. Bath application of ifenprodil partially blocked the LTP. n = 8 neurons D. Bath application of Ro25-6981 partially blocked the LTP. n = 7 neurons for 0.3 μM Ro25-6981; n = 8 neurons for 3 μM Ro25-6981. E. Histograms showing the effects of ifenprodil and Ro25-6981 on the LTP. *p < 0.05 vs. control. F. NR2A-NMDARs are required for LTP induced by spike-timing protocol in area CA1. Bath application of NVP-AAM077 blocked the LTP. n = 7 neurons. inset: Histogram showing the effect of NVP-AAM077 on the LTP. *p < 0.05 vs. control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2570668&req=5

Figure 1: NR2B-NMDARs are required for LTP induced by spike-timing protocol in area CA1. A. Schematic diagram of the spike-timing protocol. B. Spike-timing protocol, as indicated by the arrow, induced a significant LTP in CA1 pyramidal neurons (n = 8). Sample traces of EPSC are the averages of 7 consecutive responses recorded during 5–10 min and 25–30 min, respectively. C. Bath application of ifenprodil partially blocked the LTP. n = 8 neurons D. Bath application of Ro25-6981 partially blocked the LTP. n = 7 neurons for 0.3 μM Ro25-6981; n = 8 neurons for 3 μM Ro25-6981. E. Histograms showing the effects of ifenprodil and Ro25-6981 on the LTP. *p < 0.05 vs. control. F. NR2A-NMDARs are required for LTP induced by spike-timing protocol in area CA1. Bath application of NVP-AAM077 blocked the LTP. n = 7 neurons. inset: Histogram showing the effect of NVP-AAM077 on the LTP. *p < 0.05 vs. control.
Mentions: To test whether the involvement of NR2B-NMDARs is dependent on specific LTP induction paradigm, we first examined the role of NR2B- and NR2A-NMDARs in LTP induced by spike-timing protocol (also named EPSPs-APs protocol) (Figure 1A). To be consistent with the experimental conditions used by Wang's Group [9], we first performed whole-cell patch clamp recordings in CA1 pyramidal neurons from rat hippocampus. Spike-timing protocol caused a significant potentiation of synaptic responses (Figure 1B: 190.8 ± 12.2% of baseline at 25–30 min post-induction, n = 8 slices; p < 0.05 vs. baseline). We then tested the possible contribution of NR2B-NMDARs. The non-competitive, selective NR2B-NMDAR antagonist ifenprodil (3 μM) was perfused throughout the experiments. As shown in Figure 1C and 1E, ifenprodil significantly reduced the potentiation (121.4 ± 10.7% of baseline, n = 8 slices, p < 0.05 vs. control). Similar inhibitory effects were found with another NR2B-NMDAR antagonist Ro25-6981 (Figure 1D and 1E: For 0.3 μM Ro25-6981, 130.6 ± 13.1% of baseline, n = 7 slices, p < 0.05 vs. control; For 0.3 μM Ro25-6981, 116.1 ± 13.4% of baseline, n = 8 slices, p < 0.05 vs. control).

Bottom Line: Studies using genetic and pharmacological approaches have reported inconsistent results of the requirement of NR2B-containing NMDARs in LTP in the CA1 region.Inhibition of NR2B-NMDARs did not affect the late phase LTP induced by four-train HFS.Pre-training intra-CA1 infusion of ifenprodil or Ro25-6981 impaired the contextual fear memory induced by five CS-US pairings, with no effect on the memory induced by one CS-US pairing.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institutes of Brain Science, Fudan University, Shanghai, PR China. xuehan.zhang@utoronto.ca

ABSTRACT
Long-term potentiation (LTP) in the hippocampal CA1 region requires the activation of N-methyl-D-aspartate receptors (NMDARs). Studies using genetic and pharmacological approaches have reported inconsistent results of the requirement of NR2B-containing NMDARs in LTP in the CA1 region. Pharmacological studies showed that NR2B-containing NMDARs are not required for LTP, while genetic studies reported that over-expression of NR2B-NMDARs enhances LTP and hippocampus-dependent memory. Here, we provide evidence showing that the functional role of NR2B-NMDARs in hippocampal LTP and memory depends on LTP-inducing and behavior-conditioning protocols. Inhibition of NR2B-NMDARs with the NR2B selective antagonist ifenprodil or Ro25-6981 suppressed LTP induced by spike-timing protocol, with no impact on LTP induced by pairing protocol or two-train high-frequency stimulation (HFS) protocol. Inhibition of NR2B-NMDARs did not affect the late phase LTP induced by four-train HFS. Ca²(+) imaging showed that there was difference in kinetics of intracellular Ca²(+) signals induced by spiking-timing and pairing protocols. Pre-training intra-CA1 infusion of ifenprodil or Ro25-6981 impaired the contextual fear memory induced by five CS-US pairings, with no effect on the memory induced by one CS-US pairing.

Show MeSH
Related in: MedlinePlus