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 - PubMed (original) (raw)

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

Xue-Han Zhang et al. Mol Brain. 2008.

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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Figures

Figure 1

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.

Figure 2

Figure 2

NR2B-NMDARs are not required for LTP induced by pairing protocol in area CA1. A. Schematic diagram of the pairing protocol. B. Pairing protocol, as indicated by the arrow, induced a significant LTP in CA1 pyramidal neurons (n = 6). 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 Ro25-6981 (0.5 μM) had no effect on the LTP (n = 5). D. Histogram showing the effect of Ro25-6981 on the LTP. p > 0.05 vs. control.

Figure 3

Figure 3

NR2B-NMDARs are not required for LTP induced by HFS protocol in area CA1. A. Schematic diagram of the high frequency stimulation (HFS; 2 train). B. LTP of field EPSP induced by the HFS in control (n = 10 slices) and in the presence of Ro25-6981 (n = 7 slices). Ro25-7981 had no effect on the LTP.

Figure 4

Figure 4

NR2B-NMDARs are not required for L-LTP induced by HFS protocol in area CA1. A. Schematic diagram of the high frequency stimulation (HFS; 4 trains). B. Late phase LTP of field EPSP induced by the HFS in control (n = 7 slices) and in the presence of Ro25-6981 (n = 5 slices). Ro25-7981 had no effect on the L-LTP.

Figure 5

Figure 5

NR2B-NMDAR mediated Ca2+ influx under spiking-timing and pairing protocols. A. A representative image showing the CA1 pyramidal neuron filled with OGB-1. ROI, region of interests. B. Raw sample fluorescence images from the ROI before (1), during (2) and after (3) induction of LTP with the spike-timing protocol. Scale bar, 1.0 μm. C. Elevation of Ca2+ signal in the ROI during induction of LTP with the spike-timing protocol (upper). Treatment with ifenprodil (3 μM) reduced the Ca2+ signal (middle). The difference of [Ca2+] signals in control and in the presence of ifenprodil (lower) shows the NR2B-NMDAR mediated Ca2+ influx. D. Elevation of Ca2+ signal in the ROI during induction of LTP with the pairing protocol (upper). Treatment with ifenprodil (3 μM) reduced the Ca2+ signal (middle). The difference of [Ca2+] signals in control and in the presence of ifenprodil (lower) shows the NR2B-NMDAR mediated Ca2+ influx.

Figure 6

Figure 6

NR2B-NMDARs are required for the acquisition of contextual fear memory induced by the five but not one CS-US pairing conditioning. A. Pre-training intra-CA1 inhibition of NR2B-NMDARs had no impact on, while inhibition of NR2A-NMDARs impaired 48-h contextual fear memory induced by the single CS-US pairing protocol (A1). The acquisition of auditory fear memory was intact (A2). The result with Ro25-6981 was reported in the previous study (Zhao et al., 2005). *p < 0.05 vs. vehicle B. Pre-training intra-CA1 inhibition of NR2B- or NR2A-NMDARs impaired 48-h contextual fear memory induced by the five CS-US pairing protocol (B1). The acquisition of auditory fear memory was intact (B2). **p < 0.01 vs. vehicle. C. Reconstruction of the infusion sites in the CA1 region. Filled squares: vehicle; Open circles: 0.012 μg NVP-AAM077; Filled circles: 0.12 μg NVP-AAM077; Open triangles: ifenprodil; Grey squares: Ro25-6981. D. A representative coronal section showing an infusion site of ifenprodil in the CA1 region.

Figure 7

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.

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