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Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior

Nature Neuroscience volume 16, pages 25–32 (2013)Cite this article

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An Erratum to this article was published on 22 November 2013

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Abstract

Two genome duplications early in the vertebrate lineage expanded gene families, including GluN2 subunits of the NMDA receptor. Diversification between the four mammalian GluN2 proteins occurred primarily at their intracellular C-terminal domains (CTDs). To identify shared ancestral functions and diversified subunit-specific functions, we exchanged the exons encoding the GluN2A (also known as Grin2a) and GluN2B (also known as Grin2b) CTDs in two knock-in mice and analyzed the mice's biochemistry, synaptic physiology, and multiple learned and innate behaviors. The eight behaviors were genetically separated into four groups, including one group comprising three types of learning linked to conserved GluN2A/B regions. In contrast, the remaining five behaviors exhibited subunit-specific regulation. GluN2A/B CTD diversification conferred differential binding to cytoplasmic MAGUK proteins and differential forms of long-term potentiation. These data indicate that vertebrate behavior and synaptic signaling acquired increased complexity from the duplication and diversification of ancestral GluN2 genes.

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Figure 1: Design and generation of mouse models a phylogeny illustrating the invertebrate GluN2 and four vertebrate GluN2 paralogs (GluN2A, GluN2B, GluN2C and GluN2D).
Figure 2: NMDAR channel physiology.
Figure 3: Learning behavior.
Figure 4: Emotion, motivation and motor behavior.
Figure 5: Summary of behavioral phenotypes resulting from GluN2 CTD deletion and swap mutations.
Figure 6: Evolutionary grouping of behavioral phenotypes.
Figure 7: Synaptic plasticity.

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  • 07 March 2013

    In the version of this article initially published, the citations to Figures 3a, 3b and 3c should have read 3a–d, 3e–h and 3i–l, respectively, and the citations to Figures 4a, 4b and 4c should have read 4a–d, 4e–h and 4i–l, respectively. Also, under Gene Targeting in Online Methods, the incorporation of a GluN2A intronic fragment was omitted from the description of the GluN2B C-terminal exon construct. The sentence should read "The GluN2B C-terminal exon was amplified by PCR from 129/OlaHsd mouse genomic DNA (using primers 5'-GTATACACGGAGTAGCTATAGAGGAGCG-3' and 5'-GTTTAAACTCAGACATCAGACTCAATACTAGAAA-3') and attached to a small fragment of GluN2A intronic DNA (amplified using primers 5'-GGCGCGCCTAGGGCATCAATGACAGGG-3' and 5'- GTATACAACTGTAGATGCCCTGTGAGGG-3'), and the assembled product was inserted into AscI and PacI engineered to lie between the homology arms and the 3' exon." The errors have been corrected in the PDF and HTML versions of this article.

  • 10 December 2012

    In the version of this article initially published online, the sentence "We rely on published studies of GluN2B conditional homozygous knockout mutants to establish that GluN2B is necessary for a behavior when we do not see a phenotype for that behavior with GluN2B heterozygous null mutants" was absent from the section "Genetic dissection of multiple behaviors." The GluN2B+/+ bar in Figure 3c was mislabeled GluN2A+/+, and the GluN2B2A(CTR)/2A(CTR) bar was mislabeled GluN2A2B(CTR)/2B(CTR). The note "although this was due to enhanced performance on initial trials" was absent from the Figure 3i legend. The GluN2AΔC/ΔC column of Figure 4 was mislabeled GluN2AΔC, and the GluN2B+/ΔC column was mislabeled GluN2BΔC. The Figure 7b legend mentioned the GluN2B CTR; the correct text is GluN2B CTD. The Figure 7h legend cited both GluN2A2B(CTR)/2B(CTR) and GluN2B2A(CTR)/2A(CTR) mice, and three NMDAR-binding MAGUKs; only the latter genotype should have been included, and the text should have read "two NMDAR-binding MAGUKs." The errors have been corrected for the print, PDF and HTML versions of this article.

  • 10 December 2012

    In the version of this article initially published online, the genotype GluN2B2A(CTR)/2A(CTR) was misstated as GluN2A2B(CTR)/2B(CTR) in four locations in the Figure 3 legend: following (a–d), (c), (d) and (i–l). Finally, the first GluN2A2B(CTR) genotyping primer was given as 5′-CCACACGTACGGGGATGACCA-3′; the correct primer is 5′-TCAGTGCTTGCTTCACGGCAGC-3′. The errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank D. Fricker and E. Tuck for technical support, M. Price for animal care, K. Elsegood for management of the GluN2AΔC and GluN2BΔC mouse colonies, and D. Maizels for artwork. We thank P. Seeburg (Max Planck Institute for Medical Research) for providing the GluN2AΔC and GluN2BΔC mouse lines, and P. Kind (University of Edinburgh) for sharing unpublished data. We are grateful to A. Bayés, G. Hardingham, T. Kitamura, A. McLysaght, R. Redondo, J. Sarinana and D. Wyllie for critical reading of early manuscript drafts, and R. Frank, I. Greger, D. Stemple, A. Bari, L. van de Lagemaat, S. Manakov and J. Symonds for discussions. This project was supported by the Wellcome Trust, Genes to Cognition Program, the UK Medical Research Council and European Union programs (Project GENCODYS No. 241995, Project EUROSPIN No. 242498, Project SYNSYS No. 242167 and Project PharMEA No. SME-2008-1-232554). T.J.R. was supported by a Wellcome Trust PhD Studentship for most of this project.

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  1. Tomás J Ryan

    Present address: Present address: Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.,

Authors and Affiliations

  1. Genes to Cognition Programme, Wellcome Trust Sanger Institute, Cambridge, UK

    Tomás J Ryan, Maksym V Kopanitsa, Jess Nithianantharajah, Nurudeen O Afinowi, Charles Pettit, Lianne E Stanford, Seth G N Grant & Noboru H Komiyama

  2. Wolfson College, University of Cambridge, Cambridge, UK

    Tomás J Ryan

  3. Synome Ltd, Cambridge, UK

    Maksym V Kopanitsa & Nurudeen O Afinowi

  4. Interdepartmental Ph.D. Program for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA.,

    Tim Indersmitten

  5. Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK

    Jess Nithianantharajah, Seth G N Grant & Noboru H Komiyama

  6. Department of Experimental Psychology, University of Cambridge, Cambridge, UK

    Jess Nithianantharajah, Lisa M Saksida, Timothy J Bussey & Seth G N Grant

  7. MRC and Wellcome Trust Behavioral and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK

    Jess Nithianantharajah, Lisa M Saksida, Timothy J Bussey & Seth G N Grant

  8. Max Planck Institute for Medical Research, Heidelberg, Germany

    Rolf Sprengel

  9. Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.,

    Thomas J O'Dell

  10. Integrative Center for Learning and Memory, University of California, Los Angeles, Los Angeles, California, USA.,

    Thomas J O'Dell

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  1. Tomás J Ryan
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Contributions

T.J.R., S.G.N.G. and N.H.K. conceived and designed the project. T.J.R., M.V.K., T.I., J.N., N.O.A., C.P., T.J.O. and N.H.K. performed the experiments. T.J.R., M.V.K., L.E.S., R.S., L.M.S., T.J.B., T.J.O. and N.H.K. contributed new reagents and/or analytic tools. T.J.R., M.V.K., T.I., J.N. and T.J.O. analyzed the data. T.J.R., S.G.N.G. and N.H.K. wrote the manuscript.

Corresponding author

Correspondence to Noboru H Komiyama.

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Ryan, T., Kopanitsa, M., Indersmitten, T. et al. Evolution of GluN2A/B cytoplasmic domains diversified vertebrate synaptic plasticity and behavior. Nat Neurosci 16, 25–32 (2013). https://doi.org/10.1038/nn.3277

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