Social Isolation-Induced Increase in NMDA Receptors in the Hippocampus Exacerbates Emotional Dysregulation in Mice
Social Isolation-Induced Increase in NMDA Receptors in the Hippocampus Exacerbates Emotional Dysregulation in Mice
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DOI：
10.1002/hipo.22384
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发表时间：
2015-04-01
期刊：
影响因子：
3.5
通讯作者：
Gean, Po-Wu
中科院分区：
文献类型：
--
作者：
Chang, Chih-Hua;Hsiao, Ya-Hsin;Gean, Po-Wu
流行病学研究表明，早期生活不良事件对青春期后续应激暴露的易感性有长期影响，但确切机制尚不清楚。在本研究中，将出生后第21-28天的小鼠随机分配到一组或隔离笼中8周。社会隔离（SI）小鼠表现出更高水平的自发运动活动，在强迫游泳试验（FST）中的不动持续时间更长，前脉冲抑制（PPI）显著减少，攻击性（但不是攻击）行为增加。然而，急性应激显著加剧了SI小鼠的攻击次数，但不影响组舍（GH）小鼠。与GH小鼠相比，SI小鼠在海马中表现出更高的突触体NR 2A和NR 2B水平。全细胞膜片钳记录显示，SI小鼠海马脑片CA 1区神经元的NMDAR-EPSC的输入-输出关系比GH小鼠高。NR 2B特异性拮抗剂艾芬地尔的应用对来自SI小鼠的切片中的NMDAR-EPSC产生更大的衰减作用。从SI小鼠记录的NMDAR EPSC具有较慢的失活动力学。NMDA拮抗剂MK-801、CPP和ifenprodil可逆转急性应激引起的攻击和抑郁行为的夸大。此外，急性应激诱导的SI小鼠攻击行为的恶化在NR 2B表达敲低后被消除。这些结果表明，社交孤立诱导的海马NMDA受体表达增加涉及攻击行为的应激加剧。通过NMDA拮抗剂改善攻击行为可能为治疗被忽视儿童中情绪攻击爆发的精神病理学开辟了新的途径。(c)2014 Wiley Periodicals，Inc.
Epidemiological studies have shown that early life adverse events have long-term effects on the susceptibility to subsequent stress exposure in adolescence, but the precise mechanism is unclear. In the present study, mice on postnatal day 21-28 were randomly assigned to either a group or isolated cages for 8 weeks. The socially isolated (SI) mice exhibited a higher level of spontaneous locomotor activity, a longer duration of immobility in the forced swimming test (FST), significantly less prepulse inhibition (PPI) and an increase in aggressive (but not attack) behavior. However, acute stress markedly exacerbated the attack counts of the SI mice but did not affect the group housing (GH) mice. SI mice exhibited higher synaptosomal NR2A and NR2B levels in the hippocampus as compared to the GH mice. Whole-cell patch clamp recordings of CA1 neurons in hippocampal slices showed that the SI mice exhibited a higher input-output relationship of NMDAR-EPSCs as compared to the GH mice. Application of the NR2B-specific antagonist ifenprodil produced a greater attenuating effect on NMDAR-EPSCs in slices from the SI mice. NMDAR EPSCs recorded from the SI mice had a slower deactivation kinetic. MK-801, CPP and ifenprodil, the NMDA antagonists, reversed acute stress-induced exaggeration of aggressive and depressive behaviors. Furthermore, acute stress-induced exacerbation of attack behavior in the SI mice was abolished after the knockdown of NR2B expression. These results suggest that social isolation-induced increased expression of NMDA receptors in the hippocampus involves stress exacerbation of aggressive behaviors. Amelioration of aggressive behaviors by NMDA antagonists may open a new avenue for the treatment of psychopathologies that involve outbursts of emotional aggression in neglected children. (c) 2014 Wiley Periodicals, Inc.