7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome
7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome
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DOI：
10.1016/j.neuropharm.2014.09.006
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发表时间：
2015-02-01
影响因子：
4.7
通讯作者：
McClintock, Shawn M.
中科院分区：
文献类型：
--
作者：
Tian, Mi;Zeng, Yan;McClintock, Shawn M.
脆性X综合征（FXS）的特征是树突棘结构不成熟和认知障碍。7，8-二羟基黄酮（7，8-DHF）是一种高亲和力的原肌球蛋白受体激酶B（Trk B）激动剂。本论文的目的是研究7，8-DHF作为一种有效的药物治疗剂，靶向树突病理和认知障碍的FXS突变体的效用。我们综合了药理学、行为学和生物化学方法来研究7，8-DHF对脆性X智力低下1（Fmr 1）基因敲除小鼠的空间和恐惧记忆功能以及形态学脊柱异常的影响。该研究发现，用7，8-DHF治疗4周改善了空间和恐惧记忆，并改善了形态学上的脊柱异常，包括海马体和杏仁核中脊柱的数量和伸长。进一步的机制分析表明，7，8-DHF增强了α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）GluA 1受体的表达，但降低了正常的Fmr 1突触GluA 2水平。可能与药物诱导的AMPA受体亚单位的变化有关，突触处的7，8-DHF导致GluA 1的Ser 818和Ser 813亚单位以及GluA 2的Ser 880亚单位上的特定丝氨酸位点的磷酸化，以及TrkB、钙/钙调蛋白依赖性蛋白激酶II和蛋白激酶C的磷酸化。而7，8-DHF对WT小鼠的行为表现无影响，也不增加TrkB磷酸化，提示其具有FXS特异性的纠正作用。总之，这些结果表明，7，8-DHF改善学习和记忆，并减少脊柱形态学异常，从而为FXS提供了一个潜在的药理学策略。(C)2014爱思唯尔有限公司版权所有。
Fragile X syndrome (FXS) is characterized by immature dendritic spine architectures and cognitive impairment. 7, 8-Dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist. The purpose of this paper was to examine the utility of 7, 8-DHF as an effective pharmacotherapeutic agent that targets dendritic pathology and cognitive impairments in FXS mutant. We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7, 8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile X mental retardation 1 (Fmr1) gene knock-out mice. The study found that 4 weeks of treatment with 7, 8-DHF improved spatial and fear memory, and ameliorated morphological spine abnormalities including the number and elongation of spines in the hippocampus and amygdala. Further mechanism analysis revealed that 7, 8-DHF enhanced the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor, but reduced the normal levels of GluA2 at the synapses in Fmr1., Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses led to phosphorylation of specific serine sites on subunits Ser818 and Ser813 of GluA1, and Ser880 of GluA2, as well as phosphorylation of TrkB, calcium/calmodulin-dependent protein kinase II, and protein kinase C. However, 7, 8-DHF neither affected behavioral performance nor increased TrkB phosphorylation in WT mice, which suggested that it had FXS-specific correcting effect. Altogether, these results demonstrated that 7, 8-DHF improved learning and memory, and reduced abnormalities in spine morphology, thus providing a potential pharmacotherapeutic strategy for FXS. (C) 2014 Elsevier Ltd. All rights reserved.