Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome
Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome
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DOI：
10.1007/s00213-010-2130-2
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发表时间：
2011-05
影响因子：
3.4
通讯作者：
T. Su;H. Fan;Tao Jiang;Wei-Wen Sun;Wei-Yi Den;Mei-Mei Gao-Mei;Sheng-qiang Chen;Qi-hua Zhao;Yong-Hong Yi
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文献类型：
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作者：
T. Su;H. Fan;Tao Jiang;Wei-Wen Sun;Wei-Yi Den;Mei-Mei Gao-Mei;Sheng-qiang Chen;Qi-hua Zhao;Yong-Hong Yi
树突棘形态异常是脆性X染色体智力低下的一个重要神经解剖缺陷。研究表明，过度活跃的第1组代谢型谷氨酸受体（mGlu）信号传导与脆性X综合征（FXS）中发生的脊柱畸形相关。因此，在本发明中，第1组mGlu成为治疗FXS的新靶点。本研究的目的是鉴定抑制mGlu信号在FXS中的作用。结果第1组mGlu的激活导致来自Fmr 1 KO小鼠和野生型小鼠的培养神经元中树突棘的延长。型（WT）小鼠。第1组mGlu的拮抗作用使Fmr 1 KO神经元的平均脊髓长度减少。此外，选择性组1 mGlu 5拮抗剂2-甲基-6-苯乙炔基吡啶（MPEP）的全身给药降低了发育年龄的Fmr 1 KO小鼠皮质神经元的平均棘长度和密度。对于成年小鼠，MPEP给药对脊柱长度的恢复效果较差。未成熟脊柱的百分比显示出类似的减少平行于脊柱长度的变化。临时MPEP干预与单剂量treatment.ConclusionThese结果表明，MPEP管理可以部分挽救在Fmr 1 KO小鼠在发育年龄的树突棘的形态缺陷没有表现出任何效果。
RationaleAbnormal dendritic spine morphology is a significant neuroanatomical defect in fragile X mental retardation. It has been suggested that overactive group 1 metabotropic glutamate receptor (mGlu) signaling is associated with the spine dysmorphology occurring in fragile X syndrome (FXS). Thus, group 1 mGlu became a new therapeutic target for the treatment of FXS.ObjectiveThe purpose of this study was to identify the effect of inhibition of mGlu signaling in FXS.MethodsWe observed the changes in dendritic spines after pharmacological modulation of mGlu signaling in anFmr1knockout (KO) mouse model.ResultsThe activation of group 1 mGlu resulted in elongation of dendritic spines in the cultured neurons derived fromFmr1KO mice and wild-type (WT) mice. Antagonism of group 1 mGlu reduced the average spine length ofFmr1KO neurons. Furthermore, systemic administration of the selective group 1 mGlu5 antagonist 2-methyl-6-phenylethynyl pyridine (MPEP) reduced the average spine length and density in the cortical neurons ofFmr1KO mice at developmental age. For the adult mice, MPEP administration was less effective for the restoration of spine length. The percentage of immature spines showed a similar reduction in parallel to the changes of spine length. Temporary MPEP intervention with single-dose treatment did not show any effect.ConclusionThese results show that MPEP administration could partially rescue the morphological deficits of dendritic spines inFmr1KO mice at developmental age.