5 January 2012. The NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor plays a crucial role in the development and function of the cortex, according to a new report in the December 8 issue of Neuron. Led by Benjamin Hall of Tulane University in New Orleans, Louisiana, a team of researchers created a mouse model in which the NR2B subunit of the NMDA receptor was genetically replaced by the NR2A subunit. They observed altered α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor signaling in these animals, as well as a behavioral phenotype reminiscent of schizophrenia.
The glutamate hypothesis of schizophrenia, which posits dysfunction of the NMDA receptor (see SRF Current Hypothesis), is based, in part, on the observation that NMDA receptor antagonists can reproduce symptoms of the illness, and the fact that many genes reported to confer risk for schizophrenia are glutamatergic. Additionally, mice with reduced NMDA function have been utilized as models of schizophrenia (Mohn et al., 1999; see also SRF related news story).
The heteromultimeric NMDA receptor is composed of two NR1 and two NR2 subunits. NR1 is encoded by a single gene, while four genes encode NR2, producing subunits NR2A-D. During embryogenesis and early postnatal life, NMDA receptors exclusively contain NR1 and NR2B; NR2A incorporation occurs later in development (Monyer et al., 1994; Sheng et al., 1994). The study of the role of the NR2B subtype during development has been particularly difficult due to the lethality of NR2B knockout mice, as well as the fact that, in traditional models, loss of NR2B early in development also results in loss of all NMDA signaling. In the current study, Hall and colleagues have circumvented these issues by creating the "NR2B --> NR2A" mouse, which exhibits functional NMDA receptor current despite complete loss of the NR2B subunit.
Role of NR2B in AMPA receptor-mediated signaling
NMDA receptors primarily regulate synaptic strength through control of AMPA receptors (Esteban, 2008). To examine the role of NR2B loss on AMPA signaling, first author Chih-Chieh Wang and colleagues measured AMPA receptor-mediated current in cortical cultures from NR2B --> NR2A mice. They found that AMPA-mediated current was increased, consistent with prior data showing that NMDA receptor activation suppresses AMPA receptor function (Hall et al., 2007). In these animals, Wang and colleagues also observed a deficit in a protein translation-dependent form of homeostatic synaptic plasticity, the scaling of synaptic strength to maintain stability mediated in part by changes in AMPA receptor signaling (Turrigiano, 2008; Gainey et al., 2009). A similar deficit was observed in conditional NR2B knockout mice that lack NR2B only in the cortex and hippocampus, but have normal levels in subcortical regions, suggesting that the impaired homeostatic synaptic plasticity is due to a loss of NR2B rather than premature expression of NR2A. After further probing the mechanisms underlying NR2B-mediated regulation of AMPA receptor current, the researchers found that the regulation of protein translation was dependent on the mammalian/mechanistic target of rapamycin (mTOR) pathway, and also required an association between NR2B and α calcium-calmodulin kinase II (CaMKII).
Role of NR2B in social functioning
Behavioral testing of the NR2B --> NR2A animals revealed hyperlocomotion and reduced social exploratory behavior, as measured by a social approach assay. The researchers also examined conditional NR2B conditional knockout mice and observed similar locomotive and social deficits, suggesting (similar to the homeostatic synaptic plasticity data) that the behavioral effects observed are due to a loss of NR2B rather than early expression of NR2A. However, since NR2B --> NR2A mice performed worse on the social interaction task than the conditional NR2B knockouts, premature NR2A expression may also enhance the social deficit.
This study demonstrates that signaling through NR2A is unable to rescue the deficits produced by loss of NR2B, and points to the NR2B subunit as a crucial determinant of signaling through AMPA receptors, synaptic function, and social behavior.—Allison A. Curley.
Wang CC, Held RG, Chang SC, Yang L, Delpire E, Ghosh A, Hall BJ. A Critical Role for GluN2B-Containing NMDA Receptors in Cortical Development and Function. Neuron . 2011 Dec 8 ; 72(5):789-805. Abstract