Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen.
Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen.
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DOI：
10.1126/scitranslmed.3004218
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发表时间：
2012-09-19
影响因子：
17.1
通讯作者：
Healy AM
中科院分区：
文献类型：
--
作者：
Henderson C;Wijetunge L;Kinoshita MN;Shumway M;Hammond RS;Postma FR;Brynczka C;Rush R;Thomas A;Paylor R;Warren ST;Vanderklish PW;Kind PC;Carpenter RL;Bear MF;Healy AM
脆性X综合征（FXS）是智力残疾和自闭症的最常见遗传原因，其起因是FMR 1的转录沉默和mRNA翻译抑制蛋白脆性X智力低下蛋白（FMRP）的丢失。FXS患者表现出神经元树突棘形态的变化，这是一种与突触功能改变相关的病理学。在脆性X染色体小鼠模型中的研究表明，FMRP的缺失导致突触蛋白合成过量，这导致突触功能障碍和脊柱形态改变。我们测试了γ-氨基丁酸B型（GABAB）受体的药理学激活是否可以纠正或逆转Fmr 1敲除小鼠的这些表型。基础蛋白合成，这是在Fmr 1基因敲除小鼠海马升高，纠正了在体外应用的选择性GABAB受体激动剂STX 209（arbaclofen，R-巴氯芬）。STX 209还将Fmr 1敲除培养的神经元中升高的AMPA受体内化降低至野生型值，这是蛋白质合成增加的已知功能结果。在体内以改变行为的剂量急性给予STX 209，减少了Fmr 1敲除小鼠皮质中的mRNA翻译。最后，STX 209在幼年小鼠中的长期给药纠正了Fmr 1敲除小鼠中增加的脊柱密度，而不影响野生型小鼠的脊柱密度。因此，用STX 209激活GABAB受体校正了被认为是脆性X病理生理学的中心的突触异常，这一发现表明STX 209可能是治疗FXS核心症状的潜在有效疗法。
Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, results from the transcriptional silencing of FMR1 and loss of the mRNA translational repressor protein fragile X mental retardation protein (FMRP). Patients with FXS exhibit changes in neuronal dendritic spine morphology, a pathology associated with altered synaptic function. Studies in the mouse model of fragile X have shown that loss of FMRP causes excessive synaptic protein synthesis, which results in synaptic dysfunction and altered spine morphology. We tested whether the pharmacologic activation of the γ-aminobutyric acid type B (GABAB) receptor could correct or reverse these phenotypes in Fmr1-knockout mice. Basal protein synthesis, which is elevated in the hippocampus of Fmr1-knockout mice, was corrected by the in vitro application of the selective GABAB receptor agonist STX209 (arbaclofen, R-baclofen). STX209 also reduced to wild-type values the elevated AMPA receptor internalization in Fmr1-knockout cultured neurons, a known functional consequence of increased protein synthesis. Acute administration of STX209 in vivo, at doses that modify behavior, decreased mRNA translation in the cortex of Fmr1-knockout mice. Finally, the chronic administration of STX209 in juvenile mice corrected the increased spine density in Fmr1-knockout mice without affecting spine density in wild-type mice. Thus, activation of the GABAB receptor with STX209 corrected synaptic abnormalities considered central to fragile X pathophysiology, a finding that suggests that STX209 may be a potentially effective therapy to treat the core symptoms of FXS.
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影响因子：
2.5
作者：
Auerbach, Benjamin D.;Bear, Mark F.
通讯作者：
Bear, Mark F.
影响因子：
11.4
作者：
Fridell, RA;Benson, RE;Cullen, BR
通讯作者：
Cullen, BR
影响因子：
2.5
作者：
El Idrissi, A;Ding, XH;Dobkin, C
通讯作者：
Dobkin, C
DOI：
10.1523/jneurosci.0402-10.2010
发表时间：
2010-08-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Gross C;Nakamoto M;Yao X;Chan CB;Yim SY;Ye K;Warren ST;Bassell GJ
通讯作者：
Bassell GJ
影响因子：
17.1
作者：
Berry-Kravis, Elizabeth M.;Hessl, David;Hagerman, Randi J.
通讯作者：
Hagerman, Randi J.