Boyce-Rustay Janel M, Holmes Andrew
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. 2006 Nov;31(11):2405-14. doi: 10.1038/sj.npp.1301039. Epub 2006 Feb 8.
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.
越来越多的证据表明谷氨酸系统与情绪和焦虑障碍的病理生理学及治疗有关。谷氨酸能神经传递由几个受体亚家族介导，包括多个NMDA受体亚基（NR2A-D）。然而，由于缺乏亚基特异性配体，目前对NMDA亚基在介导情绪行为中的具体作用了解甚少。在本研究中，我们采用小鼠基因靶向方法来研究NR2A亚基在介导焦虑和抑郁相关行为中的作用。结果表明，在多项测试（高架十字迷宫、明暗探索试验、新奇旷场试验）中，与野生型同窝小鼠（WT）相比，NR2A基因敲除（KO）小鼠的焦虑样行为减少。与WT对照组相比，NR2A KO小鼠在强迫游泳试验和悬尾试验中表现出抗抑郁样特征。NR2A KO小鼠在家庭笼舍或熟悉的旷场等非厌恶环境中的运动活动正常，其总体神经和感觉功能也正常，包括惊吓前脉冲抑制。综上所述，这些数据表明NMDA受体NR2A亚基KO小鼠的焦虑和抑郁相关行为有选择性且显著减少。目前的结果支持NR2A亚基在调节啮齿动物情绪行为中的作用，并为谷氨酸在情绪和焦虑障碍的病理生理学及治疗中的作用提供了见解。
