The Developmental Shift of NMDA Receptor Composition Proceeds Independently of GluN2 Subunit-Specific GluN2 C-Terminal Sequences

Sean McKay; Tomás J. Ryan; Jamie McQueen; Tim Indersmitten; Katie F.M. Marwick; Philip Hasel; Maksym V. Kopanitsa; Paul S. Baxter; Marc-André Martel; Peter C. Kind; David J.A. Wyllie; Thomas J. O’Dell; Seth G.N. Grant; Giles E. Hardingham; Noboru H. Komiyama

Cell Reports (Oct 2018)

The Developmental Shift of NMDA Receptor Composition Proceeds Independently of GluN2 Subunit-Specific GluN2 C-Terminal Sequences

Sean McKay,
Tomás J. Ryan,
Jamie McQueen,
Tim Indersmitten,
Katie F.M. Marwick,
Philip Hasel,
Maksym V. Kopanitsa,
Paul S. Baxter,
Marc-André Martel,
Peter C. Kind,
David J.A. Wyllie,
Thomas J. O’Dell,
Seth G.N. Grant,
Giles E. Hardingham,
Noboru H. Komiyama

Affiliations

Sean McKay: Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School, Edinburgh EH16 4SB, UK
Tomás J. Ryan: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland; Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia
Jamie McQueen: Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School, Edinburgh EH16 4SB, UK
Tim Indersmitten: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Katie F.M. Marwick: Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
Philip Hasel: Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School, Edinburgh EH16 4SB, UK
Maksym V. Kopanitsa: The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; UK Dementia Research Institute at Imperial College London, Hammersmith Hospital Campus, Imperial College, London W12 0NN, UK
Paul S. Baxter: Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School, Edinburgh EH16 4SB, UK
Marc-André Martel: Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
Peter C. Kind: Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
David J.A. Wyllie: Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
Thomas J. O’Dell: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Seth G.N. Grant: Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Centre for Clinical Brain Sciences, University of Edinburgh Chancellor’s Building, Edinburgh, UK
Giles E. Hardingham: Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; UK Dementia Research Institute at the University of Edinburgh, Chancellor’s Building, Edinburgh Medical School, Edinburgh EH16 4SB, UK; Corresponding author
Noboru H. Komiyama: Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK; Centre for Clinical Brain Sciences, University of Edinburgh Chancellor’s Building, Edinburgh, UK; Corresponding author

Journal volume & issue: Vol. 25, no. 4
pp. 841 – 851.e4

Abstract

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Summary: The GluN2 subtype (2A versus 2B) determines biophysical properties and signaling of forebrain NMDA receptors (NMDARs). During development, GluN2A becomes incorporated into previously GluN2B-dominated NMDARs. This “switch” is proposed to be driven by distinct features of GluN2 cytoplasmic C-terminal domains (CTDs), including a unique CaMKII interaction site in GluN2B that drives removal from the synapse. However, these models remain untested in the context of endogenous NMDARs. We show that, although mutating the endogenous GluN2B CaMKII site has secondary effects on GluN2B CTD phosphorylation, the developmental changes in NMDAR composition occur normally and measures of plasticity and synaptogenesis are unaffected. Moreover, the switch proceeds normally in mice that have the GluN2A CTD replaced by that of GluN2B and commences without an observable decline in GluN2B levels but is impaired by GluN2A haploinsufficiency. Thus, GluN2A expression levels, and not GluN2 subtype-specific CTD-driven events, are the overriding factor in the developmental switch in NMDAR composition. : An important milestone in forebrain neuronal development is the switch in composition of the NMDA receptor: GluN2A becomes incorporated into previously GluN2B-dominated NMDARs. Using knockin mice, McKay et al. find that, contrary to earlier proposed models, the switch does not require GluN2A and GluN2B to possess distinct C-terminal domain sequences. Keywords: NMDA receptor, neurodevelopment, synaptogenesis, synaptic plasticity

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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