Abstract
SummaryThe 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.
Highlights
NMDA receptors (NMDARs) (N-methyl-D-aspartate [NMDA] receptors) are glutamate-gated cation channels with high Ca2+ permeability that play key roles in CNS processes, such as synaptic transmission, learning and memory, development, neuroprotective signaling, and redox balance, as well as in neurodegenerative and neurological disorders (Baxter and Hardingham, 2016; Bell and Hardingham, 2011a, 2011b; Paoletti et al, 2013)
Given that CaMKIIa activity is implicated in synaptogenesis, we looked at the levels of phospho-Thr286 CaMKIIa in hippocampal postsynaptic densities and found them to be similar in mice of both genotypes (Figure S2D)
We found that theta burst (TBS)-long term potentiation (LTP) was not significantly different in GluN2BDCaMKII/DCaMKII versus GluN2BWT/WT slices (Figures 2J and 2K; n = 8 animals per genotype), suggesting that the GluN2B CaMKII site is not critical for this form of NMDAR-dependent synaptic plasticity
Summary
NMDARs (N-methyl-D-aspartate [NMDA] receptors) are glutamate-gated cation channels with high Ca2+ permeability that play key roles in CNS processes, such as synaptic transmission, learning and memory, development, neuroprotective signaling, and redox balance, as well as in neurodegenerative and neurological disorders (Baxter and Hardingham, 2016; Bell and Hardingham, 2011a, 2011b; Paoletti et al, 2013). During forebrain development, there is a shift in NMDAR subunit composition, from near-exclusively GluN2B-containing NMDARs to NMDARs containing a significant GluN2A contribution, e.g., GluN12-GluN2A2 diheteromeric receptors and GluN12-GluN2A-GluN2B triheteromeric receptors (Wyllie et al, 2013). This has been referred to as the ‘‘switch’’ in composition, which is partly experience dependent and takes place over postnatal weeks 2–5 in mice
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