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Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A

Abstract

The NMDA (N -methyl-D-aspartate) subclass of glutamate receptor1 is essential for the synaptic plasticity thought to underlie learning and memory2,3,4 and for synaptic refinement during development5,6. It is currently believed that the NMDA receptor (NMDAR) is a heteromultimeric channel comprising the ubiquitous NR1 subunit and at least one regionally localized NR2 subunit7,8,9,10,11. Here we report the characterization of a regulatory NMDAR subunit, NR3A (formerly termed NMDAR-L or χ-1), which is expressed primarily during brain development12,13. NR3Aco-immunoprecipitates with receptor subunits NR1 and NR2 in cerebrocortical extracts. In single-channel recordings from Xenopus oocytes, addition of NR3A to NR1 and NR2 leads to the appearance of a smaller unitary conductance. Genetic knockout of NR3A in mice results in enhanced NMDA responses and increased dendritic spines in early postnatal cerebrocortical neurons. These data suggest that NR3A is involved in the development of synaptic elements by modulating NMDAR activity.

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Figure 1: Biochemical characterization of NR3A.
Figure 2: Single-channel recordings from outside-out patches expressing NR1, NR2A and NR3A.
Figure 3: Biochemical and electrophysiological studies of NR3A−/− mice.
Figure 4: Changes in dendritic morphology of NR3A−/− versus wild-type male mice at P19.

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Acknowledgements

We thank N. J. Sucher, M. Wyszynski, D. Zurakowski, J. Yuan, T. S. Khurana, C.Yiannoutsos and K. Rosen for advice and discussion; N. J. Sucher, M. Sheng, R. Wenthold and K.Buckley for antibodies; and J. Cohen and M. Sheng for critical reading of the manuscript. This work was supported by fellowships from the HHMI (S.D., W.C.) and the Harvard Mahoney Neuroscience Institute (Y.F.S.), grants from the NIH (J.E.C., S.A.L., N.N.), the Klingenstein Foundation, the Edward R. and Anne G. Lefler Center, NARSAD and the Funds for Discovery (N.N.). S.A.L. has consultancy and sponsored research agreements with Neurobiological Technologies, Inc. (Richmond, CA) and Allergan, Inc. (Irvine, CA) in the field of NMDAR antagonists.

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Correspondence to Stuart A. Lipton or Nobuki Nakanishi.

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Das, S., Sasaki, Y., Rothe, T. et al. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393, 377–381 (1998). https://doi.org/10.1038/30748

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