Molecular Imaging Branch, National Institute of Mental Health, 10 Center Drive, Bethesda, MD 20892-1026, USA.
Mol Autism. 2013 May 24;4(1):15. doi: 10.1186/2040-2392-4-15.
Fragile X syndrome (FXS) is a common inherited form of intellectual disability caused by loss of function of the fragile X mental retardation protein. Recent animal studies suggest that upregulated downstream signaling by metabotropic glutamate receptor 5 (mGluR5) might be an important mechanism for cognitive and behavioral abnormalities associated with FXS. However, mGluR5 density in human FXS remains unknown.
Receptor binding and protein expression were measured in the postmortem prefrontal cortex of 14 FXS patients or carriers and 17 age- and sex-matched control subjects without neurological disorders. In-vitro binding assays were performed using [3H]-labeled 3-methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity negative allosteric modulator of mGluR5, to measure receptor density and the radioligand's dissociation constant, which is inversely proportional to affinity. Immunoblotting was also performed, to measure mGluR5 protein expression.
The mGluR5 density increased with marginal significance (+16%; P = 0.058) in the prefrontal cortex of FXS patients or carriers compared with matched healthy controls. No significant change in dissociation constant (-4%; P = 0.293) was observed. Immunoblotting found a significant elevation (+32%; P = 0.048) in mGluR5 protein expression.
Both mGluR5 binding density and protein expression were increased in the brains of FXS patients or carriers, but only expression was significantly different, which could be because of the small sample size and moderate variability. Another important caveat is that the effects of psychotropic medications on mGluR5 expression are largely unknown. Future in-vivo measurement of mGluR5 with positron emission tomography might characterize the role of this receptor in the pathophysiology of FXS and facilitate trials of mGluR5-oriented treatments for this disorder.
脆性 X 综合征（FXS）是一种常见的遗传性智力障碍，由脆性 X 智力低下蛋白功能丧失引起。最近的动物研究表明，代谢型谷氨酸受体 5（mGluR5）的下游信号上调可能是与 FXS 相关的认知和行为异常的重要机制。然而，人类 FXS 中的 mGluR5 密度尚不清楚。
在 14 名 FXS 患者或携带者和 17 名年龄和性别匹配的无神经障碍对照者的尸检前额叶皮层中测量受体结合和蛋白表达。使用 [3H]-标记的 3-甲氧基-5-吡啶-2-基乙炔基吡啶（MPEPy）进行体外结合测定，MPEPy 是 mGluR5 的选择性和高亲和力负变构调节剂，用于测量受体密度和放射性配体的解离常数，后者与亲和力成反比。还进行了免疫印迹，以测量 mGluR5 蛋白表达。
与匹配的健康对照者相比，FXS 患者或携带者的前额叶皮层中 mGluR5 密度增加了 16%（P = 0.058），具有边缘显著性。未观察到解离常数的显著变化（-4%；P = 0.293）。免疫印迹发现 mGluR5 蛋白表达显著升高（+32%；P = 0.048）。
在 FXS 患者或携带者的大脑中，mGluR5 结合密度和蛋白表达均增加，但只有表达显著不同，这可能是由于样本量小且变异性适中。另一个重要的注意事项是，精神药物对 mGluR5 表达的影响在很大程度上尚不清楚。未来使用正电子发射断层扫描对 mGluR5 进行体内测量可能有助于表征该受体在 FXS 病理生理学中的作用，并促进针对该疾病的 mGluR5 靶向治疗试验。
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