Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in fragile X syndrome
Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in fragile X syndrome
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DOI：
10.1016/j.neuron.2005.07.005
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发表时间：
2005-08-04
期刊：
影响因子：
16.2
通讯作者：
De Zeeuw, CI
中科院分区：
文献类型：
--
作者：
Koekkoek, SKE;Yamaguchi, K;De Zeeuw, CI
功能性 FMRP 的缺失会导致脆性 X 综合征。大脑皮层和海马突触过程的异常会导致脆性 X 型患者的认知缺陷。到目前为止，小脑缺陷的潜在作用尚未得到研究。在这里，我们证明 Fmr1 的全局和浦肯野细胞特异性敲除都显示出经典延迟眨眼条件反射的缺陷，因为条件反射的百分比及其峰值幅度和峰值速度降低了。这些小鼠的浦肯野细胞显示出细长的棘，并且在支配这些棘的平行纤维突触处的LTD诱导增强。此外，脆性X染色体患者在眨眼调节方面表现出与突变小鼠相同的小脑缺陷。这些数据表明，FMRP 的缺乏会导致细胞和行为水平上的小脑缺陷，并增加了小脑功能障碍可能导致脆性 X 型患者运动学习缺陷的可能性。
Absence of functional FMRP causes Fragile X syndrome. Abnormalities in synaptic processes in the cerebral cortex and hippocampus contribute to cognitive deficits in Fragile X patients. So far, the potential roles of cerebellar deficits have not been investigated. Here, we demonstrate that both global and Purkinje cell-specific knockouts of Fmr1 show deficits in classical delay eyeblink conditioning in that the percentage of conditioned responses as well as their peak amplitude and peak velocity are reduced. Purkinje cells of these mice show elongated spines and enhanced LTD induction at the parallel fiber synapses that innervate these spines. Moreover, Fragile X patients display the same cerebellar deficits in eyeblink conditioning as the mutant mice. These data indicate that a lack of FMRP leads to cerebellar deficits at both the cellular and behavioral levels and raise the possibility that cerebellar dysfunctions can contribute to motor learning deficits in Fragile X patients.