FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype.
FMRP Expression Levels in Mouse Central Nervous System Neurons Determine Behavioral Phenotype.
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DOI：
10.1089/hum.2016.090
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发表时间：
2016-12
影响因子：
4.2
通讯作者：
Hampson DR
中科院分区：
文献类型：
--
作者：
Arsenault J;Gholizadeh S;Niibori Y;Pacey LK;Halder SK;Koxhioni E;Konno A;Hirai H;Hampson DR
脆性X智力迟钝蛋白（FMRP）在脆性X综合征中缺失或高度减少，脆性X综合征是一种导致认知障碍和自闭症行为的遗传疾病。先前的原理验证研究表明，使用病毒载体恢复大脑中的FMRP可以改善脆性x小鼠模型的病理异常。然而，与小分子药物不同，小分子药物的剂量可以在治疗过程中随时调整，基于病毒载体的生物治疗药物在达到最佳剂量和表达水平方面存在挑战。本研究的目的是研究在Fmr1敲除小鼠和野生型（WT）小鼠的神经元中选择性表达不同水平的FMRP的后果。在脑室内给予编码FMRP的腺相关病毒载体后，在单个小鼠中实现了大范围的神经元FMRP转基因水平。在所有处理过的敲除小鼠中，FMRP转基因在前脑结构中显著表达，而在大脑的更多尾侧区域中表达水平较低。Fmr1基因敲除小鼠的突触蛋白PSD-95水平降低，转录调节因子MeCP2水平升高，运动活动、焦虑和声惊反应异常，在Fmr1基因敲除小鼠中，FMRP的表达量约为WT表达量的35-115%（取决于所检测的大脑区域）后，全部或部分恢复。在WT小鼠中，高达2倍左右的中度FMRP过表达对PSD-95和MeCP2水平或行为内表型的影响很小或没有影响。相比之下，Fmr1敲除小鼠前脑中的过度过度表达（约为WT的2.5 - 6倍）诱导病理性运动过度活跃，并抑制了相对于WT小鼠的惊吓反应。这些结果描绘了中枢神经系统中FMRP表达水平的范围，赋予脆性X小鼠表型改善。总的来说，这些发现与治疗脆性X综合征和其他神经发育障碍的长期治疗性基因治疗策略的发展有关。
Fragile X mental retardation protein (FMRP) is absent or highly reduced in Fragile X Syndrome, a genetic disorder causing cognitive impairment and autistic behaviors. Previous proof-of-principle studies have demonstrated that restoring FMRP in the brain using viral vectors can improve pathological abnormalities in mouse models of fragile X. However, unlike small molecule drugs where the dose can readily be adjusted during treatment, viral vector–based biological therapeutic drugs present challenges in terms of achieving optimal dosing and expression levels. The objective of this study was to investigate the consequences of expressing varying levels of FMRP selectively in neurons of Fmr1 knockout and wild-type (WT) mice. A wide range of neuronal FMRP transgene levels was achieved in individual mice after intra-cerebroventricular administration of adeno-associated viral vectors coding for FMRP. In all treated knockout mice, prominent FMRP transgene expression was observed in forebrain structures, whereas lower levels were present in more caudal regions of the brain. Reduced levels of the synaptic protein PSD-95, elevated levels of the transcriptional modulator MeCP2, and abnormal motor activity, anxiety, and acoustic startle responses in Fmr1 knockout mice were fully or partially rescued after expression of FMRP at about 35–115% of WT expression, depending on the brain region examined. In the WT mouse, moderate FMRP over-expression of up to about twofold had little or no effect on PSD-95 and MeCP2 levels or on behavioral endophenotypes. In contrast, excessive over-expression in the Fmr1 knockout mouse forebrain (approximately 2.5–6-fold over WT) induced pathological motor hyperactivity and suppressed the startle response relative to WT mice. These results delineate a range of FMRP expression levels in the central nervous system that confer phenotypic improvement in fragile X mice. Collectively, these findings are pertinent to the development of long-term curative gene therapy strategies for treating Fragile X Syndrome and other neurodevelopmental disorders.
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影响因子：
2.9
作者：
Gholizadeh, Shervin;Halder, Sebok Kuvnar;Hampson, David R.
通讯作者：
Hampson, David R.
影响因子：
--
作者：
Gholizadeh, Shervin;Tharmalingam, Sujeenthar;Hampson, David R.
通讯作者：
Hampson, David R.
影响因子：
7.6
作者：
Gholizadeh, Shervin;Arsenault, Jason;Hampson, David R.
通讯作者：
Hampson, David R.
DOI：
10.1523/jneurosci.6000-11.2012
发表时间：
2012-02-29
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Na ES;Nelson ED;Adachi M;Autry AE;Mahgoub MA;Kavalali ET;Monteggia LM
通讯作者：
Monteggia LM
影响因子：
4.5
作者：
Bagga, Joetsaroop S.;D'Antonio, Lawrence A.
通讯作者：
D'Antonio, Lawrence A.