Mathur P, Graybeal C, Feyder M, Davis MI, Holmes A. Fear memory impairing effects of systemic treatment with the NMDA NR2B subunit antagonist, Ro 25-6981, in mice: attenuation with ageing. Pharmacol Biochem Behav 91: 453-460

Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Rockville, MD, USA
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 01/2009; 91(3):453-460. DOI: 10.1016/j.pbb.2008.08.028


N-methyl-d-aspartate receptors (NMDARs) are mediators of synaptic plasticity and learning and are implicated in the pathophysiology of neuropsychiatric disease and age-related cognitive dysfunction. NMDARs are heteromers, but the relative contribution of specific subunits to NMDAR-mediated learning is not fully understood. We characterized pre-conditioning systemic treatment of the NR2B subunit-selective antagonist Ro 25-6981 for effects on multi-trial, one-trial and low-shock Pavlovian fear conditioning in C57BL/6J mice. Ro 25-6981 was also profiled for effects on novel open field exploration, elevated plus-maze anxiety-like behavior, startle reactivity, prepulse inhibition of startle, and nociception. Three-month (adult) and 12-month old C57BL/6Tac mice were compared for Ro 25-6981 effects on multi-trial fear conditioning, and corticolimbic NR2B protein levels. Ro 25-6981 moderately impaired fear learning in the multi-trial and one-trial (but not low-shock) conditioning paradigms, but did not affect exploratory or anxiety-related behaviors or sensory functions. Memory impairing effects of Ro 25-6981 were absent in 12-month old mice, although NR2B protein levels were not significantly altered. Present data provide further evidence of the memory impairing effects of selective blockade of NR2B-containing NMDARs, and show loss of these effects with ageing. This work could ultimately have implications for elucidating the pathophysiology of learning dysfunction in neuropsychiatric disorders and ageing.

13 Reads
  • Source
    • "We specifically tested if acute, transient, and broad blockade of GluN2B affects klotho-mediated enhancement of cognition without disrupting baseline cognitive functions. To this end, we used low doses of pharmacological GluN2B antagonists that minimally affect NTG mice (Mathur et al., 2009; Sotres-Bayon et al., 2007). Young mice were injected intraperitoneally (i.p.) with ifenprodil (5 mg/kg) or vehicle before training in fear conditioning and then tested 1 day later. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.
    Cell Reports 05/2014; 7(4). DOI:10.1016/j.celrep.2014.03.076 · 8.36 Impact Factor
  • Source
    • "Moreover, selective inhibition of GluN2B-containing NMDARs could potentially avoid the known side effects of non-selective NMDAR antagonists (Chazot, 2004; Mony et al, 2009) because of their preferential presence at extrasynaptic but not synaptic regions on excitatory pyramidal neurons in adult brain (Harris and Pettit, 2007; Papouin et al, 2012; Tovar and Westbrook, 1999). However, aside from pathological activation, evidence from both genetic deletion of GluN2B and acute systemic administration of GluN2B antagonists suggest a physiological role for GluN2B receptors in the adult brain during memory function (Mathur et al, 2009; von Engelhardt et al, 2008). Furthermore, a significant portion of the excitatory drive to inhibitory interneurons is mediated by NMDARs (Lei and McBain, 2002; Wang and Gao, 2009), and GluN2B subunits are expressed in GABAergic interneurons (Lei and McBain, 2002; Porter et al, 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: While antagonists to GluN2B-containing N-Methyl-d-Aspartate receptors (NMDARs) have been widely considered to be neuroprotective under certain pathological conditions, their immediate and lasting impacts on synaptic, circuit, and cognitive functions are poorly understood. In hippocampal slices, we found that the GluN2B-selective antagonist Ro25-6981 (Ro25) reduced synaptic NMDAR responses and consequently neuronal output in a subpopulation of GABAergic interneurons, but not pyramidal neurons. Consistent with these effects, Ro25 reduced GABAergic responses in pyramidal neurons and hence could affect circuit functions by altering the excitation/inhibition balance in the brain. In slices from Ts65Dn mice, a Down syndrome model with excess inhibition and cognitive impairment, acutely applied Ro25 rescued long-term potentiation (LTP) and gamma oscillation deficits, while prolonged dosing induced persistent rescue of LTP. In contrast, Ro25 did not impact LTP in wt mice but reduced gamma oscillations both acutely and following prolonged treatment. While acute Ro25 treatment impaired memory performance in wt mice, memory deficits in Ts65Dn mice were unchanged. Thus, GluN2B-NMDARs contribute to the excitation/inhibition balance via impacts on interneurons, and blocking GluN2B-NMDARs can alter functions that depend on this balance, including synaptic plasticity, gamma oscillations, and memory. That prolonged GluN2B antagonism leads to persistent changes in synaptic and circuit functions and that the influence of GluN2B antagonism differs between wild-type and disease model mice provides critical insight into the therapeutic potential and possible liabilities of GluN2B antagonists.Neuropsychopharmacology accepted article preview online, 22 January 2013; doi:10.1038/npp.2013.19.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2013; 38(7). DOI:10.1038/npp.2013.19 · 7.05 Impact Factor
  • Source
    • "In male mice, the absence of Kal7 produced a substantial impairment in passive-avoidance acquisition (Ma et al., 2008). Administration of an NR2B antagonist, [-(4-hydroxyphenyl)--methyl-4-(phenylmethyl)-1-piperi- dine propanol (Ro 25-6981)], impaired acquisition of conditioned fear behavior in male mice (Mathur et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Estradiol treatment of ovariectomized rodents is known to affect the morphology of dendritic spines and produce behavioral and cognitive effects. Kalirin-7 (Kal7), a PSD-localized Rho-guanine nucleotide exchange factor, is important for dendritic spine formation and stability. Male Kal7 knockout (Kal7(KO)) mice exhibit a number of abnormal behavioral and biochemical phenotypes. Given that chronic estradiol (E2) replacement of ovariectomized rats enhanced Kal7 expression in the hippocampus and in primary hippocampal cultures, we assessed the behavioral and biochemical effects of chronic E2 treatment of ovariectomized female wildtype and Kal7(KO) mice. Both intact and ovariectomized Kal7(KO) female mice exhibited decreased anxiety-like behavior compared to the corresponding wildtype in the elevated zero maze, unaffected by E2 treatment. Chronic E2 decreased locomotor activity in the open field and enhanced performance in a passive avoidance fear conditioning task, which were both unaffected by genotype. Kal7(KO) female mice engaged in significantly more object exploration, both familiar and novel, than did wildtype females. E2 enhanced the acute locomotor response to cocaine, with no significant effect of genotype. Similar to Kal7(KO) males, Kal7(KO) females had decreased levels of NR2B in hippocampal post-synaptic density fractions, with no effect of E2 treatment. The differing behavioral effects of Kal7 ablation in female and male mice may offer insight into the molecular underpinnings of these differences.
    Molecular pharmacology 09/2012; 82(6). DOI:10.1124/mol.112.080838 · 4.13 Impact Factor
Show more