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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 the retrieval of contextual fear memory induced by both five and one CS-US pairing conditioning. A. Pre-retrieval intra-CA1 inhibition of NR2B- or NR2A-NMDARs impaired the expression of 48-h contextual fear memory induced by the single CS-US pairing protocol (A1). The expression of 48-h auditory fear memory was intact (A2). **p < 0.01 vs. vehicle. B. Pre-retrieval intra-CA1 inhibition of NR2B- or NR2A-NMDARs impaired the expression of 48-h contextual fear memory induced by the five CS-US pairing protocol (B1). The expression of 48-h auditory fear memory was intact (B2). **p < 0.01 vs. vehicle. C. Reconstruction of the infusion sites in the CA1 region. Filled squares: vehicle; Filled circles: NVP-AAM077; Open triangles: ifenprodil; Open circles: Ro25-6981. D. A representative coronal section showing an infusion site of ifenprodil in the CA1 region.
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Figure 7: NR2B-NMDARs are required for the retrieval of contextual fear memory induced by both five and one CS-US pairing conditioning. A. Pre-retrieval intra-CA1 inhibition of NR2B- or NR2A-NMDARs impaired the expression of 48-h contextual fear memory induced by the single CS-US pairing protocol (A1). The expression of 48-h auditory fear memory was intact (A2). **p < 0.01 vs. vehicle. B. Pre-retrieval intra-CA1 inhibition of NR2B- or NR2A-NMDARs impaired the expression of 48-h contextual fear memory induced by the five CS-US pairing protocol (B1). The expression of 48-h auditory fear memory was intact (B2). **p < 0.01 vs. vehicle. C. Reconstruction of the infusion sites in the CA1 region. Filled squares: vehicle; Filled circles: NVP-AAM077; Open triangles: ifenprodil; Open circles: Ro25-6981. D. A representative coronal section showing an infusion site of ifenprodil in the CA1 region.

Mentions: First, we examined the effects of intra-CA1 blockade of NR2B- as well as NR2A-NMDARs on memory retrieval for the single CS-US pair conditioning. NVP-AAM077 (0.012 μg in 1 μl PBS, n = 6 rats; 0.12 μg in 1 μl PBS, n = 7 rats), ifenprodil (0.2 μg in 1 μl PBS, n = 8 rats), or Ro25-6981 (5.0 μg in 1 μl PBS, n = 6 rats) was infused into the CA1 region 15 min before memory retention was tested. PBS was similarly infused as vehicle control (1 μl, n = 9 rats). As shown in Figure 7A1, An one-way ANOVA revealed a significant group effect on contextual freezing scores (F(4,31) = 8.12, p < 0.05). Planned comparison showed that the rats treated with NVP-AAM077, ifenprodil, or Ro25-6981 exhibited a deficient contextual fear memory (F(1,13) = 15.48, p < 0.01 for 0.012 μg NVP-AAM077 vs. vehicle; F(1,14) = 10.61, p < 0.01 for 0.12 μg NVP-AAM077 vs. vehicle; F(1,15) = 20.71, p < 0.01 for ifenprodil vs. vehicle; F(1, 13) = 13.23, p < 0.01 for Ro25-6981 vs. vehicle). However, each group of rats demonstrated a normal auditory fear memory (Figure 7A2: F(4, 21) = 0.62, p > 0.05).


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 the retrieval of contextual fear memory induced by both five and one CS-US pairing conditioning. A. Pre-retrieval intra-CA1 inhibition of NR2B- or NR2A-NMDARs impaired the expression of 48-h contextual fear memory induced by the single CS-US pairing protocol (A1). The expression of 48-h auditory fear memory was intact (A2). **p < 0.01 vs. vehicle. B. Pre-retrieval intra-CA1 inhibition of NR2B- or NR2A-NMDARs impaired the expression of 48-h contextual fear memory induced by the five CS-US pairing protocol (B1). The expression of 48-h auditory fear memory was intact (B2). **p < 0.01 vs. vehicle. C. Reconstruction of the infusion sites in the CA1 region. Filled squares: vehicle; Filled circles: NVP-AAM077; Open triangles: ifenprodil; Open circles: Ro25-6981. D. A representative coronal section showing an infusion site of ifenprodil in the CA1 region.
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Figure 7: NR2B-NMDARs are required for the retrieval of contextual fear memory induced by both five and one CS-US pairing conditioning. A. Pre-retrieval intra-CA1 inhibition of NR2B- or NR2A-NMDARs impaired the expression of 48-h contextual fear memory induced by the single CS-US pairing protocol (A1). The expression of 48-h auditory fear memory was intact (A2). **p < 0.01 vs. vehicle. B. Pre-retrieval intra-CA1 inhibition of NR2B- or NR2A-NMDARs impaired the expression of 48-h contextual fear memory induced by the five CS-US pairing protocol (B1). The expression of 48-h auditory fear memory was intact (B2). **p < 0.01 vs. vehicle. C. Reconstruction of the infusion sites in the CA1 region. Filled squares: vehicle; Filled circles: NVP-AAM077; Open triangles: ifenprodil; Open circles: Ro25-6981. D. A representative coronal section showing an infusion site of ifenprodil in the CA1 region.
Mentions: First, we examined the effects of intra-CA1 blockade of NR2B- as well as NR2A-NMDARs on memory retrieval for the single CS-US pair conditioning. NVP-AAM077 (0.012 μg in 1 μl PBS, n = 6 rats; 0.12 μg in 1 μl PBS, n = 7 rats), ifenprodil (0.2 μg in 1 μl PBS, n = 8 rats), or Ro25-6981 (5.0 μg in 1 μl PBS, n = 6 rats) was infused into the CA1 region 15 min before memory retention was tested. PBS was similarly infused as vehicle control (1 μl, n = 9 rats). As shown in Figure 7A1, An one-way ANOVA revealed a significant group effect on contextual freezing scores (F(4,31) = 8.12, p < 0.05). Planned comparison showed that the rats treated with NVP-AAM077, ifenprodil, or Ro25-6981 exhibited a deficient contextual fear memory (F(1,13) = 15.48, p < 0.01 for 0.012 μg NVP-AAM077 vs. vehicle; F(1,14) = 10.61, p < 0.01 for 0.12 μg NVP-AAM077 vs. vehicle; F(1,15) = 20.71, p < 0.01 for ifenprodil vs. vehicle; F(1, 13) = 13.23, p < 0.01 for Ro25-6981 vs. vehicle). However, each group of rats demonstrated a normal auditory fear memory (Figure 7A2: F(4, 21) = 0.62, p > 0.05).

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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