Furuie Hiroki, Yamada Mitsuhiko
Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8553, Japan.
Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8553, Japan.
Neurosci Res. 2022 Mar;176:57-65. doi: 10.1016/j.neures.2021.10.005. Epub 2021 Oct 14.
The immature brain is highly sensitive to disturbances in the functioning of N-methyl-d-aspartate (NMDA) receptor in rodents, and blockade of the receptor during postnatal brain development period causes schizophrenia-like behavior in adulthood. During the postnatal period, NR2A- and NR2B-containing NMDA receptors are highly expressed, and these two subunits show different expression patterns in the brain. However, the functions of these two NMDA receptors are unknown. In this study, we treated rats with an NR2A-preferring NMDA receptor antagonist (PEAQX, 10 mg/kg), an NR2B-selective NMDA receptor antagonist (ifenprodil, 7.5 mg/kg), or a nonselective blocker of the NMDA receptor (MK-801, 0.4 mg/kg) during the neonatal period. Rats neonatally treated with MK-801 or PEAQX showed spatial working memory deficits in the Y-maze test. PEAQX-treated rats also showed greater reactivity to acoustic stimuli and hypersensitivity to acute MK-801 challenge. However, ifenprodil treatment did not cause any detectable behavioral changes. These results suggest that the NR2A-containing NMDA receptor is indispensable for proper brain development in rats, and functional disturbances in this subunit impair hippocampus-dependent spatial working memory in adulthood.
未成熟的大脑对啮齿动物中N-甲基-D-天冬氨酸（NMDA）受体功能的紊乱高度敏感，在出生后大脑发育期间阻断该受体可导致成年期出现精神分裂症样行为。在出生后时期，含NR2A和NR2B的NMDA受体高度表达，且这两个亚基在大脑中表现出不同的表达模式。然而，这两种NMDA受体的功能尚不清楚。在本研究中，我们在新生期用一种优先作用于NR2A的NMDA受体拮抗剂（PEAQX，10毫克/千克）、一种NR2B选择性NMDA受体拮抗剂（ifenprodil，7.5毫克/千克）或一种NMDA受体的非选择性阻滞剂（MK-801，0.4毫克/千克）处理大鼠。新生期用MK-801或PEAQX处理的大鼠在Y迷宫试验中表现出空间工作记忆缺陷。用PEAQX处理的大鼠对听觉刺激也表现出更大的反应性以及对急性MK-801激发的超敏反应。然而，ifenprodil处理未引起任何可检测到的行为变化。这些结果表明，含NR2A的NMDA受体对大鼠大脑的正常发育不可或缺，且该亚基的功能紊乱会损害成年期依赖海马体的空间工作记忆。
