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Deletion of the C-terminal domain of the NR2B subunit alters channel properties and synaptic targeting of N-methyl-D-aspartate receptors in nascent neocortical synapses

MPG-Autoren
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Köhr,  Georg
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

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Sprengel,  Rolf
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society;

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Zitation

Mohrmann, R., Köhr, G., Sprengel, R., Hatt, H., & Gottmann, K. (2002). Deletion of the C-terminal domain of the NR2B subunit alters channel properties and synaptic targeting of N-methyl-D-aspartate receptors in nascent neocortical synapses. Journal of Neuroscience Research, 68(3), 265-275. doi:10.1002/jnr.10219.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0029-7402-0
Zusammenfassung
Channel properties and synaptic targeting of N-methyl-D-aspartate (NMDA) receptors determine their importance in synaptic transmission, long-term synaptic plasticity, and developmental reorganization of synaptic circuits. To investigate the involvement of the C-terminal domain of the NR2B subunit in regulating channel properties and synaptic localization, we analyzed gene-targeted mice expressing C-terminally truncated NR2B subunits (NR2BΔC/ΔC mice; Sprengel et al. [1998] Cell 92:279–89). Because homozygous NR2BΔC/ΔC mice die perinatally, we studied embryonic neocortical neurons differentiating in culture. At early stages in vitro, neurons predominantly expressed NR1/NR2B receptors, as shown by the NR2B subunit-specific antagonist ifenprodil. At these nascent synapses, NMDA excitatory postsynaptic currents (EPSCs) in neurons from NR2BΔC/ΔC mice showed a strong-amplitude reduction to 20% of control, but AMPA EPSCs were unaltered. Analysis of the MK-801 block of NMDA receptor-mediated whole-cell currents revealed a decreased peak open probability of NMDA receptor channels (to about 60%) in neurons from NR2BΔC/ΔC mice, although their single channel conductance was unchanged. To study effects on synaptic targeting, we determined the fraction of synaptically localized NMDA receptors relative to the whole-cell NMDA receptor population. In neurons from NR2BΔC/ΔC mice, the synaptic NMDA receptor fraction was drastically reduced, suggesting that the C-terminal domain of the NR2B subunit plays a major role in synaptic targeting of NMDA receptors at nascent synapses. With increasing time in culture, the reduction in NMDA EPSCs in neurons from NR2BΔC/ΔC mice diminished. This is explained by the expression of additional NMDA receptor subtypes containing NR2A subunits at more mature synapses.