1. The Developmental Shift of NMDA Receptor Composition Proceeds Independently of GluN2 Subunit-Specific GluN2 C-Terminal Sequences
- Author
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McKay, Sean, Ryan, Tomás J., McQueen, Jamie, Indersmitten, Tim, Marwick, Katie F.M., Hasel, Philip, Kopanitsa, Maksym V., Baxter, Paul S., Martel, Marc-André, Kind, Peter C., Wyllie, David J.A., O’Dell, Thomas J., Grant, Seth G.N., Hardingham, Giles E., and Komiyama, Noboru H.
- Subjects
synaptogenesis ,synaptic plasticity ,Binding Sites ,neurodevelopment ,musculoskeletal, neural, and ocular physiology ,Neurogenesis ,Long-Term Potentiation ,NMDA receptor ,Receptors, N-Methyl-D-Aspartate ,Article ,Rats ,Mice, Inbred C57BL ,Protein Subunits ,nervous system ,lcsh:Biology (General) ,Mutation ,Synapses ,Animals ,Amino Acid Sequence ,Phosphorylation ,Theta Rhythm ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,lcsh:QH301-705.5 - Abstract
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., Graphical Abstract, Highlights • Mutating the GluN2B CaMKII site affects phosphorylation of its C-terminal domain • The developmental changes in NMDAR composition and synaptogenesis occur normally • Changes in NMDAR composition do not require distinct GluN2 C-terminal domains • Developmental changes in NMDAR composition are primarily sensitive to GluN2A levels, 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.
- Published
- 2018