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

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 CaMKII alpha(+) 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 CaMKII alpha(+) 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 )-> FNCaMKII alpha+ circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.

Automated summary

This study reveals a novel circuit in the cerebellum that regulates sensorimotor coordination. The role of BOD1 in this circuit is validated through experiments in mice. These findings provide potential neuromodulatory targets for the treatment of ataxia.