Editing NMDA receptor (section)

===GluN2B to GluN2A switch===
[[File: NR2B-NR2A switch in human cerebellum, microarrays, Bar-Shira et al 2015.png| thumb|The timecourse of GluN2B-GluN2A switch in human cerebellum. Bar-Shira et al., 2015 <ref name="pmid26636753">{{cite journal | vauthors = Bar-Shira O, Maor R, Chechik G | title = Gene Expression Switching of Receptor Subunits in Human Brain Development | journal = PLOS Computational Biology | volume = 11 | issue = 12 | pages = e1004559 | date = December 2015 | pmid = 26636753 | pmc = 4670163 | doi = 10.1371/journal.pcbi.1004559 | bibcode = 2015PLSCB..11E4559B | doi-access = free }}</ref>]]

While [[GRIN2B|GluN2B]] is predominant in the early postnatal brain, the number of GluN2A subunits increases during early development; eventually, [[GRIN2A|GluN2A]] subunits become more numerous than GluN2B. This is called the GluN2B-GluN2A developmental switch, and is notable because of the different kinetics each GluN2 subunit contributes to receptor function.<ref name="pmid15470155">
{{cite journal | vauthors = Liu XB, Murray KD, Jones EG | title = Switching of NMDA receptor 2A and 2B subunits at thalamic and cortical synapses during early postnatal development | journal = The Journal of Neuroscience | volume = 24 | issue = 40 | pages = 8885–8895 | date = October 2004 | pmid = 15470155 | pmc = 6729956 | doi = 10.1523/JNEUROSCI.2476-04.2004 }}</ref> For instance, greater ratios of the GluN2B subunit leads to NMDA receptors which remain open longer compared to those with more GluN2A.<ref name="pmid10789248">{{cite journal | vauthors = Tsien JZ | title = Building a brainier mouse | journal = Scientific American | volume = 282 | issue = 4 | pages = 62–68 | date = April 2000 | pmid = 10789248 | doi = 10.1038/scientificamerican0400-62 | bibcode = 2000SciAm.282d..62T }}</ref> This may in part account for greater memory abilities in the immediate postnatal period compared to late in life, which is the principle behind genetically altered '[[doogie mice]]'.
The detailed time course of this switch in the human cerebellum has been estimated using expression microarray and RNA seq and is shown in the figure on the right.

There are three hypothetical models to describe this switch mechanism:
* Increase in synaptic GluN2A along with decrease in GluN2B
* Extrasynaptic displacement of GluN2B away from the synapse with increase in GluN2A
* Increase of GluN2A diluting the number of GluN2B without the decrease of the latter.

The GluN2B and GluN2A subunits also have differential roles in mediating [[excitotoxicity|excitotoxic]] neuronal death.<ref name="pmid17360906">{{cite journal | vauthors = Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT | display-authors = 6 | title = NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo | journal = The Journal of Neuroscience | volume = 27 | issue = 11 | pages = 2846–2857 | date = March 2007 | pmid = 17360906 | pmc = 6672582 | doi = 10.1523/JNEUROSCI.0116-07.2007 }}</ref> The developmental switch in subunit composition is thought to explain the developmental changes in NMDA neurotoxicity.<ref name="pmid16540573">{{cite journal | vauthors = Zhou M, Baudry M | title = Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors | journal = The Journal of Neuroscience | volume = 26 | issue = 11 | pages = 2956–2963 | date = March 2006 | pmid = 16540573 | pmc = 6673978 | doi = 10.1523/JNEUROSCI.4299-05.2006 }}</ref> Homozygous disruption of the gene for GluN2B in mice causes perinatal [[lethality]], whereas disruption of the GluN2A gene produces viable mice, although with impaired hippocampal plasticity.<ref>{{cite journal | vauthors = Sprengel R, Suchanek B, Amico C, Brusa R, Burnashev N, Rozov A, Hvalby O, Jensen V, Paulsen O, Andersen P, Kim JJ, Thompson RF, Sun W, Webster LC, Grant SG, Eilers J, Konnerth A, Li J, McNamara JO, Seeburg PH | display-authors = 6 | title = Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo | journal = Cell | volume = 92 | issue = 2 | pages = 279–289 | date = January 1998 | pmid = 9458051 | doi = 10.1016/S0092-8674(00)80921-6 | s2cid = 9791935 | doi-access = free }}</ref> One study suggests that [[reelin]] may play a role in the NMDA receptor maturation by increasing the GluN2B subunit mobility.<ref name="pmid17881522">{{cite journal | vauthors = Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P | title = NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin | journal = The Journal of Neuroscience | volume = 27 | issue = 38 | pages = 10165–10175 | date = September 2007 | pmid = 17881522 | pmc = 6672660 | doi = 10.1523/JNEUROSCI.1772-07.2007 }}</ref>