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The Journal of Neuroscience, November 15, 2002, 22(22):9687-9697

NMDA Receptor 2 (NR2) C-Terminal Control of NR Open Probability Regulates Synaptic Transmission and Plasticity at a Cerebellar Synapse

Paola Rossi¹, Elisabetta Sola¹, Vanni Taglietti¹, Thilo Borchardt³, Frank Steigerwald³, Jo Kristian Utvik⁴, Ole Petter Ottersen⁴, Georg Köhr³, and Egidio D'Angelo^{1, 2}

¹ Department of Molecular and Cellular Physiology and Istituto Nazionale per la Fisica della Materia, University of Pavia, I 27100 Pavia, Italy, ² Department of Evolutionary and Functional Biology, University of Parma, I-43100 Parma, Italy, ³ Max-Planck Institute for Medical Research, D-69120 Heidelberg, Germany, and ⁴ Centre for Molecular Biology and Neuroscience, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, N-0314 Oslo, Norway

The C-terminal domain of NMDA receptor 2 (NR2) subunits has been proposed to play a critical role in regulating NMDA receptor localization and function in postsynaptic densities. However, the mechanism of this regulation is not completely understood. In this paper we show that C-terminal truncation of NR2A and NR2C subunits in mice (NR2A/C^C/C) impairs synaptic transmission and plasticity at the cerebellar mossy fiber-granule cell relay. Activation of synaptic NMDA receptors could be distinguished from that of extrasynaptic receptors by using the glutamate scavenger glutamate pyruvate transaminase and the open channel blocker MK801. NR2A/C^C/C mice exhibited a specific reduction in synaptic NMDA receptor activation attributable to a severalfold decrease in channel open probability but not channel conductance. Immunodetection revealed normal developmental expression of NR subunit proteins. Quantitative immunogold analyses with an antibody to NR1 indicated that the reduction in receptor activation is not attributed to a reduced number of NR1-containing receptors in postsynaptic densities. Thus, NR2A/NR2C subunits and particularly their C termini regulate synaptic NMDA receptor activation and function by enhancing channel open probability, which is critical for long-term potentiation induction.

Key words: NMDA receptor; LTP; channel open probability; cerebellum; granule cell; gene knock-out

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22229687-11$05.00/0

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