Genetic Inactivation of the NMDA Receptor NR2A Subunit has Anxiolytic- and Antidepressant-Like Effects in Mice

Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20892, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 12/2006; 31(11):2405-14. DOI: 10.1038/sj.npp.1301039
Source: PubMed


There is growing evidence implicating the glutamate system in the pathophysiology and treatment of mood and anxiety disorders. Glutamatergic neurotransmission is mediated by several receptor subfamilies including multiple NMDA receptor subunits (NR2A-D). However, little is currently understood about the specific roles of NMDA subunits in the mediation of emotional behavior due to a lack of subunit-specific ligands. In the present study, we employed a mouse gene-targeting approach to examine the role of the NR2A subunit in the mediation of anxiety- and depressive-related behaviors. Results showed that NR2A knockout (KO) mice exhibit decreased anxiety-like behavior relative to wild-type littermates (WT) across multiple tests (elevated plus maze, light-dark exploration test, novel open field). NR2A KO mice showed antidepressant-like profiles in the forced swim test and tail suspension test, as compared to WT controls. Locomotor activity in the nonaversive environments of the home cage or a familiar open field were normal in the NR2A KO mice, as were gross neurological and sensory functions, including prepulse inhibition of startle. Taken together, these data demonstrate a selective and robust reduction in anxiety- and depression-related behavior in NMDA receptor NR2A subunit KO mice. Present results support a role for the NR2A subunit in the modulation of emotional behaviors in rodents and provide insight into the role of glutamate in the pathophysiology and treatment of mood and anxiety disorders.

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    • "Cholinergic inputs from the basal forebrain can modulate hippocampal activity[23]which is significantly increased following stress[24]although the way in which cholinergic function converges to regulate hippocampal inputs in these responses is unclear. There is growing evidence supporting the role of the glutamatergic system in the control of stress and affective disorders, mainly showing abnormal NMDAR transmission252627282930. In rodents, acute stress largely increases extracellular levels of glutamate and aspartate in pivotal limbic brain areas involving affective-like behaviors[31]which are also attenuated when glucocorticoids are withdrawn after adrenalectomy[32]. "
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    ABSTRACT: Extensive evidence indicates the influence of the cholinergic system on emotional processing. Previous findings provided new insights into the underlying mechanisms of long-term anxiety, showing that rats injected with a single systemic dose of pilocarpine—a muscarinic receptor (mAChR) agonist—displayed persistent anxiogenic-like responses when evaluated in different behavioral tests and time-points (24 h up to 3 months later). Herein, we investigated whether the pilocarpine-induced long-term anxiogenesis modulates the HPA axis function and the putative involvement of NMDA receptors (NMDARs) following mAChRs activation. Accordingly, adult male Wistar rats presented anxiogenic-like behavior in the elevated plus-maze (EPM) after 24 h or 1 month of pilocarpine injection (150 mg/kg, i.p.). In these animals, mAChR activation disrupted HPA axis function inducing a long-term increase of corticosterone release associated with a reduced expression of hippocampal GRs, as well as consistently decreased NMDAR subunits expression. Furthermore, in another group of rats injected with memantine–an NMDARs antagonist (4 mg/kg, i.p.)–prior to pilocarpine, we found inhibition of anxiogenic-like behaviors in the EPM but no further alterations in the pilocarpine-induced NMDARs downregulation. Our data provide evidence that behavioral anxiogenesis induced by mAChR activation effectively yields short- and long-term alterations in hippocampal NMDARs expression associated with impairment of hippocampal inhibitory regulation of HPA axis activity. This is a novel mechanism associated with anxiety-like responses in rats, which comprise a putative target to future translational studies.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "NMDARs are hetero-oligomers consisting of GluN1 and GluN2 (GluN2A, GluN2B, GluN2C, and GluN2D) subunits (Schorge and Colquhoun, 2003; Luo et al., 1997). The GluN2 subunit, present in a functional NMDAR, determines the physiological characteristics of NMDAR (Luo et al., 1997; Boyce-Rustay and Holmes, 2006; Cull-Candy et al., 2001). In the adult hippocampus, GluN2A and GluN2B are the predominantly expressed NR2 subunits (Schorge and Colquhoun, 2003). "
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    ABSTRACT: Early adverse life experiences have been associated with anxiety-like behavior and memory impairment. N-methyl-d-aspartate receptors (NMDARs) play an important role in brain development. Enriched environments are known to positively influence emotional and cognitive functions in the brain. We examined the effects of maternal deprivation (MD) on NMDAR subunits in the hippocampus, locomotor activity, anxiety behaviors, and learning-memory performance of Balb/c mice. We also examined whether these effects could be reversed by raising the offspring in an enriched environment. The mice were separated from their mothers for a single 24h episode on postnatal day (PND) 9. The mice were weaned on day 21 and were housed under either standard (SE) or enriched (EE) environmental conditions. Emotional behaviors and cognitive processes of mice were evaluated using an open field (OF) test, an elevated plus maze (EPM) test, and a Morris water-maze (MWM). NMDAR subunits (GluN1, GluN2A, and GluN2B) mRNA expression levels in the hippocampus were examined by real-time PCR. In OF, MD had no effect on horizontal locomotor activity. MD increased anxiety-like behaviors in the EPM and decreased spatial learning performance in MWM; however, these effects were not reversed by EE. MD (in SE and EE conditions) increased GluN1, GluN2A, and GluN2B mRNA expressions in the hippocampus. In conclusion, MD led to the deterioration of the emotional and cognitive processes during adulthood. Moreover, environmental enrichment did not reverse the deleterious effects of the MD on emotional and cognitive functions and increased the NMDAR levels. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Aug 2015 · Brain research
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    • "The NMDAR is a heteromeric receptor complex comprised of a functionally obligatory GluN1 subunit and combinations of GluN2-3 subunits. Constitutive deletion of GluN2A in mice mimics the antidepressant-like profile of NMDAR antagonists [18]. Furthermore, systemic administration of compounds that selectively block GluN2B, such as CP-101-606, ifenprodil, and Ro 25-6981, produces antidepressantlike effects in rodents [7,9,13,19–23] and therapeutic efficacy in human depression [24]. "
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    ABSTRACT: Drugs targeting the glutamate N-methyl-D-aspartate receptor (NMDAR) may be efficacious for treating mood disorders, as exemplified by the rapid antidepressant effects produced by single administration of the NMDAR antagonist ketamine. Though the precise mechanisms underlying the antidepressant-related effects of NMDAR antagonism remain unclear, recent studies implicate specific NMDAR subunits, including GluN2A and GluN2B, as well as the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) subunit glutamate receptor interacting molecule, PSD-95. Here, integrating mutant and pharmacological in mice, we investigated the contribution of these subunits and molecules to antidepressant-related behaviors and the antidepressant-related effects of the GluN2B blocker, Ro 25-6981. We found that global deletion of GluA1 or PSD-95 reduced forced swim test (FST) immobility, mimicking the antidepressant-related effect produced by systemically administered Ro 25-6981 in C57BL/6J mice. Moreover, the FST antidepressant-like effects of systemic Ro 25-6981 were intact in mutants with global GluA1 deletion or GluN1 deletion in forebrain interneurons, but were absent in mutants constitutively lacking GluN2A or PSD-95. Next, we found that microinfusing Ro 25-6981 into the medial prefrontal cortex (mPFC), but not basolateral amygdala, of C57BL/6J mice was sufficient to produce an antidepressant-like effect. Together, these findings extend and refine current understanding of the mechanisms mediating antidepressant-like effects produced by NMDAR-GluN2B antagonists, and may inform the development of a novel class of medications for treating depression that target the GluN2B subtype of NMDAR. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Mar 2015 · Behavioural brain research
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