BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination

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.