BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination
Xiuxiu Liu, Xing-Hui Chen, Zhi-Wei Zheng, Qin Jiang, Chen Li, Lin Yang, Xiang Chen, Xingfeng Mao, Haoyang Yuan, Lili Feng, Quan Jiang, Wei‐Xing Shi, Takuya Sasaki, Kohji Fukunaga, Zhong Chen, Feng Han, Ying‐Mei Lu
Abstract
Abstract 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 ; BOD1 f/f mice. Together, these findings further suggest that specific regulation of the cerebellar IV/V lobe PCs → FN CaMKIIα+ circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.