Fear memory impairing effects of systemic treatment with the NMDA NR2B subunit antagonist, Ro 25-6981, in mice: attenuation with ageing.
Fear memory impairing effects of systemic treatment with the NMDA NR2B subunit antagonist, Ro 25-6981, in mice: attenuation with ageing.
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DOI：
10.1016/j.pbb.2008.08.028
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发表时间：
2009-01
影响因子：
3.6
通讯作者：
Holmes, Andrew
中科院分区：
文献类型：
--
作者：
Mathur, Poonam;Graybeal, Carolyn;Feyder, Michael;Davis, Margaret I.;Holmes, Andrew
关键词：
N-甲基-D-天冬氨酸受体（NMDAR）是突触可塑性和学习的介质，并且与神经精神疾病和年龄相关的认知功能障碍的病理生理学有关。NMDAR是异聚体，但特定亚基对NMDAR介导的学习的相对贡献尚未完全了解。我们表征了NR 2B亚基选择性拮抗剂Ro 25-6981对C57 BL/6 J小鼠的多试验、单试验和低休克巴甫洛夫恐惧条件反射的预处理系统性治疗。还分析了Ro 25-6981对新开放视野探索、增加的十字迷宫焦虑样行为、惊吓反应性、惊吓前脉冲抑制和伤害性感受的影响。比较了三个月（成年）和12个月大的C57 BL/6 Tac小鼠的Ro 25-6981对多次试验恐惧条件反射和皮质边缘NR 2B蛋白水平的影响。Ro 25-6981在多次试验和一次试验（但不是低冲击）条件反射范式中中度损害恐惧学习，但不影响探索或焦虑相关行为或感觉功能。Ro 25-6981在12月龄小鼠中不存在记忆损害作用，尽管NR 2B蛋白水平没有显著改变。目前的数据提供了进一步的证据表明，选择性阻断含NR 2B的NMDAR的记忆损害作用，并显示这些作用随着年龄的增长而丧失。这项工作最终可能对阐明神经精神疾病和衰老中学习功能障碍的病理生理学产生影响。
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.
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