Role of corticotropin-releasing factor in cerebellar motor control and ataxia
Role of corticotropin-releasing factor in cerebellar motor control and ataxia
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促肾上腺皮质激素释放因子在小脑运动控制和共济失调中的作用
DOI：
10.1016/j.cub.2017.07.035
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发表时间：
2017
期刊：
影响因子：
9.2
通讯作者：
Zhu Jing-Ning
中科院分区：
文献类型：
--
作者：
Wang Yi;Chen Zhang-Peng;Zhuang Qian-Xing;Zhang Xiao-Yang;Li Hong-Zhao;Wang Jian-Jun;Zhu Jing-Ning
小脑性共济失调以运动不协调、姿势不稳定和步态异常为特征[1-3]，极大地影响日常活动和生活质量。虽然积累的遗传和非遗传病因已被揭示[4-7]，小脑性共济失调的有效治疗仍然缺乏。有趣的是，促肾上腺皮质激素释放因子（CRF），一种肽激素和神经递质[8，9]，被认为是橄榄-小脑系统中的假定神经递质[10-14]。值得注意的是，在脊髓小脑变性或橄榄脑桥小脑萎缩的患者中，下橄榄（IO）（小脑攀爬纤维的唯一来源）的CRF水平降低[15，16]，但对CRF在小脑运动协调和共济失调中的确切作用知之甚少。在这里，我们报告，缺乏CRF在橄榄小脑系统诱导共济失调样运动异常。IO中的CRF能神经元直接投射到小脑的最终整合和输出节点小脑核，并且CRF通过两种CRF受体CRFR 1和CRFR 2及其下游的内向整流性K+通道和/或超极化激活的环核苷酸门控（HCN）通道选择性地兴奋小脑间位核（IN）中的谷氨酸能投射神经元而不是GABA能神经元。此外，CRF促进小脑运动协调和拯救共济失调运动缺陷。这些发现定义了CRF在橄榄小脑系统中控制步态、姿势和运动协调的一个先前未知的作用，并为小脑性共济失调的病因、病理生理学和治疗策略提供了新的见解。
Cerebellar ataxia, characterized by motor incoordination, postural instability, and gait abnormality [1–3], greatly affects daily activities and quality of life. Although accumulating genetic and non-genetic etiological factors have been revealed [4–7], effective therapies for cerebellar ataxia are still lacking. Intriguingly, corticotropin-releasing factor (CRF), a peptide hormone and neurotransmitter [8, 9], is considered a putative neurotransmitter in the olivo-cerebellar system [10–14]. Notably, decreased levels of CRF in the inferior olive (IO), the sole origin of cerebellar climbing fibers, have been reported in patients with spinocerebellar degeneration or olivopontocerebellar atrophy [15, 16], yet little is known about the exact role of CRF in cerebellar motor coordination and ataxia. Here we report that deficiency of CRF in the olivo-cerebellar system induces ataxia-like motor abnormalities. CRFergic neurons in the IO project directly to the cerebellar nuclei, the ultimate integration and output node of the cerebellum, and CRF selectively excites glutamatergic projection neurons rather than GABAergic neurons in the cerebellar interpositus nucleus (IN) via two CRF receptors, CRFR1 and CRFR2, and their downstream inward rectifier K+channel and/or hyperpolarization-activated cyclic nucleotide-gated (HCN) channel. Furthermore, CRF promotes cerebellar motor coordination and rescues ataxic motor deficits. The findings define a previously unknown role for CRF in the olivo-cerebellar system in the control of gait, posture, and motor coordination, and provide new insight into the etiology, pathophysiology, and treatment strategy of cerebellar ataxia.