What is the significance for synaptic plasticity of the developmental change in N-methyl-D-aspartate receptor subunit expression?

Life Sciences 2007 (2007) Proc Life Sciences, PC52

Poster Communications: What is the significance for synaptic plasticity of the developmental change in N-methyl-D-aspartate receptor subunit expression?

T. Bartlett1, N. Bannister1, V. Collett1, S. Fitzjohn1, Z. Bashir1, D. Lodge1, G. Collingridge1

1. MRC Centre for Synaptic Plasticity, University Of Bristol, Bristol, United Kingdom.

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Long term potentiation (LTP) and long term depression (LTD) are forms of synaptic plasticity important for learning and memory. In area CA1 of the hippocampus the NMDA receptor is crucial for the induction of LTP and LTD induced by high and low frequency stimulation respectively. The NMDA receptor comprises four subunits, two NR1 and two NR2 from four possible types (NR2A-NR2D). The expression of NR2 subunits is developmentally regulated, with NR2A appearing at P7 while NR2B is already high at birth (Sheng, Cummings et al. 1994). To detect if different subtypes of the NR2 subunit are involved in the induction of LTP and LTD at different stages in development we studied the effect of subunit selective antagonists on the induction of LTD induced by low frequency stimulation (1 Hz, 15 mins) or LTP induced by high frequency stimulation (100 Hz, 1 s) in area CA1 of hippocampal slices from P14 and P56 Wistar rats. We tested subunit selective antagonists in HEK293 cells expressing NMDAR subunits and found NVP-AAM077 (NVP) to be 14-fold selective for NR2A over NR2B, whereas Ro 25-6981 (Ro) was very selective for NR2B. In P14 hippocampal slices we measured NMDA EPSCs and found NVP and Ro both reduced the EPSC amplitude, but changed the time constant of EPSC decay in a manner consistent with selective actions at NR2A and NR2B receptors respectively. Together this data led us to conclude that 0.1μM NVP and 5μM Ro are selective doses for antagonising NR2A and NR2B NMDARs respectively. In P14 hippocampal slices, neither NVP (0.1μM), nor Ro (5μM) blocked LTD, but higher concentrations of NVP blocked LTD in a linearly dose-dependent manner. This suggests that NR2B NMDARs are not involved in the induction of LTD at this developmental stage under our experimental conditions. In P56 hippocampal slices, LTD could only be induced using the glutamate uptake blocker, threo-β-benzylaspartic acid (TBOA) and this LTD was insensitive to Ro (5μM). However, the highest NVP concentration tested (0.4μM) completely blocked LTD at this developmental stage. These results suggest that at both developmental stages NR2B NMDARs are not involved, but that extrasynaptic receptors are important at P56. LTP in P14 slices was reduced 63% and 45% by NVP (0.1μM) and Ro (5μM) respectively, suggesting that both NR2A and NR2B are involved in the induction of LTP at this developmental stage. However, initial experiments showed that in P42-56 slices LTP is insensitive to NVP (0.4μM) and Ro (5μM).



Where applicable, experiments conform with Society ethical requirements.

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