@Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses (Ferreira et al. 2017)

2022-04-29: reference:

@Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses (Ferreira et al. 2017) #

• This ‘synaptic shift’ of NMDA maturation is characterized by a higher ratio of NR2B:NR2A as stated in @Global view of transcriptome in the brains of aged NR2B transgenic mice (Li et al. 2013), and it is also characterized by a change of the NMDA co-agonist from Glycine to D-Serine. NR2B-containing NMDARs have 10x the affiniy for glycine than NR2A-containing.
  • Postsynaptic Serine Racemase Regulates NMDA Receptor Function (Wong et al. 2020)
    • Single-neuron genetic deletion of SR resulted in the elimination of LTP at 1 month of age, which could be rescued by exogenous d-serine. Interestingly, there was a restoration of LTP by 2 months of age that was associated with an upregulation of synaptic NR2B.
• mGluR5 and NMDA Receptors Drive the Experience- and Activity-Dependent NMDA Receptor NR2B to NR2A Subunit Switch
  • So calcium. Maybe the SS amounts to homeostatic downregulation?
  • mGluR5 KO the switch in CA1 is deficient.

• There is little evidence that NMDAR subtypes have a preferred co-agonist.

• D-serine alters the membrane dynamics and content of GluN2B-NMDAR, but not GluN2A-NMDAR, at synapses through a process requiring PDZ binding scaffold partners.

  • It’s only natural to assume that PDZs mediate internalization, plasticity, etc. But are they just work horses and levers, or is it worth checking out?
    • In particular, changes in the postsynaptic scaffold apparatus have been thoroughly investigated during development, providing evidence that PDZ-scaffold proteins (e.g. SAP-102, PSD-95) are differentially involved in the regulation of the GluN2A/B subunit ratio: SAP102 mediates synaptic clearance of NMDA receptors,
    • extracellular molecules (e.g. reelin, ephrinB) and genetic mechanisms (e.g. transcriptional repressor REST) have also been identified as important regulators of the GluN2-NMDAR switch

• D-Serine causes internalization of NR2B through modulation of the receptor’s C-terminus interactions. Thus, genetic removal of D-serine prevents the synaptic shift:

  • Single-neuron genetic deletion of Serine Racemase resulted in the elimination of LTP at 1 month of age, which could be rescued by exogenous d-serine. Interestingly, there was a restoration of LTP by 2 months of age that was associated with an upregulation of synaptic NR2B

• The decreased interaction between GluN2B-NMDAR and PSD-95 after D-serine incubation may favor the receptor endocytosis by unmasking a GluN2B internalization signal