关于mGluR在脆性X综合征发病机制中的研究新进展

Advance in mGluR and Fragile X syndrome

脆性X综合征为最常见的遗传性智力低下性疾病之一,是由于FMR1基因异常导致其编码的脆性X智力低下蛋白减少或缺失所致。研究发现脆性X综合征尸解病人和FMR1基因敲除小鼠(KO鼠)神经元树突棘发育不成熟,模型小鼠海马区代谢性谷氨酸受体所触发的长时程抑制(LTD)延长,不成熟的树突棘导致突触功能障碍被认为是脑功能异常的基础。最近的研究表明,应用代谢性谷氨酸受体拮抗剂能改善由FMRP缺失所导致的突触和行为缺陷,表明mGluR功能过度激活可能参与了脆性X综合征的发病过程,但具体机制不明。FMRP是一种mRNA结合蛋白,可作为翻译抑制因子负性调节突触后膜mRNA的翻译和表达。因此推测FMRP缺乏和减少可能导致mGluR激发的mRNA翻译增多,参与神经系统发育的蛋白过度表达,而影响树突棘的发育,但具体机制仍不清楚。本文对mGluR和脆性X综合征的研究历史和最新进展进行了讨论。

Fragile X syndrome is the most common inherited form of human mental retardation.It is typically caused by a trinucleotide repeat expansion in the X-linked FMR1 gene that prevents expression of the encoded protein,called fragile X mental retardation protein（FMRP）.Brain development in the absence of FMRP gives rise to the major symptoms of fragile X syndrome in humans.A significant neuroanatomical defection associated with Fragile X is abnormal dendritic spine morphology that has been identified in affected humans and mice.Dendritic spines are the primary postsynaptic targets of excitatory glutamatergic synapses in the mature brain.This is consistent with the theory that dendritic spine dysgenesis is involved in mental retardation.Multiple lines of evidence suggest that FMRP protein can bind to several mRNAs and suppress their translation,which in turn modulates synaptic development and plasticity.Several recent electrophysiological studies of synaptic plasticity in the Fmr1 knockout mouse have suggested an imbalance between long-term depression（LTD） and long-term potentiation（LTP）.Fmr1 knockout mice have enhanced LTD in the hippocampus as a result of increased activity of the metabotropic glutamate receptor.The mGluR-dependent mRNA might be exaggerated in the absence of FMRP,and it may contribute to increased long dendritic spines in fragile X syndrome.So we discussed the history and advances of CRAC channels here.