Effects of the GluN2B-NMDA receptor antagonist Ro 25-6981 on two types of behavioral flexibility in rats

Clark, Emma; Antoniak, Kristen; Feniquito, Alyssandra; Dringenberg, Hans C.

doi:10.1016/j.bbr.2016.11.032

Cited by 8 publications

(4 citation statements)

References 19 publications

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“…Alcohol is well known to affect not only GABAergic function, but also glutamatergic transmission in cortex (Carpenter-Hyland et al, 2004;Skorput & Yeh, 2016;Thomas et al, 2004). Studies have also found that N-methyl-D-aspartate receptors (NMDARs) play a critical role in several aspects of learning and behavioral flexibility in rodent models (Clark et al, 2017;Dong et al, 2013;Marquardt et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Sex‐specific effect of prenatal alcohol exposure on N‐methyl‐D‐aspartate receptor function in orbitofrontal cortex pyramidal neurons of mice

Licheri

Chandrasekaran

Bird

et al. 2021

Alcoholism Clin & Exp Res

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Background: Alcohol consumption during pregnancy can produce behavioral and cognitive deficits that persist into adulthood. These include impairments in executive functions, learning, planning, and cognitive flexibility. We have previously shown that moderate prenatal alcohol exposure (PAE) significantly impairs reversal learning, a measure of flexibility mediated across species by different brain areas that include the orbital frontal cortex (OFC). Reversal learning is likewise impaired by genetic or pharmacological inactivation of GluN2B subunit-containing N-methyl-D-aspartate receptors (NMDARs). In the current study, we tested the hypothesis that moderate PAE persistently alters the number and function of GluN2B subunit-containing NMDARs in OFC pyramidal neurons of adult mice. Methods:We used a rodent model of fetal alcohol spectrum disorders and left offspring undisturbed until adulthood. Using whole-cell, patch-clamp recordings, we assessed NMDAR function in slices from 90-to 100-day-old male and female PAE and control mice. Pharmacologically isolated NMDA receptor-mediated evoked excitatory postsynaptic currents (NMDA-eEPSCs) were recorded in the absence and presence of the GluN2B antagonist, Ro25-6981(1 µM). In a subset of littermates, we evaluated the level of GluN2B protein expression in the synaptic fraction using Western blotting technique. Results:Our results indicate that PAE females show significantly larger (~23%) NMDA-eEPSC amplitudes than controls, while PAE induced a significant decrease (~17%) in NMDA-eEPSC current density of pyramidal neurons recorded in slices from male mice. NMDA-eEPSC decay time was not affected in PAE-exposed mice from either sex. The contribution of GluN2B subunit-containing NMDARs to the eEPSCs was not significantly altered by PAE. Moreover, there were no significant changes in protein expression in the synaptic fraction of either PAE males or females.Conclusions: These findings suggest that low-to-moderate PAE modulates NMDAR function in pyramidal neurons in a sex-specific manner, although we did not find evidence that the effect is mediated by dysfunction of synaptic GluN2B subunitcontaining NMDARs.

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Section: Introductionmentioning

confidence: 99%

Sex‐specific effect of prenatal alcohol exposure on N‐methyl‐D‐aspartate receptor function in orbitofrontal cortex pyramidal neurons of mice

Licheri

Chandrasekaran

Bird

et al. 2021

Alcoholism Clin & Exp Res

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“…In adult rodents, disruption of medial prefrontal NMDAR or AMPA receptor function impaired set-shift performance, increasing perseverative errors, but had no effect on reversal learning [84][85][86]. More selective manipulations, targeting GluN2A and GluN2B specifically, have demonstrated their important role in extradimensional set-shifting and spatial reversal learning [80,[87][88][89]. In terms of aging, age-related reductions in GluN1 expression in the mPFC were correlated with impaired set-shifting performance in aged rats, while expression of AMPA receptor subunits that were found to be decreased with aging (GluR1, GluR2) did not relate to set-shifting performance [90].…”

Section: Discussionmentioning

confidence: 99%

Viral vector-mediated upregulation of serine racemase expression in medial prefrontal cortex improves learning and synaptic function in middle age rats

Yegla

Rani

Kumar

2023

Aging

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An age-associated decrease in N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic function contributes to impaired synaptic plasticity and is associated with cognitive impairments. Levels of serine racemase (SR), an enzyme that synthesizes D-serine, an NMDAR co-agonist, decline with age. Thus, enhancing NMDAR function via increased SR expression in middle age, when subtle declines in cognition emerge, was predicted to enhance performance on a prefrontal cortex-mediated task sensitive to aging. Middle-aged (~12 mo) male Fischer-344 rats were injected bilaterally in the medial prefrontal cortex (mPFC) with viral vector (LV), SR (LV-SR) or control (LV-GFP). Rats were trained on the operant attentional set-shift task (AST) to examine cognitive flexibility and attentional function. LV-SR rats exhibited a faster rate of learning compared to controls during visual discrimination of the AST. Extradimensional set shifting and reversal were not impacted. Immunohistochemical analyses demonstrated that LV-SR significantly increased SR expression in the mPFC. Electrophysiological characterization of synaptic transmission in the mPFC slices obtained from LV-GFP and LV-SR animals indicated a significant increase in isolated NMDAR-mediated synaptic responses in LV-SR slices. Thus, results of the current study demonstrated that prefrontal SR upregulation in middle age rats can improve learning of task contingencies for visual discrimination and increase glutamatergic synaptic transmission, including NMDAR activity.

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“…These findings concur with data that administration of Ro25-6981 (10 mg/kg) selectively impairs the early phase of reversal learning. In view of this, spatial reversal learning but not set-shifting has been shown to be sensitive to Ro-25-6981 treatment (Clark et al 2017 ). Additionally, it is of note from our findings that blockade of NR2B/NMDA receptors subsequently discloses a stimulant effect on memory reconsolidation at the repeated training stage of the experimental protocol where stored memories become more labile.…”

Section: Discussionmentioning

confidence: 99%

“…However, Ro25-6981 facilitated the formation of spatial skill in those animals with initial inferior learning ability (Soloviova et al 2011 ). More recent data has suggested that spatial reversal learning is sensitive to Ro25-6981 whereby NR2B/NMDA receptor signaling may be implicated in behavioral plasticity involved in updating spatial information (Clark et al 2017 ).…”

Section: Introductionmentioning

confidence: 99%

The Neurogenesis Actuator and NR2B/NMDA Receptor Antagonist Ro25-6981 Consistently Improves Spatial Memory Retraining Via Brain Region-Specific Gene Expression

et al. 2018

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NR2B-containing NMDA (NR2B/NMDA) receptors are important in controlling neurogenesis and are involved in generating spatial memory. Ro25-6981 is a selective antagonist at these receptors and actuates neurogenesis and spatial memory. Inter-structural neuroanatomical profiles of gene expression regulating adult neurogenesis and neuroapoptosis require examination in the context of memory retrieval and reversal learning. The aim was to investigate spatial memory retrieval and reversal learning in relation to gene expression-linked neurogenetic processes following blockade of NR2B/NMDA receptors by Ro25-6981. Rats were trained in Morris water maze (MWM) platform location for 5 days. Ro25-6981 was administered (protocol days 6–7) followed by retraining (days 15–18 or 29–32). Platform location was tested (on days 19 or 33) then post-mortem brain tissue sampling (on days 20 or 34). The expression of three genes known to regulate cell proliferation (S100a6), differentiation (Ascl1), and apoptosis (Casp-3) were concomitantly evaluated in the hippocampus, prefrontal cortex, and cerebellum in relation to the MWM performance protocol. Following initial training, Ro25-6981 enhanced visuospatial memory retrieval performance during further retraining (protocol days 29–32) but did not influence visuospatial reversal learning (day 33). Hippocampal Ascl1 and Casp-3 expressions were correspondingly increased and decreased while cerebellar S100a6 and Casp-3 activities were decreased and increased respectively 27 days after Ro25-6981 treatment. Chronological analysis indicated a possible involvement of new mature neurons in the reconfiguration of memory processes. This was attended by behavioral/gene correlations which revealed direct links between spatial memory retrieval enhancement and modified gene activity induced by NR2B/NMDA receptor blockade and upregulation.

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Effects of the GluN2B-NMDA receptor antagonist Ro 25-6981 on two types of behavioral flexibility in rats

Cited by 8 publications

References 19 publications

Sex‐specific effect of prenatal alcohol exposure on N‐methyl‐D‐aspartate receptor function in orbitofrontal cortex pyramidal neurons of mice

Sex‐specific effect of prenatal alcohol exposure on N‐methyl‐D‐aspartate receptor function in orbitofrontal cortex pyramidal neurons of mice

Viral vector-mediated upregulation of serine racemase expression in medial prefrontal cortex improves learning and synaptic function in middle age rats

The Neurogenesis Actuator and NR2B/NMDA Receptor Antagonist Ro25-6981 Consistently Improves Spatial Memory Retraining Via Brain Region-Specific Gene Expression

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