BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination
SIGNAL TRANSDUCTION AND TARGETED THERAPY(2022)
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.
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Key words
Diseases of the nervous system,Neurodevelopmental disorders,Medicine/Public Health,general,Internal Medicine,Cancer Research,Cell Biology,Pathology,Oncology
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