BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination.
BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination.
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DOI：
10.1038/s41392-022-00989-x
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发表时间：
2022-06-01
影响因子：
39.3
通讯作者：
Lu, Ying-Mei
中科院分区：
文献类型：
--
作者：
Liu, Xiu-Xiu;Chen, Xing-Hui;Zheng, Zhi-Wei;Jiang, Qin;Li, Chen;Yang, Lin;Chen, Xiang;Mao, Xing-Feng;Yuan, Hao-Yang;Feng, Li-Li;Jiang, Quan;Shi, Wei-Xing;Sasaki, Takuya;Fukunaga, Kohji;Chen, Zhong;Han, Feng;Lu, Ying-Mei
小脑共济失调的特征是运动协调性的进行性下降，但具体的输出回路和潜在的病理机制仍然知之甚少。通过细胞类型特异性操作，我们在小脑IV/V叶中发现了一种新的GABA能浦肯野细胞（PC）回路，该回路投射到顶核（FN）中的CaMKIIα+神经元，调节感觉运动协调。此外，转录组学分析揭示了各种小脑神经元的身份，我们验证了双向缺陷1（BOD 1）在IV/V叶到FN的回路中发挥了重要作用。IV/V叶PCs内BOD 1的缺失使PCs的兴奋性和棘密度降低，并伴有共济失调行为。相反，IV/V叶PC中的BOD 1富集逆转了FN中CaMKIIα+神经元的过度兴奋性，并改善了L7-Cre; BOD 1f/f小鼠的共济失调行为。总之，这些发现进一步表明，小脑IV/V叶PC → FNCaMKIIα+回路的特异性调节可能为共济失调行为的治疗提供神经调节靶点。
Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly understood. Through cell-type-specific manipulations, we discovered a novel GABAergic Purkinje cell (PC) circuit in the cerebellar IV/V lobe that projected to CaMKIIα+ neurons in the fastigial nucleus (FN), which regulated sensorimotor coordination. Furthermore, transcriptomics profiling analysis revealed various cerebellar neuronal identities, and we validated that biorientation defective 1 (BOD1) played an important role in the circuit of IV/V lobe to FN. BOD1 deficit in PCs of IV/V lobe attenuated the excitability and spine density of PCs, accompany with ataxia behaviors. Instead, BOD1 enrichment in PCs of IV/V lobe reversed the hyperexcitability of CaMKIIα+ neurons in the FN and ameliorated ataxia behaviors in L7-Cre; BOD1f/f mice. Together, these findings further suggest that specific regulation of the cerebellar IV/V lobePCs → FNCaMKIIα+ circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.
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DOI：
10.1073/pnas.0801689105
发表时间：
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影响因子：
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影响因子：
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作者：
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作者：
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