State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China.
State Key Laboratory of Pharmaceutical Biotechnology and Department of Biological Science and Technology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China.
Curr Biol. 2017 Sep 11;27(17):2661-2669.e5. doi: 10.1016/j.cub.2017.07.035. Epub 2017 Aug 24.
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.
小脑共济失调，表现为运动不协调、姿势不稳和步态异常[1-3]，严重影响日常生活和生活质量。尽管已经揭示了累积的遗传和非遗传病因[4-7]，但仍缺乏有效的小脑共济失调治疗方法。有趣的是，促肾上腺皮质释放因子（CRF）是一种肽类激素和神经递质[8,9]，被认为是橄榄小脑系统中的一种假定神经递质[10-14]。值得注意的是，在脊髓小脑变性或橄榄脑桥小脑萎缩患者中，下橄榄核（IO）中 CRF 的水平降低，IO 是小脑攀附纤维的唯一起源[15,16]，但 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，我们报告说，橄榄小脑系统中 CRF 的缺乏会引起类似共济失调的运动异常。IO 中的 CRF 能神经元直接投射到小脑核，小脑核是小脑的最终整合和输出节点，CRF 通过两种 CRF 受体（CRFR1 和 CRFR2）及其下游内向整流钾通道和/或超极化激活环核苷酸门控（HCN）通道，选择性兴奋谷氨酸能投射神经元，而不是 GABA 能神经元小脑间位核（IN）。此外，CRF 促进小脑运动协调并挽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、姿势和运动协调的先前未知作用，并为小脑共济失调的病因、病理生理学和治疗策略提供了新的见解。
