NR2B subunit in the prefrontal cortex: A double-edged sword for working memory function and psychiatric disorders

Abstract

The prefrontal cortex (PFC) is a brain region featured with working memory function. The exact mechanism of how working memory operates within the PFC circuitry is unknown, but persistent neuronal firing recorded from prefrontal neurons during a working memory task is proposed to be the neural correlate of this mnemonic encoding. The PFC appears to be specialized for sustaining persistent firing, with N-methyl-D-aspartate (NMDA) receptors, especially slow-decay NR2B subunits, playing an essential role in the maintenance of sustained activity and normal working memory function. However, the NR2B subunit serves as a double-edged sword for PFC function. Because of its slow kinetics, NR2B endows the PFC with not only “neural psychic” properties, but also susceptibilities for neuroexcitotoxicity and psychiatric disorders. This review aims to clarify the interplay among working memory, the PFC, and NMDA receptors; demonstrate the importance of the NR2B subunit in the maintenance of persistent activity; understand the risks and vulnerabilities of how NR2B is related to the development of neuropsychiatric disorders; identify gaps that currently exist in our understanding of these processes; and provide insights regarding future directions that may clarify these issues. We conclude that the PFC is a specialized brain region with distinct delayed maturation, unique neuronal circuitry, and characteristic NMDA receptor function. The unique properties and development of NMDA receptors, especially enrichment of NR2B subunits, endows the PFC with not only the capability to generate sustained activity for working memory, but also serves as a major vulnerability to environmental insults and risk factors for psychiatric disorders.

Differential role of interleukin‐1β in neuroinflammation‐induced impairment of spatial and nonspatial memory in hyperammonemic rats

“…The GluN1 subunit is essential for membrane insertion of the NMDA receptor in the membrane, so it is an indispensable component of the receptor. However, GluN2A and GluN2B subunits act more as modulators of NMDA receptor function, determining its different role in synaptic plasticity through its different properties (83). There exists some controversy regarding the relative implication of these 2 modulating subunits in the PFC in WM performance.…”

“…There exists some controversy regarding the relative implication of these 2 modulating subunits in the PFC in WM performance. Some studies point to GluN2A-containing NMDA receptors as the main effectors for WM performance in the PFC (84,85), whereas other studies have highlighted GluN2B-containing NMDA receptors (83). Both GluN2A and GluN2B membrane expression are decreased in the PFC of hyperammonemic rats, and GluN1 membrane expression is also reduced.…”

Early life esophageal acid exposure reduces expression of NMDAR1 in the adult rat dorsal hippocampus and medial prefrontal cortex: Potential relationship with hyperlocomotion

“…Male Sprague-Dawley rats were administered with an esophageal acid or saline infusion once per day (postnatal days [7][8][9][10][11][12][13][14]. Some of these rats were given acute esophageal acid rechallenge in adulthood (postnatal day 60).…”

“…6 Synaptic plasticity, mediated by the N-methyl-D-aspartate receptor (NMDAR), has been found to be involved in cerebral functions ranging from memory formation to the development of visceral hypersensitivity. 7,8 Generally, active NMDAR exists as a heterotetramer composed of NMDAR1 (NR1) and NMDAR2 (NR2; classified into NR2A, NR2B, NR2C and NR2D) subunits, which combine with glycine or dextro-serine (D-serine) and glutamate, respectively. 9,10 Early life esophageal acid exposure increases longterm expression of NR1, NR2A and phosphorylated NR2B in the rostral cingulate cortex, indicating central neuroplasticity.…”

Adolescent maturation of the prefrontal cortex: Role of stress and sex in shaping adult risk for compromise

“…Additionally, there was a significant increase in NR2B transcript, an essential subunit of the N-methyl-D-aspartate receptor related to neural function and working memory, 73 in the PFC of males, but not females, with a history of adolescent stress. 72 The authors suggest that these differences may give rise to the vulnerability of males to stress during adolescence.…”