Blockade of corticotropin-releasing hormone receptor 1 attenuates early-life stress-induced synaptic abnormalities in the neonatal hippocampus
Blockade of corticotropin-releasing hormone receptor 1 attenuates early-life stress-induced synaptic abnormalities in the neonatal hippocampus
复制标题
阻断促肾上腺皮质激素释放激素受体 1 可减轻生命早期应激引起的新生儿海马突触异常
DOI：
10.1002/hipo.22254
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发表时间：
2014-05-01
期刊：
影响因子：
3.5
通讯作者：
Wang, Xiao-Dong
中科院分区：
文献类型：
--
作者：
Liao, Xue-Mei;Yang, Xiao-Dun;Wang, Xiao-Dong
成年人早期应激经验表现出受损的海马神经元形态，突触可塑性和认知能力。虽然我们的知识的持续影响的早期生活应激对海马结构和功能和潜在的机制，近年来取得了进展，立即出生后应激对海马发育的影响的分子基础仍有待研究。在这里，我们报道了反复阻断促肾上腺皮质激素释放激素受体1（CRHR 1）改善出生后应激诱导的新生小鼠海马突触异常。在应激暴露后，母体护理片段化的幼鼠表现出CA 3锥体神经元树突生长和棘形成迟缓，海马突触相关蛋白水平降低。在应激暴露期间，通过每日给予RU 486（100 μ g/g）反复阻断糖皮质激素受体（GR）未能减轻出生后应激诱发的突触损伤。相反，每天给予应激幼崽CRHR 1拮抗剂盐酸安他拉明（20 μ g/g）使海马突触素、突触后密度-95、nectin-1和nectin-3的蛋白水平正常化，但N-甲基-d-天冬氨酸受体亚单位NR 1和NR 2A没有正常化。此外，GR或CRHR 1拮抗剂减弱产后应激诱导的内分泌改变，但不是身体生长迟缓。我们的数据表明，CRH-CRHR 1系统调节早期生活压力对树突发育，棘发生和突触形成的有害影响，该系统的早期干预可能会防止应激诱导的海马发育不良。(c)2014 Wiley Periodicals，Inc.
Adult individuals with early stressful experience exhibit impaired hippocampal neuronal morphology, synaptic plasticity and cognitive performance. While our knowledge on the persistent effects of early-life stress on hippocampal structure and function and the underlying mechanisms has advanced over the recent years, the molecular basis of the immediate postnatal stress effects on hippocampal development remains to be investigated. Here, we reported that repeated blockade of corticotropin-releasing hormone receptor 1 (CRHR1) ameliorated postnatal stress-induced hippocampal synaptic abnormalities in neonatal mice. Following the stress exposure, pups with fragmented maternal care showed retarded dendritic outgrowth and spine formation in CA3 pyramidal neurons and reduced hippocampal levels of synapse-related proteins. During the stress exposure, repeated blockade of glucocorticoid receptors (GRs) by daily administration of RU486 (100 mu g g(-1)) failed to attenuate postnatal stress-evoked synaptic impairments. Conversely, daily administration of the CRHR1 antagonist antalarmin hydrochloride (20 mu g g(-1)) in stressed pups normalized hippocampal protein levels of synaptophysin, postsynaptic density-95, nectin-1, and nectin-3, but not the N-methyl-d-aspartate receptor subunits NR1 and NR2A. Additionally, GR or CRHR1 antagonism attenuated postnatal stress-induced endocrine alterations but not body growth retardation. Our data indicate that the CRH-CRHR1 system modulates the deleterious effects of early-life stress on dendritic development, spinogenesis, and synapse formation, and that early interventions of this system may prevent stress-induced hippocampal maldevelopment. (c) 2014 Wiley Periodicals, Inc.